Choosing treatment options for patients with relapsed/refractory multiple myeloma

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Author(s) : Castelli, Orofino, Losurdo, Gualtierotti & Cugno

Article title : Choosing treatment options for patients with relapsed/refractory multiplemyeloma

Article no : 863153

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2 Nicola Orofino

3 Agnese Losurdo

4 Roberta Gualtierotti

5 Massimo Cugno

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Choosing treatment optionsfor patients with relapsed/

5refractory multiple myelomaExpert Rev. Anticancer Ther. 14(2), 000–000 (2014)

Roberto Castelli*1,Nicola Orofino1,Agnese Losurdo1,Roberta Gualtierotti1

and Massimo Cugno1,2

1Department of Pathophysiology and

Transplantation, Internal Medicine,

University of Milan, Milan, Italy2Department of Medicine, IRCCS

Fondazione Ca’ Granda Policlinico,

Milan, Italy

*Author for correspondence:

Tel.: +39 025 503 6381

Fax: +39 025 503 4722

[email protected]

Multiple myeloma (MM) is a clonal plasma cell disorder that is still incurable using conventional10treatments. Over the last decade, advances in front-line therapy have led to an increase in

survival, but there are still some doubts in the case of relapsed/refractory disease. We searchedthe PubMed database for articles on treatment options for patients with relapsed/refractoryMM published between 1996 and 2013. These treatments included hematopoietic celltransplantation (HCT), rechallenges using previous chemotherapy regimens, and trials of new

15regimens. The introduction of new agents such as the immunomodulatory drugs (IMIDs)thalidomide and lenalidomide, and the first-in-its-class proteasome inhibitor bortezomib, hasgreatly improved clinical outcomes in patients with relapsed/refractory MM, but not all patientsrespond and those that do may eventually relapse or become refractory to treatment. Thechallenge is therefore to select the optimal treatment for each patient by balancing efficacy

20and toxicity. To do this, it is necessary to consider disease-related factors, such as the qualityand duration of responses to previous therapies, and the aggressiveness of the relapse, andpatient-related factors such as age, comorbidities, performance status, pre-existing toxicitiesand cytogenetic patterns. The message from the trials reviewed in this article is that the newagents may be used to re-treat relapsed/refractory disease, and that the sequencing of their

25administration should be modulated on the basis of the various disease and patient-relatedfactors. Moreover, our understanding of the pharmacology and molecular action of the newdrugs will contribute to the possibility of developing tailored treatment.

KEYWORDS: immunomodulatory drugs • proteasome inhibitors • relapsed/refractory multiple myeloma

• salvage therapies

Multiple myeloma (MM) is a hematological35malignancy characterised by the proliferation

of clonal plasma cells in bone marrow (BM),monoclonal protein in serum or urine,destructive bone lesions, anemia, hypercalce-mia and renal insufficiency [1]. It accounts for

401.5–2% of all cancer deaths and remainsincurable [1]. Median survival after diagnosis isapproximately 3 years, treatment responses arecharacteristically short, and patients frequentlyrelapse or become refractory to treatment [1].

45The introduction of new front-line agents suchas the immunomodulatory drugs (IMIDs) tha-lidomide and lenalidomide, and the protea-some inhibitor bortezomib, has significantlyimproved overall survival (OS) by achieving

50deeper levels of responses and prolonging theduration of remission. However, not allpatients respond to these new drugs, and thedevelopment of drug resistance is common.

Relapsed and refractory MM AQ5describes thedisease in a subject who has previouslyachieved at least a minor response, but thenexperiences progressive disease, receives salvagetherapy, and is either unresponsive to salvagetherapy or progresses within 60 days of thelast treatment [2].

Recent studies have begun to clarify the bio-logical basis of the mechanism of relapsed orrefractory MM. There is evidence concerningthe existence of minor sub-clones that can sur-vive chemotherapy and thus become a reser-voir for relapse or resistance [3]. The twodriving forces conditioning relapse or resistanceare the genetic instability of aggressive MMsub-clones and the selective pressures intro-duced by therapy during the course of thedisease [4].

Previous treatments for relapsed/refractoryMM consisted of standard combinations of

www.expert-reviews.com 10.1586/14737140.2014.863153 � 2014 Informa UK Ltd ISSN 1473-7140 1

Review

mailto:[email protected]

alkylating agents, anthracyclines and corticosteroids, with or55 without hematopoietic stem cell rescue [5,6], but the new IMIDs

and proteasome inhibitors have improved clinical outcomes [7–9].In the relapse setting, the impact of complete responses (CRs)on survival is still controversial, and it is unclear whether theduration of response/progression-free survival or the depth of

60 the response is more important. Nevertheless, a number ofrecent studies [10,11] have shown a clear relationship between thedepth of response and survival, thus further demonstrating thata better quality of response may be associated with an improvedoutcome even beyond front-line therapy. Studies that have ana-

65 lyzed outcomes on the basis of the quality of a so-called ‘goodremission’ (i.e., CR, near-CR and very good partial remission[VGPR]) have shown that survival is virtually identical inpatients achieving a near-CR, VGPR or partial remission (PR),but significantly worse than that of patients in CR. In this

70 respect, negative minimal residual disease (supported by multi-parameter flow cytometry or molecular studies) seems to be aprerequisite for long-term remission and prolonged survival.

The aim of this article is to review the pharmacology andmolecular action of the drugs used to treat relapsed/refractory

75 MM, and consider approaches for managing such patientsusing strategies aimed at tailoring different treatments.

Materials & methods

We searched the PubMed database for papers publishedbetween January 1996 and March 2013 using the key words

80 ‘immunomodulatory drugs’, ‘proteasome inhibitors’ and‘relapsed/refractory multiple myeloma’. The search was limitedto randomized controlled trials, but had no language restrictionand, in order to ensure its completeness, was complemented bysearches of the Web of Science, EMBASE and Cochrane

85 Library databases. In the case of duplicate publications, wereviewed each article and included only the most recent or themost complete version in the analysis.

Current treatment options

The challenge when treating patients with relapsed or refractory90MM is to select the optimal treatment by balancing efficacy

and toxicity, which involves considering both disease andpatient-related factors. In the case of patients whose perform-ance status allows them to tolerate aggressive treatment, the ulti-mate goal at the time of induction and the time of relapse

95should be to obtain the deepest possible response in order toimprove survival; in the case of patients who cannot tolerateaggressive treatment, palliative therapy should be used with theaim of stabilizing the disease and preventing further progression.

Chemotherapy & transplantation

100The use of conventional or high-dose chemotherapy is a long-standing approach to salvage therapy in patients with relapsedMM. In the past, various standard chemotherapy-based regi-mens were used, the most widely administered of which areshown in TABLE 1. The overall rates of response to salvage combi-

105nation chemotherapy are between 30 and 60%, with morbidityand mortality related to the intensity of the therapy itself [12].

Even in the era of the new targeted agents, single or doubleautologous stem cell transplantation (ASCT) remains the stand-ard front-line approach for MM patients eligible for high-dose

110therapy, although the new drugs used during the induction,consolidation, and maintenance phases of ASCT have helpedin reaching 5-year OS and event-free survival (EFS) rates of70% [13,14]. Recent studies have shown that a second ASCT isa feasible and safe option for salvage therapy in MM patients

115who have undergone a front-line single ASCT [15,16].Michaelis et al. reported the outcomes of 187 patients whounderwent a second ASCT (ASCT2) for the treatment ofrelapsed/progressive MM at a median age of 59 years (range:28–72), and were followed up for a median of 47 months

120(range: 3–97). Non-relapse mortality was 2% 1 year afterASCT2 and 4% after 3 years. The median interval from

Table 1. Conventional chemotherapeutic regimens for relapsing/refractory multiple myeloma.

Chemotherapy ORR (%) Mediansurvival(months)

Median durationof response(months)

Ref.

M2 PROTOCOL (vincristine, cyclophosphamide, carmustine, melphalan and

steroids)

47 NA 7 [71]

VAMP (continuous infusions of vincristine, adriamycin, high-dose

methylprednisolone)

36 20 11 [72]

VAD (continuous infusions of vincristine, adriamycin, pulsed high-dose

dexamethasone)

60 12 9 [73]

Intermediate-dose (25 mg/m2) melphalan 35 8 16 [74]

VAD-PECC (alternating vincristine, doxorubicin and dexamethasone/

prednisone, vindesine, carmustine and cyclophosphamide)

54 18 NA [75]

VECD (vincristine, epirubicin, cyclophosphamide and oral dexamethasone) 44 13 NA [76]

CIDEX (lomustine, idarubicin and dexamethasone) 49 NA NA [77]

ORR: Overall response rate; NA: Not available.

Review Castelli, Orofino, Losurdo, Gualtierotti & Cugno

2 Expert Rev. Anticancer Ther. 14(2), (2014)

ASCT1 to relapse/progression was 18 months, and the medianinterval between transplantations was 32 months. AfterASCT2, the one and three-year incidence of relapse/progression

125 was 51% and 82%, respectively. Three years after ASCT2,progression-free survival was 13%, and OS was 46%. Multi-variate analyses showed that the patients relapsing 36 monthsafter ASCT1 had better progression-free (p = 0.045) and OS(p = 0.019) [17]. These data support the use of a late second

130 ASCT in patients with relapsed/progressive MM but, with theaim of verifying the timing of the second ASCT, researchers ofthe European Group for Blood and Marrow Transplantationreviewed the cases of 7452 patients, of whom 2655 underwenta planned ASCT2 and 4797 an unplanned ASCT2 between

135 1993 and 2002. They found that outcomes were better whenthe ASCT2 was performed before relapse (within 6–12 monthsof ASCT1) [18].

Myeloablative or non-myeloablative allogeneic stem celltransplantation (allo-SCT) is considered potentially curative for

140 myeloma, but offers only a limited clinical benefit in the caseof relapsed/refractory MM [12].

Immunomodulatory drugs

Thalidomide

Thalidomide (a-N-phthalimido-glutarimide) is a synthetic145 derivative of glutamic acid that was initially introduced in

1956 as a sedative hypnotic. An important part of its in vivoefficacy is attributablility to its immunomodulatory propertiesas it potentiates the immune response by restoring dendriticcell function and inhibiting T cell regulatory activity. This

150 leads to the activation of T lymphocytes and natural killerT (NKT) cells by increasing the production of IL-2 and IFN-gand activating natural killer (NK) cells. IMIDs are characterizedby their anti-tumoral activity, which disrupts the interactionsbetween neoplastic clones and the bone marrow microenviron-

155 ment. Another important mechanism is their anti-angiogenicactivity [19,20].

Thalidomide induces the apoptosis of neoplastic cells bydown-regulating anti-apoptotic proteins via the caspase 8-medi-ated pathway [19]. It has been reported that thalidomide alone

160 induces partial remission in 50% of newly diagnosed patients,and that its combination with oral dexamethasone increasesthis to 60–70% [19,20]. Thalidomide was the first novel agentevaluated in patients with relapsed/refractory MM, and a num-ber of studies have demonstrated that, alone, it leads to

165 response rates of 25–35% [5,21]. Similarly, Mothy et al. foundthat thalidomide salvage therapy is also feasible and beneficialin a significant proportion of patients with progressive MMafter allo-SCT [22]. Taken together, these studies show that tha-lidomide monotherapy can induce at least a PR in 30% of

170 patients with relapsed/refractory disease, with a 1-year OS rateof 60% and a median OS of 14 months.

The addition of dexamethasone leads to higher response ratesthan those obtained using thalidomide alone, and the additionof cyclophosphamide to thalidomide and dexamethasone leads

175 to even higher response rates [23]. Thalidomide has also been

combined with conventional cytotoxic drugs (alkylating agentsand anthracyclines), and other novel agents such as bortezomib.Trials have shown that a combination of thalidomide and con-ventional chemotherapy is clearly active, leading to overall

180response rates (ORR) of 60–75%, with CR rates of approxi-mately 20% in a number of early Phase I/II studies [24,25]. TABLE 2

summarizes the main clinical trials of thalidomide in MMpatients refractory or relapsing after different front-linetherapies.

185Lenalidomide

Lenalidomide (Revlimid�; Celgene, NJ, USA) is an oral immu-nomodulatory derivative of thalidomide that has a differenttoxicity profile, different pleiotropic (immunomodulatory, anti-angiogenic and anti-neoplastic) activity, and different anti-

190inflammatory effects. These properties have led to the drugbeing investigated in other hematological malignancies, such asaggressive non-Hodgkin lymphomas and myelodysplasticsyndromes [26–31]. Lenalidomide is the most recent agentapproved for relapsed/refractory myeloma in the USA and

195Europe. The approval was based on the results of two paralleltrials (MM-009 and MM-010) in which lenalidomide plusdexamethasone was compared with dexamethasone alone inpatients with progressive myeloma who had received 1–3 pre-vious regimens. The dose of lenalidomide was 25 mg on days

2001–21 of a 28-day schedule, whereas pulsed dexamethasone wasgiven on days 1–4, 9–12 and 17–20 for the first four cycles,with the dose being reduced for subsequent cycles [10,32]. Theresults of these two trials demonstrated that continuing treat-ment with lenalidomide plus dexamethasone led to the best

205responses, the absence of disease progression and toxicity andprovided deeper remissions and greater clinical advantages. Allof the patients in the thalidomide-exposed subgroup (includingthose who had relapsed on or had been refractory to thalido-mide) also significantly benefited from the combination of

210lenalidomide and dexamethasone. Further trials confirmed theefficacy of lenalidomide in relapsed/refractory MM (TABLE 3).

Pomalidomide

The third IMID is pomalidomide (CC4047), a new drug witha high degree of in vitro activity that was developed to improve

215the clinical efficacy and reduce the toxicity of its parent mole-cule thalidomide. Pomalidomide has a good toxicity profile,with neutropenia being its most frequent adverse effect.Thromboembolic complications are as frequent as with theother IMIDs, whereas other side effects such as neuropathy are

220rare [28]. In vitro studies have demonstrated that pomalidomideis more effective than thalidomide in inhibiting the prolifera-tion of malignant B cells, and preclinical studies have shownthat pomalidomide significantly increases the serum levels ofIL-2 receptors and IL-12, and may promote the switch to an

225effector T-cell phenotype. In addition, some evidence suggeststhat pomalidomide may inhibit the destructive effects of MMin the bone microenvironment by inhibiting osteoclastdifferentiation. [7]

Choosing treatment options for patients with relapsed/refractory multiple myeloma Review

www.expert-reviews.com 3

Table

2.Thalidomide-basedclinicaltrials.

Study(year)

Patients

(n)

Regim

en

Dose/day

Resp

onse

(%)

Meandurationof

resp

onse/survival

rates

Sideeffects

Ref.

SinghalSetal.

(1999)

84

TT:200–800mg/day

R:32CR:2

EFS:22±5%

OS:58±5%

G1/2

constipation59%

Fatigue:48%

Somnolence:

43%

(inpatients

treated

with800mg).

[21]

KnellerAetal.

(2000)

17

TT:200–800mg/day

R:64VGPR:29

PR:29MR:6

NR

G1/2:Somnolence:64%

Fatigue:29%

Constipation:29%

[20]

LeeCKetal.

(2003)

229

DTPACE

D:40mgp.o.daily

x

4days;T:400mgp.o.

atnight,days

1–28;

Cis:10mg/m

2/dayx

4days,CIV;

Dox:

10mg/m

2/dayx

4days,CIV;

C:400mg/m

2/dayx

4days,CIV;E:40mg/

m2/dayx4days,CIV;

CR:7nCR:9

PR:16

NR

G2neutropenia:65%

ofcycles

Neu

tropenicfever:12%

ofcycles

G2thrombocytopenia:11%

of

cyclesNauseaandvomiting:21%

ofcyclesMucositis:19%

of

cyclesH

ypophosphatemia:17%

of

cycles

[78]

Anagno-

stopoulosA

etal.(2003)

47

TD

T:200–600mgp.o.at

night,days1–28;

D:20mg/m

2p.o.,

days

1–5andrepeated

every

15days

R:47CR:13

Median

OS:38months

G1/2

constipation:51%

Paresthesias:47%

Skindryness

or

rash:27%

Fatigueor

somnolence:21%

Thrombotic

complications:8%

[79]

Garcia-SanzR

etal.(2004)

71

CTD

T:200–800mgp.o.at

night,days1–28;

C:50mg/dayp.o.,

days

1–28;D:40mg/

dayp.o.,days

1–

4every

3weeks

CR:2PR:55

PFS:57%

OS:66%

G‡2constipation:24%

Somnolence:18%

Fatigue:17%

[24]

KyriakouC

etal.(2005)

52

CTD

C:300mg/m

2p.o.

once

weekly;

D:40mg/dayp.o.,

days

1–4once

monthly;T:50–

300mg/dayp.o.at

individually

escalated

dosesbasedonmg/

dayp.o.ondays1–28

CR:17PR:61.5

MR:11.5

PFS:34%

OS:73%

Neu

tropenia:38.5%

Infections:27%

G2neuropathy:

23%

Constipation:58%

[80]

C:Cyclophosphamide;CR:Complete

response;CIV:Continuousintravenousinfusion;D:Dexamethasone;EFS:

Event-freesurvival;M:Melphalan;MR:Minim

alresponse;nCR:Near-complete

response;OS:Overallsur-

vival;P:

Prednisone;

PFS:Progression-freesurvival;PR

:Partialresponse.



As pomalidomide is the latest IMID undergoing develop-230ment, it has so far only been investigated in Phase I and

Phase II trials involving heavily pre-treated patients. The resultsof the Phase I trials show that the maximum tolerated dose(MTD) is 1–5 mg/day, and that both daily and alternate daydosing regimens lead to encouraging ORR of 50% [33–35].

235Two Phase II trials have been carried out. The first enrolled60 patients who had received 1–3 previous treatments, andadministered pomalidomide (2 mg/day continuously) and dexa-methasone. The ORR of 60% included 33% VGPRs and CRs.The median PFS was 11.6 months without any significant dif-

240ferences between the patients with high-risk disease and thosewith standard-risk disease [36]. Interestingly, pomalidomideproved to be active in a subgroup of patients who were refrac-tory to lenalidomide, in whom the ORR was almost 50%. Inthe second Phase II trial, 70 patients were randomized to

245receive pomalidomide 2 or 4 mg/day in combination with dex-amethasone. The results showed a small advantage in the 2 mgarm, thus suggesting that responses are not dose related [37].

Proteasome inhibitors

Bortezomib

250Bortezomib (PS-341) was the prototype proteasome inhibitor.It has potent anti-myeloma activity as a single agent (TABLE 4)

and in combination with other drugs (TABLE 5). The ubiquitinproteasome system is a multi-catalytic proteinase complex thatdegrades a wide variety of protein substrates in normal and

255transformed cells in order to maintain cell homeostasis. Conse-quently proteasome inhibition affects a wide range of cell func-tions such as cell cycle regulation and apoptosis. Cancer (andespecially MM) cells seem to be highly dependent onproteasome-homeostatic pathways. In addition to anti-MM

260activity, bortezomib stabilises the nuclear factor kappa lightchain-enhancer of activated B cells (NF kappa B) and up-regulates anti-apoptotic factors in tubular cells.

The large randomized APEX (Assessment of ProteasomeInhibition for Extending Remissions) trial demonstrated the

265superiority of bortezomib given intravenously on days 1, 4,8 and 11 of a 21-day cycle over pulse dexamethasone inpatients with relapsed/refractory myeloma, who had receivedno more than three previous treatment regimens. The ORRwas 38%, and the median time to progression (TTP) was

2706.2 months, as against only 18% and 3.5 months with dexame-thasone at the time of the first analysis [38]. Bortezomib combi-nations have been evaluated in a number of different settingsand are being widely tested due to their minimal marrow toxic-ity, ease of use in the case of renal failure, and absence of

275thrombogenicity. Various studies have demonstrated the activityof bortezomib in patients with MM and renal insuffi-ciency [39,40]. Bortezomib does not undergo renal clearance, andtherefore allows prompt therapy without the need for doseadjustments. Retrospective analyses of Phase III trials have

280shown that bortezomib can overcome the poor prognosis ofpatients with unfavorable chromosomal abnormalities, such asthe del(13q14) and t(4:14) mutations. There are also initialT

able

2.Thalidomide-basedclinicaltrials

(cont.).

Study(year)

Patients

(n)

Regim

en

Dose/day

Resp

onse

(%)

Meandurationof

resp

onse/survival

rates

Sideeffects

Ref.

HovengaS

etal.(2005)

38

CT

T:100–400mg/dayp.

o.;C:100–150mg/day

p.o..

PR:53CR:11

Median

PFS:20months

MedianOS:months

30

Dizziness

90%

Constipation56%

Neurotoxicity

68%

[81]

PalumboA

etal.(2006)

24

MPT

M:20mg/m

2,day

1every

4th

month;

T:50–100mg/day,

days1–28;p:50mg/

day

p.o.every

other

day

nCR:12.5

PR:29MR:17

MedianPFS:9months

ConstipationTinglingSedationG1/

2Anemia:64%

G1/

2Thrombocytopen

ia:81%

G1/

2Neutropenia:63%

[82]

C:Cyclophospham

ide;

CR:Complete

response;CIV:Continuousintraven

ousinfusion;D:Dexamethasone;EFS:Event-freesurvival;M:Melphalan;MR:Minim

alresponse;nCR:Near-complete

response;OS:Overallsur-

vival;P:Prednisone;PFS:Progression-freesurvival;PR:Partial

response.



Table

3.Lenalidomide-basedclinicaltrials.

Study(year)

Patients

(n)

Regim

en

Previous

treatm

ent(%

)Dosage/day

Resp

onse

(%)

Mean

durationof

resp

onse/

survivalrate

Sideeffects

Ref.

MM-009;

Web

er

DM

etal.

(2007)

177

LDThal41.8;Bort

10.7;stem-cell

transplantation

61.6

L:25mg,days

1–21ofa

28–daycycleD:40mg,

days

1–4,9–12,17–

20forthefirstfour

cycles,thereafter40mg/

day,

days

1–4

CR:14.1

nCR:

10.2

PR:36.7

MedianTTP:

11.1

months

MedianOS:

29.6

months

Neutropenia:41.2%

Anemia:13%

Thrombocytopenia:

14.7%Venous

thromboembolism:11.9%

[83]

MM-010;

Dim

o-poulos

Metal.(2007)

176

LDThal30;Bort

4.5;stem-cell

transplantation

55

L:25mg/day,

days1–

21ofa28-daycycle;D:

40mg/day,

days1–4

,9–

12,17–2

0forthefirst

fourcycles,thereafter

40mg/day,

days1–4

CR:15.9

nCR:

8.5

PR:35.8

MedianTTP:

11.3

months

MedianOS:

not

reached

Neutropenia:29.5%

Thrombocytopenia:

11.4%

Venous

thromboembolism:11.4%

[84]

KnopSetal.

(2009)

69

RAD

Thal20Bort

57Len0

DL1:Len10mg/day,

days

1–21;ADR4mg/m

2,day

1;Dex

40mg,days

1–

4and17–2

0DL2:Len

10mg/day,

days1–2

1;

ADR6mg/m

2,day1;Dex

40mg/day,

days

1–4and

17–20.DL3:Len10mg/

day,

days

1–21;ADR

9mg/m

2,day1;Dex

40mg/day,

days

1–4and

17–20.DL4:Len15mg/

day,

days

1–21;ADR

9mg/m

2,day1;Dex

40mg/day,

days

1–4and

17–20.DL5:Len25mg/

day,

days

1–21;ADR

9mg/m

2,day1;Dex

40mg/day,

days

1–4and

17–20+G-CSF

(Knop,

Blood2009).

ORR:73CR:

15VGPR:45

MedianTTP:

10.4

months

G3/4

neutropen

ia:48%

G3/4

thrombocytopen

ia:

38%

Thromboembolic

events:4.5%

Severe

infections:10.5%

[85]

A:Adriamycin;ASCT:Autologousstem

celltransplantation;C:Cyclophopham

ide;D:Dexamethasone;L:

Lenalidomide.VGPR:Very

goodpartialremission;TTP:Tim

eto

progression.



Table

3.Lenalidomide-basedclinicaltrials

(cont.).

Study(year)

Patients

(n)

Regim

en

Previous

treatm

ent(%

)Dosage/day

Resp

onse

(%)

Mean

durationof

resp

onse/

survivalrate

Sideeffects

Ref.

Schey

S(2010)

31

RCD

Thal90Bort

26Len0

RCD1:Cyc

300mg/day,

days

1–8ofa28cycle;

lenalidomide25mg/day,

days

1–21;dexamethasone

20mg/day,days

1–4,8–

11.RCD2:Cyc

400mg/

day,

days1–8

ofa

28cycle;lenalidomide

25mg/day,days

1–21;

dexamethasone20mg/

day,

days1-4,8–1

1.

RCD3:Cyc

500mg/day,

days

1–8ofa28cycle;

lenalidomide25mg/day,

days

1–21;dexamethasone

20mg/day,days

1–4,8–

11.RCD4:Cyc

600mg/

day,

days1–8

ofa


25mg/day,days

1–21;

dexamethasone20mg/

day,

days1–4

,8–

11RCD5:Cyc

700mg/

day,

days1–8

ofa


25mg/day,days

1–21;

dexamethasone20mg/

day,

days1–4

,8–11

CR:29VGPR:

%PR:45ORR:

81

2-yearPFS:

56%

30-m

onth

OS:80%

G3–4hematological

toxicity:26%G

3–

4infections:3%

Thromboembolic

complications:6%

[86]

Lentzschetal.

25

BLD

Thal48BortNA

Len79

Len10mgdayondays

1–21;Bendamustine

75mg/m

2,days

1and2;

Dex40mg/day,

days

1,8,

15,22

VGPR:24%

PR:

52%

PFS:6.1

months

Hematological

toxicity:15.4%Cardiac

toxicity(prolongedQTc):

3.8%

[50]

A:Adriamycin;ASCT:Autologousstem

celltransplantation;C:Cyclophophamide;

D:Dexamethasone;L:

Lenalidomide.VGPR:Verygoodpartialremission;TTP:

Timeto

progression.



Table

4.Bortezomib-basedclinicaltrials

(single

agent).

Study(year)

Patients

(n)

Regim

en

Previous

treatm

ent

Dose/day

Resp

onse

(%)

Mean

durationof

resp

onse

Sideeffects

Ref.

Richardsonetal.

(SUMMIT

study,

2003)

202

Bortezomib-

dexamethasone

Corticosteroids;

alkylating

agents,

anthracyclines

stem-cell

transplant

B:1.3

mg/m

2,

days

1,4,8,

11ofa21-day

cycle;D:20mg/

day,

days1,2,4,

5,8,9,11,12

ORR:27

CR/nCR:10

DOR

12.7

months

TTP:7months

OS:

17months

Thrombocytopen

ia:31%

Neutropenia:14%

PN:12%

[87]

Jagannath

etal.

(CRESTstudy,

2008)

54

Bortezomib

+

dexamethasone

Corticosteroids;

alkylating

agents,

anthracyclines

stem-cell

transplant

B:1mg/m

2,days

1,4,8,11ofa

21-daycycle;

B:1.3

mg/m

2,

days

1,4,8,

11ofa21-day

cycle;D:20mg/

day,

days1,2,4,

5,8,9,11,12

ORR:30

ORR:38

DOR:9.5

monthsTTP:7months

OS:26.8

monthsDOR:13.7

months

TTP:11monthsOS:60months

Thrombocytopen

ia:29%

Neutropenia:11%

PN:8%

Thrombocytopen

ia:23%

Neutropenia:23%

PN:15%

[88]

Richardsonetal.

(APEXstudy,

2007)

333

336

Bortezomib

single

agent

vsdexamethasone

Corticosteroids;

alkylating

agents,

anthracyclines

stem-cell

transplant

B:1.3

mg/m

2,

days

1,4,8,

11ofcycles1–

8(21-daycycles)

andondays

1,8,

15,22ofcycles

9–11(35-day

cycles);D:40mg/

day,

days1–4

,9–

12,17–20of

cycles1–4(35-day

cycles)andon

days

1–4ofcycles

5–9(28-day

cycles)

ORR:43

CR/nCR:15

ORR:18

CR/nCR:2

DOR:7.8

monthsTTP:6.2

months

OS:29.8

monthsD

OR:5.6

months

TTP:3.5

monthsOS:

23.7

months

Thrombocytopen

ia:30%

Neutropenia:14%

PN:8%

Anemia

11%

Thrombocytopenia

6%

[38]

B:Bortezomib;CR:Complete

response;D:Dexam

ethasone;DOR:Duration

ofresponse;nCR:Near-complete

response;ORR:Overall

response

rate;OS:

Overall

survival;

PN:Peripheralneu

ropath;TTP:Tim

eto

progression.



Table


(combinations).

Study(year)

Patients

(n)

Regim

en

Previous

treatm

ent

Dose/day

Resp

onse

(%)

Mean

durationof

resp

onse/

survivalrates

Sideeffects

Ref.

Berensonetal.

(2006)

35

BM

Glucocorticoids;

melphalan-

basedregim

en;

thalidomide;

lenalidomide;

VAD;

bortezomib;

ASCT

B:1mg/m

2,days

1,4,8,11ofa

28-daycycle;

M:0.10mg/kgp.

o.,days1–4

ORR:47CR:6

Median

PFS:8months

Hematologicaltoxicitiy

[89]

Orlowskietal.

(2007)

324

322

B-PLD

BCorticosteroids;

alkylating

agents;

thalidomide/

lenalidomide;

anthracycline;

stem-cell

transplantation

B:1.3

mg/m

2,days

1,4,8,11ofa

21-daycycle;

PLD

:30mg/m

2,

day4B:1.3

mg/m

2,

days

1,4,8,11of

a21-daycycle

ORR:44CR:4ORR:41CR:2

Med

ian

TTP:9.3

months

15-m

onths

OS:

76%

Med

ian

TTP:6.5

months

15-m

onth

OS:

65%

Thrombocytopnia:23%

Neutropenia:29%

Thrombocytopnia:16%

Neutropenia:15%

[90]

Kropffetal.

(2007)

54

BCD

NR

B:1.3

mg/m

2,days

1,4,8,11ofa

21-daycyclefor

thefirst8cycles,

followedby

1.3

mg/m

2,days

1,

8,15,22forthree

5-w

eekcycles;

C:50mgp.o.

daily;D:20mgon

days

ofBandday

after

ORR:82CR:16

Median

EFS:12months

Median

OS:22months

Leuko

cytopenia:20%

Thrombocytopenia:53%

PN:21%;Infections:38%

[91]

ASCT:Autologousstem-celltran

splantation;B:Bortezomib;C:Cyclophosphamide;CR:Complete

response;D:Dexamethasone;Dx:

Doxorubicin;EFS:

Event-freesurvival;M:Melphalan;NR:Notreported;ORR:Overall

response

rate;OS:Overallsurvival;PFS:Progression-freesurvival;PLD

:Peg

ylatedliposomal

doxorubicin;PN:Peripheralneu

ropathy.



Table


(combinations)

(cont.).

Study(year)

Patients

(n)

Regim

en

Previous

treatm

ent

Dose/day

Resp

onse

(%)

Mean

durationof

resp

onse/

survivalrates

Sideeffects

Ref.

Palumboetal.

(2008)

64

BDxD

Autologous

transplantation;

bortezomib;

anthracyclines

B:1.3

mg/m

2,days

1,4,8,11ofa

28-daycycle;

PLD

:20mg/m

2,

days

1,4or

30mg/m

2,day1;

D:40mg/day,

days

1–4

ORR:67CR:9

1-year

EFS:34%

1-yearOS:66%


Neutropen

ia:36%

Anemia:13%

Infections:15%

PN:10%

[92]

Popatetal.

(2009)

53

BM

DCorticosteroids;

alkylating

agents;

thalidomide;

anthracyclines;

radiotherapy;

bortezomib;

ASC

Tor

allogeneicstem-

cell

transplantation

B:1.3

mg/m

2,days

1,4,8,11ofa

28-daycycle

M:7.5

mg/m

2iv.,

day2;D:20mg/

day,

days

1,2,4,

5,8,9,11,12in

thecase

of

progressiveor

stable

disease

after

twoorfourcycles,

respectively

ORR:68CR:19

Median

PFS:10months

Median

OS:28months


Neutropen

ia57%

Infections:21%

PN:15%

[93]

ASCT:Autologousstem

-celltransplantation;B:Bortezomib;C:Cyclophosphamide;CR:Complete

response;D:Dexamethasone;Dx:

Doxorubicin;EFS:Event-freesurvival;M:Melphalan

;NR:Notreported

;ORR:Overall

response

rate;OS:

Overallsurvival;PFS:Progression-freesurvival;PLD

:Pegylatedliposomaldoxorubicin;PN:Peripheralneu

ropathy.



data suggesting that bortezomib-based treatment may be effec-tive in patients with the del(17p) mutation, which is usually

285 associated with refractoriness and a dismal prognosis [41–43].

Carfilzomib

The second-generation proteasome inhibitor PR-171 (carfilzo-mib) is now available and has different functional capacities,such as the irreversible inhibition of the chymotryptic activity

290 of the proteasome, the same site as that of bortezomib-inducedinhibition. Clinical studies (TABLE 6) have shown that carfilzomibhas long-lasting anti-cancer activity in patients with relapsed/refractory MM, including those previously treated with borte-zomib. Ongoing Phase II trials evaluating the efficacy of carfil-

295 zomib have shown an ORR of 23.7% with a median durationof response of 7.8 months, and a median OS of 15.6 months.Adverse events have been manageable without giving rise tocumulative toxicities. The lasting responses of this heavily pre-treated population and the drug’s acceptable tolerability profile

300 demonstrate the potential of carfilzomib to offer a significantclinical benefit [44].

In an open-label, single-arm, multicenter pilot Phase II studyof carfilzomib involving 46 patients with relapsed and refrac-tory MM after ‡2 previous therapies, the best ORR was

305 16.7%, with a median duration of response of 7.2 months [45].In 2012, the US FDA approved carfilzomib for the treatmentof patients with MM who have received at least 2 prior thera-pies, including bortezomib and IMIDs, and have demonstrateddisease progression on or within 60 days of the completion of

310 the last therapy.Other proteasome inhibitors are being developed with differ-

ent spectrums of activity (e.g., pan-proteasome inhibition withNPI-0052) and with oral formulation.

IMIDs combined with bortezomib

315 Recent discoveries concerning the fundamental molecularmechanisms underlying MM cell growth and survival have ledto the introduction of new combinations of an IMID and bor-tezomib. Both have significant activity against MM when usedas single agents, and so the challenge is to demonstrate whether

320 their combination increases their activity. The rationale forcombining an IMID and bortezomib is their complementarymechanisms of action, which would theoretically reduce therisk of the emergence of resistant clones. However, as cumula-tive toxicity is a concern, various groups are evaluating the

325 impact of other bortezomib-based combination therapies,including the association with thalidomide and dexamethasone(BTD). In one study [46], Wang et al. administered 38 patientswith newly diagnosed myeloma dexamethasone 20 mg/m2/dayon days 1–4, 9–12, 17–20; bortezomib 1.3 mg/m2 on days 1,

330 4, 8 and 11, associated with thalidomide 100 mg daily, whichwas increased to 200 mg after one week if tolerated. The ther-apy was repeated every 4 weeks for a maximum of three cycles.Although the study population was small, some of the resultswere remarkable [46]. Eleven patients could proceed to ASCT

335 after only one cycle because the regimen induced rapid and Table

6.Carfilzo

mib

basedclinicaltrials.

Study(year)

Patients

(n)

Regim

en

Previous

treatm

ent

Dose/day

Resp

onse

(%)

Meanduration

ofresp

onse

Sideeffects

Ref.

Vijetal.(2012)

35

Carfilzomib

single

agent

Bortezomib

Cfz

20mg/m

2,

days

1,2,8,9,

15,16of

28-day

cycles

ORR:17ORR+

minim

al

response

31.4

TTP:4.6

months

Hematologicaltoxicities:

53%

pneumonia:14%

Fatigue:12%


61%

Pneumonia

11%

[94]

Jagannath

etal.

(2009)

46

Carfilzomib

single

agent

NR

Cfz

20mg/m

2,

days

1,2,8,9,

15,16of

28-day

cycles

ORR:17

DOR:7.2

months

Anemia:74%


Leucopoenia:22%

Fatigue:70%

Upper

respiratory

tract

infection:

37%

Dyspnea:28.3%

Renalfailure:15.2%

[45]

Siegeletal.(2012)

266

Carfilzomib

single

agent

NR

Cfz

20–27mg/

m2,days

1,2,

8,9,15,16of

28-day

cycles

ORR:

24>VGPR:5

DOR:7.8

months


60%

Pneumonia:9%

Fatigue:8%

[44]

Cfz:Carfilzomib;DOR:Durationofresponse;NR:Notreported;ORR:Overallresponse

rate;PFS:Progression-freesurvival;TTP:

Tim

eto

progression;VGPR:Verygoodpartial

response.



significant tumor cytoreduction, and an objective response wasobserved in 87%, with a low incidence of neuropathy. Thisregimen may also be attractive in patients with acute renal fail-ure due to myeloma kidney, when a rapid reduction in mono-

340 clonal protein production is important in order to restore renalfunction [47].

The combination of bortezomib (Velecade), thalidomide anddexamethasone (VTD) was compared with that of TD in aprospective multicenter Phase III study of patients with MM

345 progressing or relapsing after ASCT [47]. In this study,269 patients were randomly assigned to receive bortezomib(1.3 mg/m2 intravenous bolus) or no bortezomib for 1 year, incombination with thalidomide (200 mg/day orally) and dexa-methasone (40 mg orally once a day on 4 days once every

350 3 weeks). Bortezomib was administered on days 1, 4, 8 and11 with a 10-day rest period (day 12 to day 21) for eight cycles(6 months), and then on days 1, 8, 15 and 22 with a 20-dayrest period (day 23 to day 42) for four cycles (6 months).They found that VTD was more effective than TD in the

355 treatment of patients with MM with progressive or relapsingdisease post-ASCT (the median TTP was 19.5 months forVTD and 13.8 for TD) but was associated with a higher inci-dence of grade 3 neurotoxicity (29% for VTD and 12%for TD).

360 Morabito et al., assessed efficacy, safety, and the reversal ofrenal impairment (RI) in previously untreated MM patientswho received a combination of bortezomib, melphalan, predni-sone and thalidomide followed by maintenance treatment withbortezomib an thalidomide (VMPT-VT) or bortezomib, mel-

365 phalan and prednisone (VMP). There were statistically

significant improvements in ORR and progression-free survivalin the VMPT-VT arms across the renal cohorts, except in thegroup of patients with severe RI. In the VMPT group, severeRI reduced OS. RI was reversed in 16/63 patients receiving

370VMPT-VT (25.4%) and 31/77 receiving VMP (40.3%).VMPT-VT was superior to VMP in the patients with normalrenal function or moderate RI, but failed to outperform VMPin patients with severe renal insufficiency. Although the rela-tively small number of cases precludes any definite conclusions,

375it seems that VMPT-VT had no advantage over VMP in termsof renal insufficiency reversal [48]. TABLE 5 shows the trials of bor-tezomib combined with novel agents for the treatment ofrelapsed refractory MM

Histone deacetylase inhibitors

380Histone deacetylase (HDAC) inhibitors represent a new classof anti-myeloma agents that includes panobinostat (LBH589)and vorinostat. Inhibiting HDAC leads to histone hyperacetyla-tion and structural alterations in chromatin which cause growtharrest differentiation and/or apoptosis in a number of tumor

385cells. Microarray-based studies have shown that HDAC inhibi-tors induce transcriptional modulations in 7–10% of the genesin malignant cell lines by acetylating histone and non-histoneproteins, and HDAC inhibitor-induced cell death is one of themain mechanisms of inhibiting the survival of myeloma cells.

390Extrinsic and intrinsic apoptotic pathways, as well as non-apoptotic cell death such as autophagy, have been reported inmyeloma cells treated with an HDAC inhibitor. The intrinsicapoptotic pathway is mediated by the mitochondria, and thepro-apoptotic signals result in the release of mitochondrial

AQ4 Table 7. Conditions influencing the selection of treatment options for patients with relapsed/refractorymyeloma and suggested regimens.

Condition Treatment Option

Disease-related Duration of response to front-line therapy If relapse occurs after a long remission, consider the

same treatment used for front-line If relapse occurs

within a short time (6–12 months) or while the patient

is still undergoing treatment, consider an alternative

regimen

FISH or cytogenetic profile (patients with non-hyperdiploid

t(4:14), del(17p), and del(13q14) mutations have high-risk

disease due to poor response to the treatment)

For patients at high cytogenetic risk, consider

bortezomib- or lenalidomide-based regimens

Regimen-related Previous drug exposure (new vs classic agents) Consider treatment with a new agent A change in the

class of agent is indicated in patients whose disease

has relapsed or is refractory to a particular drug

Previous ASCT Consider second ASCT for salvage therapy

Patient-related Age and performance status Consider aggressive vs reduced or palliative therapy

Neuropathy Consider lenalidomide-based regimens

Neutropenia or cytopenia Avoid or reduce lenalidomide doses

Renal impairment Consider bortezomib- or thalidomide-based regimens

Recent thromboembolic or cardiovascular events Consider bortezomib-based regimens

ASCT: Autologous stem cell transplantation



395 inter-membrane proteins such as cytochrome c (cyto-c),apoptosis-inducing factors (AIF) and the second mitochondria-derived activator of caspase (Smac). HDAC inhibitors inducecell cycle arrest in the G1/S phase. The events in the G1 phaseare coordinated by the three early G1 D cyclins (1, 2 and 3)

400 and their associated cyclin-dependent kinases (CDKs) 4/6(G1 progression) and CDK 2 (G1/S transition).

A number of clinical trials of HDAC inhibitors alone or incombination with other anti-myeloma agents are ongoing.Phase I trials have shown that HDAC inhibitors are well toler-

405 ated by myeloma patients, but Phase II trials have found thatthe activity of HDAC inhibitors as single agents is limited.However, when combined with dexamethasone and/or bortezo-mib, the results are more promising, even in patients withrefractory and/or relapsed MM [49]. Panobinostat (LBH589)

410 and vorinostat have shown promise as adjuncts to current treat-ment options, and panobinostat is currently being tested in alarge, randomized Phase III trial. Panobinostat and vorinostatare the oral HDAC inhibitors that are farthest along the clini-cal development pathway [6].

415 Immune-based therapies

Monoclonal antibody therapy for MM patients has enteredclinical testing. Elotuzumab is a humanized monoclonalIgG1 antibody directed against a cell surface glycoproteinnamed CS-1, which is highly and uniformly expressed in MM.

420 Elotuzumab induces significant antibody-dependent cytotoxicityagainst primary MM cells in the presence of peripheral lym-phocytes and, in combination with lenalidomide and low-dosedexamethasone has led to promising results. Two other agentsin the same class have also showed promise: lorvotuzumab

425 (anti-CD56) in combination with lenalidomide and dexame-thasone and mapatumumab (anti-Trail-R1) in combinationwith bortezomib [50].

Alkylators

Bendamustine is an agent that is structurally similar to alkylat-430 ing agents and purine analogues, and it has been found to be

active in MM patients. Lentzsch et al. have recently publishedthe final results of a Phase I/II study of bendamustine com-bined with lenalidomide and dexamethasone in patients withrefractory or relapsed MM, and the combination of bendamus-

435 tine, bortezomib and dexamethasone has anti-myeloma activitywith relatively little toxicity in previously treated MMpatients. [51,52].

Toxicity of the new anti-myeloma agents

The frequency and severity of IMID side effects are dose440 related and time dependent, and should be graded using the

National Cancer Institute Common Toxicity Criteria forAdverse Events. Venous thromboembolism (VTE) and occa-sional thrombotic events have been reported in patients treatedwith thalidomide, especially when thalidomide and pulsed dex-

445 amethasone (TD) are combined [53]. The thrombogenic effectsseem to be due to a transient reduction in soluble

thrombomodulin levels during the first month of therapy andthe restoration of endothelial cell PAR-1 expression after dam-age by cytotoxic agents such as doxorubicin. Furthermore, tha-

450lidomide leads to the phosphatylserine-induced activation ofpro-coagulant tissue factor (TF) on the apoptotic cell mem-brane, thus increasing the thrombogenic risk [54–56].

Lenalidomide and pomalidomide are structurally related tothalidomide, but relatively more potent and have a different

455toxicity profile. The sedation, constipation and neuropathyassociated with thalidomide are not commonly seen, but therisk of developing thromboembolic events seems to be similarto that attributed to thalidomide combinations. There are datasuggesting that the combination of lenalidomide and dexame-

460thasone increases the risk of thromboembolic complications [56].Myelosuppression (grade 3–4 neutropenia and thrombocytope-nia), the dose-limiting side effect in Phase I studies of lenalido-mide, is the most frequent adverse event, but can be effectivelymanaged by means of dose reductions or discontinuations,

465although granulocyte colony- stimulating factor (G-CSF) orerythropoietin may be needed in more severe cases [57].

Although some concerns have been raised regarding the inci-dence of second primary malignancies (SPMs) among patientstreated with lenalidomide, including two cases of myelodisplas-

470tic syndrome, Ades et al. [58] found no significant differencesfrom a historical series. Similarly, Palumbo et al. [59] haverecently stated that the PFS benefit obtained using lenalido-mide maintenance treatment outweighs the increased risk ofSPM; moreover, in patients with relapsing/refractory MM, the

475number and types of SPM do not seem to affect the drug’srisk/benefit profile.

The toxicity of bortezomib has been well characteried, andincludes nausea, diarrhea, cyclic reversible thrombocytopenia,fatigue and peripheral neuropathy. The last occurs in about

480one-third of patients and may have a painful component,and requires dose modification or discontinuation; the neuro-pathy improves or resolves in a high proportion of patients,although recovery often takes several months. An increasedincidence of herpes zoster reactivation has been reported, and

485so acyclovir prophylaxis is recommended for all patientsreceiving bortezomib [60].

Clinical trial data show that HDAC inhibitors are gener-ally well tolerated, but there have been reports of cardiac,metabolic and hematological toxicities, consisting of reversi-

490ble QT prolongation, pericardial effusion, hypokalemia andthrombocytopenia [62,63].

Supportive care

Patients with MM not only require treatment for the diseaseitself, but also a wide range of supportive and palliative meas-

495ures to optimize their quality of life at all stages of the disease.Considerable progress has been made in terms of supportivecare for patients with MM and this can benefit them whenintegrated with conventional medical treatment.

Approximately 85% develop bone disease due to osteopenia,500osteolytic lesions and related complications, which reduces their



performance status and quality of life [63]. The first step in thetreatment of bone pain should be to consider a non-opioidanalgesic such as acetaminophene; non steroidal anti-inflammatory drugs should be avoided because of their poten-

505 tial nephrotoxicity, and opioids should only be consideredwhen patients fail to respond to first-step therapy. Local radio-therapy can also relieve the pain of skeletal disease and maypalliate soft tissue disease. Mill and Griffith [64] treated128 patients using a wide dose range, and observed pain relief

510 in 91% at a median dose of 10–15 Gy divided into 2–3 Gyfractions. Only 6% of the sites required re-treatment, and thiswas unrelated to the initial dose.

A number of clinical trials have shown that bisphosphonatescan help in the management of bone pain in MM patients by

515 reducing the incidence of new bone lesions and pathologicalfractures [65,66]. It has also been shown that zoledronic acidextends median OS by 5.5 months and PFS by two months [66].It is generally accepted that biphosphonate therapy should beoffered to MM patients with symptomatic bone disease for no

520 more than two years in order to limit the development of jawosteonecrosis, but it is possible to keep offering them furtherforms of treatment aimed at reducing bone marrow plasma cellactivity and the consequent expression of symptoms.

Even when a patient is approaching the terminal stage of the525 disease and specific anti-cancer treatments have been with-

drawn, blood and platelet transfusions can help maintain thequality of life by relieving exertional dyspnea and preventingbleeding. In patients with renal insufficiency, the deteriorationof renal function and tumor lysis syndrome can be prevented

530 by appropriate hydration, urine alkalinization, and the treat-ment of hypercalcemia, hyperuricemia and infections. In somepatients, managing symptomatic hyperviscosity by means ofregular plasma exchanges may be reasonable.

Therapeutic strategies

535 Although substantial progress has been made, MM remainsincurable in most cases due to multiple relapses. The clinicalpicture of relapsed MM ranges from an asymptomatic formthat can only be identified by means of laboratory tests to veryaggressive disease. Relapsing patients with MM should be

540 treated at the appearance of the typical clinical manifestationsof MM which are summarized by the CRAB symptoms(elevated calcium, renal impairment, anemia and bone lesions),or when monoclonal protein in serum or urine has a significantgrowth (M spike >1 g/dl, Bence Jones protein >500 mg/day or

545 serum free light chain >200 mg/dl).There are still no standard therapies for relapsed MM, and

treatment remains a challenge especially in the case of patientswho already received several lines of therapy. The first remis-sion is likely to be the period during which patients enjoy the

550 best quality of life, and so the goal should be that of achievingthe longest remission possible by using the most effective drugs.The most effective strategy for almost all patients, regardless ofwhether or not they are eligible for stem cell transplantation, isto use the new agents. Patients with indolent relapse can be

555treated first with two-drug or three-drug combinations, Patientswith more aggressive relapse often require therapy with a com-bination of active agents, for example, VCD, VTD, VRd, orVDT-PACE or ASCT.

The message coming from the trials reviewed in this article,560although the population of patients may be heterogeneous due

to the differences in prior treatments over the years, is thatthese drugs (i.e., IMIDs and proteasome inhibitors) can beused to treat relapsed/refractory disease with encouraging resultsand that the crucial factor is their sequencing. In patients who

565have relapsed and are refractory to a particular drug, a changein drug class of agent is indicated because they are likely tohave become resistant. Various disease- and patient-relatedfactors should be considered when selecting a treatment option.

The disease-related factors include the quality and duration570of response to previous therapies administered for purposes of

induction or because of a previous relapse, and the aggressive-ness of the relapse. Deep and prolonged responses are morelikely in patients with a late relapse (after a remissionof >12 months) than in those relapsing early (a remission of

575<6 months). The duration of first remission and the timing ofrelapse are key points in the treatment strategy. If the relapseoccurs after a long remission and treatment-free period, it ispossible to consider repeating the same treatment [67] but, if itoccurs earlier (6–12 months) or while the patient is still under-

580going treatment (which indicates aggressive, relapsed and refrac-tory disease), the use of an alternative regimen should beconsidered. In addition, the presence of clinical risk factorssuch as cytogenetic abnormalities may indicate high-risk dis-ease, which requires a different approach from that used in

585‘slowly’ relapsing patients.The patient-related factors include pre-existing toxicities,

comorbidities, the quality of life, age and performance status.Nearly 50% of MM patients develop some degree of renalimpairment during the course of their disease and, as many

590therapeutic agents are renally excreted, this may affect drugpharmacokinetics and limit the choice. Among the new drugs,bortezomib and thalidomide are not excreted renally, whichmakes them better for patients with renal impairment thanlenalidomide, which is renally excreted and therefore requires

595dose adjustments. A number of trials have shown the beneficialeffects of bortezomib in patients with MM and renal insuffi-ciency [39,40], thus making its use (alone or in combination withdexamethasone) the drug of choice in such patients as it rapidlyreduces light chain production and provides an opportunity for

600renal recovery. On the contrary, as neither lenalidomide northalidomide are metabolized by the liver, they are more suitablefor patients with impaired liver function than bortezomib.

The use of thalidomide and bortezomib can lead to neuropa-thy in up to 80% of previously treated patients, whereas neuro-

605pathy is less frequent in patients treated with lenalidomide-based regimens, thus making them a reasonable choice inpatients with pre-existing neuropathies.

Diabetes is a frequent comorbidity, particularly among theelderly, and may be exacerbated by the frequent use of



610 corticosteroids to treat of MM; in this case, the corticosteroid-sparing combination of bortezomib and pegylated liposomaldoxorubicin (PLD) may well be suitable.

Bortezomib alone has not been associated with any increasein VTE, and is therefore a good choice for patients with a

615 history of thromboembolic events which, although it doesnot per se exclude treatment with thalidomide or lenalido-mide, requires appropriate anti-thrombotic prophylaxis. It isgenerally accepted that acetylsalicylic acid (ASA) is suitablefor thromboprophylaxis in patients without a previous history

620 of thrombotic events and with no thrombotic risk factors,whereas anti-coagulant prophylaxis is mandatory for thosewho have previously experienced a thromboembolic event orwho are at high thrombotic risk [68]. The thromboprophylaxisshould be performed almost for three months with low

625 molecular weight heparin before switching to asprin, in factthromoembolic events are more likely in the first 3 monthsof IMIDs treatment.

One-third of MM patients are 75-years-old or older at diag-nosis, which raises more concerns about treatment tolerability

630 and toxicity than in the case of younger patients. Although ageshould not be considered an exclusion criterion, only a fewclinical trials have investigated the safety and efficacy of drugsin old and/or frail patients. Modified treatment regimens anddose reductions should be used to improve tolerability. New

635 protocols for elderly patients that also include a global geriatricevaluation should be encouraged in order to guide clinicians ineveryday clinical practice.

In the case of transplant-eligible patients, it is feasible toconsider ‘retransplantation’ at the time of relapse if an adequate

640 stem cell graft is available. In order to be eligible for a secondsalvage ASCT at the time of relapse, patients need to haveenjoyed a reasonable response duration following the firstASCT. As a relapse occurring within 12–18 months of a firstASCT is associated with a poor outcome, alternative treatments

645 should be considered, preferably incorporating novelapproaches. In the case of a disease relapse that is refractory totreatment with IMIDs and proteasome inhibitors, eligible pat-ents should be enrolled in clinical trials of experimental agents,and those who do not qualify for inclusion in a trial should

650 receive treatment aimed at alleviating their symptoms andmaintaining their quality of life while stabilizing the disease asmuch as possible. Palliative treatment can include alkylatingagents in combination with corticosteroids (i.e., oral cyclophos-phamide and prednisone), or cisplatin-containing regimens

655 such as continuous infusions of dexamethasone, cyclophospha-mide, etoposide and cisplatin [67].

Expert commentary

Emerging evidence indicates that, in addition to the pharmaco-logical characteristics of anti-myeloma drugs, disease- and

660 patient-related factors should be considered when selecting atreatment option for relapsed/refractory MM. However, opti-mal treatment and its duration has still not been fully defined.On the basis of the natural history of the disease, the duration

of responses is relatively long early in the disease course and665becomes progressively shorter with each relapse.

Novel agents targeting the tumor and its microenviron-ment such as thalidomide, lenalidomide and bortezomib haveimproved outcomes and extended survival in patients withrelapsed and/or refractory MM. Outcomes are significantly

670better when they are used at the time of a first relapse ratherthan as salvage treatment after two or more previous thera-pies. Combination therapy using agents with different mecha-nisms of action is becoming an attractive means of increasingefficacy and/or overcoming resistance to standard treatment

675regimens.When treating indolent or slow relapse, the treatment

options may be different. Lenalidomide based salvage therapy ispreferred if the patient has been previously exposed to bortezo-mib therapy, has a history of polyneuropathy or has cytogenetic

680standard risk. Bortezomib based salvage therapy is used if thepatient has been exposed to IMIDs, has renal failure or unfav-orable chromosomal abnormalities. Thalidomide based salvagetherapies are indicated in presence of a previous treatment withbortezomib or lenalidomide, when the patient has never been

685treated with IMIDs or when the patient is cytopenic. Stem-celltransplantation may be considered if deferred in first line ther-apy. Aggressive and rapid relapse requires an immediate treat-ment, which is likely a combination therapy includingtreatment with chemotherapy based regimens, chemotherapy in

690combination with novel agents (lenalidomide or bortezomib) ortransplant based regimen.

Other new agents are in clinical development. Pomalidomidehas led to encouraging results in heavily pre-treated patients.The oral HDAC inhibitors panobinostat and vorinostat can

695synergistically enhance the cytotoxic activity of lenalidomideand bortezomib, and overcome possible resistance. The second-generation proteasome inhibitor carfilzomib can be used asmonotherapy and in combination with lenalidomide plus low-dose dexamethasone.

700Consolidation and maintenance strategies are being evaluatedin order to verify whether they guarantee longer survival with-out evidence of disease.

Five-year view

One important future research goal is to use molecular studies705to guide therapeutic strategies at the time of diagnosis and at

the time of relapse. MM is a clonal disease, and a number ofsub-clones have been described. Myeloma therapies profoundlychange the bone marrow microenvironment, and this createsnew selective pressures on different sub-clones. Recent results

710suggest that the patterns of clonal evolution are different. Inpatients treated with conventional chemotherapy and thosetreated with new drugs, such as the proteasome pathways, thetechnical means of detecting and defining tumor sub-clonesmay become clinically relevant. It could be proposed that thera-

715peutic options should be chosen on the basis of the results ofserial clonal evaluations comparing the disease genome at thetime of diagnosis and at relapse [69,70].



Clinical studies of monoclonal antibody therapy in combina-tion with lenalidomide or bortezomib have led to promising

720 early results [50]. Ongoing and future research is and will beaimed at using oncogenomics to develop personalized therapies,next-generation agents targeting tumor cells and their microen-vironment, and rationally based combinations of targeted thera-pies. These approaches will lead to a more tailored therapeutic

725 strategy for MM patients.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with

any organization or entity with a financial interest in or financial conflict

with the subject matter or materials discussed in the manuscript. This

730includes employment, consultancies, honoraria, stock ownership or options,

expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this

manuscript.

Key issues

• Multiple myeloma (MM) is a clonal disorder of plasma cells that still cannot be cured using conventional treatments because of

frequent relapses.

• The introduction of thalidomide, lenalidomide and bortezomib has changed the treatment paradigm for patients with relapsed/refractory

740 disease by improving clinical outcomes in comparison with conventional chemotherapy alone.

• Relapsing patients with multiple myeloma should be treated at the appearance of the typical clinical manifestations of MM which are

summarized by the CRAB symptoms (elevated calcium, enal impairment, anemia and bone lesions), or when monoclonal protein in

serum or urine has a significant growth.

• Treatments for patients with relapsed/refractory MM include hematopoietic cell transplantation, a rechallenge using a previous chemo-

745 therapy regimen, or a trial of a new regimen.

• At the time of a relapse, the challenge is to select the optimal treatment for each patient while balancing efficacy and toxicity. The deci-

sion will depend on disease- and patient-related factors, as well as the pharmacological characteristics of the anti-myeloma agents.

• Patients with indolent relapse can be treated first with two-drug or three-drug combinations. Patients with more aggressive relapse

often require therapy with a combination of multiple active agents, consider ASCT as salvage therapy at first relapse for patients who

750 have cryopreserved stem cells early in the disease course.

• Outcomes are significantly better when novel agents are used at first relapse, rather than as salvage treatment after two or more pre-

vious therapies

• Combined therapy can be used to prevent or overcome treatment resistance, and increase the efficacy of standard treatment regimens.

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liposomal doxorubicin plus bortezomib

compared with bortezomib alone in relapsed

or refractory multiple myeloma:

combination therapy improves time to

progression. J. Clin. Oncol. 1(25),3892–3901 (2007).

91 Kropff M, Bisping G, Schuck E et al.Bortezomib in combination with

intermediate-dose dexamethasone and

continuous low-dose oral cyclophosphamide

for relapsed multiple myeloma. Br. J.Haematol. 138(3), 330–337 (2007).

92 Palumbo A, Gay F, Bringhen S et al.Bortezomib, doxorubicin and

dexamethasone in advanced multiple

myeloma. Ann. Oncol. 19(6), 1160–1165(2008).

93 Popat R, Oakervee H, Williams C et al.Bortezomib, low-dose intravenous

melphalan, and dexamethasone for patients

with relapsed multiple myeloma. Br. J.Haematol. 144(6), 887–894 (2009).

94 Vij R, Siegel DS, Jagannath S et al. Anopen-label, single-arm, phase 2 study of

single-agent carfilzomib in patients with

relapsed and/or refractory multiple myeloma

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bortezomib. Br. J. Haematol. 158(6),739–748 (2012).









































1

JOURNAL: EXPERT REVIEW OF ANTICANCER THERAPY

Article type: Review

VOL/ISS: FEB 2014 (1402)

US ENGLISH

<RRH> Choosing treatment options for patients with relapsed/refractory multiple myeloma

<VRH> Castelli, Orofino, Losurdo, Gualtierotti & Cugno

Choosing treatment options for patients with relapsed/refractory multiple myeloma

Roberto Castelli*1, Nicola Orofino1, Agnese Losurdo1 , Roberta Gualtierotti1, and Massimo

Cugno1,2

1Department of Pathophysiology and Transplantation, Internal Medicine, Department of

Pathophysiology and Transplantation, University of Milan, Milan, Italy and

2Department of Medicine, IRCCS Fondazione Ca‟ Granda Policlinico, Milan, Italy

*Author for Ccorrespondenceing author:

Roberto Castelli, MD

Department of Pathophysiology and Transplantation, Section of Internal Medicine,

Via Pace 9,

20122 Milano,

Italy.

Tel.: +39 -02 -5 503 6381; Fax: +39 -02 -5 503 4722 E-mail: [email protected]

mailto:[email protected]

2

ABSTRACT

Multiple myeloma (MM) is a clonal plasma cell disorder that is still incurable using conventional

treatments. Over the last decade, advances in front-line therapy have led to an increase in

survival, but there are still some doubts in the case of relapsed/refractory disease. We searched

the PubMed database for articles on treatment options for patients with relapsed/refractory MM

published between 1996 and 2013. These treatments included hematopoietic cell transplantation

(HCT), rechallenges using previous chemotherapy regimens, and trials of new regimens. The

introduction of new agents such as the immunomodulatory drugs (IMIDs) thalidomide and

lenalidomide, and the first-in-its-class proteasome inhibitor bortezomib, has greatly improved

clinical outcomes in patients with relapsed/refractory MM, but not all patients respond and those

that do may eventually relapse or become refractory to treatment. The challenge is therefore to

select the optimal treatment for each patient by balancing efficacy and toxicity. To do this, it is

necessary to consider disease-related factors, such as the quality and duration of responses to

previous therapies, and the aggressiveness of the relapse, and patient-related factors such as age,

comorbidities, performance status, pre-existing toxicities, and cytogenetic patterns. The message

from the trials reviewed in this article is that the new agents may be used to re-treat

relapsed/refractory disease, and that the sequencing of their administration should be modulated

on the basis of the various disease- and patient-related factors. Moreover, our understanding of

the pharmacology and molecular action of the new drugs will contribute to the possibility of

developing tailored treatment.

Key words::

immunomodulatory drugs

• proteasome inhibitors •

Rrelapsed/refractory multiple myeloma • ;

salvage therapies;

immunomodulatory drugs; proteasome inhibitors.

3

INTRODUCTION

Multiple myeloma (MM) is a hematological malignancy characterised by the proliferation of

clonal plasma cells in bone marrow (BM), monoclonal protein in serum or urine, destructive

bone lesions, anemia, hyper-calcemia, and renal insufficiency [1]. It accounts for 1.5−-2% of all

cancer deaths and remains incurable [1]. Median survival after diagnosis is approximately three

3 years, treatment responses are characteristically short, and patients frequently relapse or

become refractory to treatment [1]. The introduction of new front-line agents such as the

immunomodulatory drugs (IMIDs) thalidomide and lenalidomide, and the proteasome inhibitor

bortezomib, has significantly improved overall survival (OS) by achieving deeper levels of

responses and prolonging the duration of remission. However, not all patients respond to these

new drugs, and the development of drug resistance is common.

Relapsed and refractory MM describes the disease in a subject who has previously achieved at

least a minor response, but then experiences progressive disease, receives salvage therapy, and is

either unresponsive to salvage therapy or progresses within 60 days of the last treatment [2].

Recent studies have begun to clarify the biological basis of the mechanism of relapsed or

refractory MM. There is evidence concerning the existence of minor sub-clones that can survive

chemotherapy and thus become a reservoir for relapse or resistance [3]. The two driving forces

conditioning relapse or resistance are the genetic instability of aggressive MM sub-clones and

the selective pressures introduced by therapy during the course of the disease [4].

Previous treatments for relapsed/refractory MM consisted of standard combinations of alkylating

agents, anthracyclines and corticosteroids, with or without hematopoietic stem cell rescue [5,6],

but the new IMIDs and proteasome inhibitors have improved clinical outcomes [7−-9]. In the

relapse setting, the impact of complete responses (CRs) on survival is still controversial, and it is

unclear whether the duration of response/progression-free survival or the depth of the response is

more important. Nevertheless, a number of recent studies [10,11] have shown a clear relationship

between the depth of response and survival, thus further demonstrating that a better quality of

4

response may be associated with an improved outcome even beyond front-line therapy. Studies

that have analyzsed outcomes on the basis of the quality of a so-called „good remission‟ (i.e., ,

CR, near-CR and very good partial remission [VGPR]) have shown that survival is virtually

identical in patients achieving a near-CR, VGPR or partial remission (PR), but significantly

worse than that of patients in CR. In this respect, negative minimal residual disease (supported

by multi-parameter flow cytometry or molecular studies) seems to be a prerequisite for long-

term remission and prolonged survival.

The aim of this article is to review the pharmacology and molecular action of the drugs used to treat

relapsed/refractory MM, and consider approaches for managing such patients using strategies aimed at

tailoring different treatments.

<H1> Materials AND & methods

We searched the PubMed database for papers published between January 1996 and March 2013 using the

key words „“immunomodulatory drugs‟”, „“proteasome inhibitors‟” and „“relapsed/refractory multiple

myeloma‟”. The search was limited to randomizsed controlled trials, but had no language restriction and,

in order to ensure its completeness, was complemented by searches of the Web of Science, EMBASE, and

Cochrane Library databases. In the case of duplicate publications, we reviewed each article and included

only the most recent or the most complete version in the analysis.

<H2>Current treatment options

The challenge when treating patients with relapsed or refractory MM is to select the optimal treatment by

balancing efficacy and toxicity, which involves considering both disease- and patient-related factors. In

the case of patients whose performance status allows them to tolerate aggressive treatment, the ultimate

goal at the time of induction and the time of relapse should be to obtain the deepest possible response in

order to improve survival; in the case of patients who cannot tolerate aggressive treatment, palliative

therapy should be used with the aim of stabilizsing the disease and preventing further progression.

<H2>Chemotherapy and & transplantation

The use of conventional or high-dose chemotherapy is a long-standing approach to salvage

therapy in patients with relapsed MM. In the past, various standard chemotherapy-based

regimens were used, the most widely administered of which are shown in TABLEable 1I. The

5

overall rates of response to salvage combination chemotherapy are between 30% and 60%, with

morbidity and mortality related to the intensity of the therapy itself [12].

Even in the era of the new targeted agents, single or double autologous stem cell transplantation

(ASCT) remains the standard front-line approach for MM patients eligible for high-dose therapy,

although the new drugs used during the induction, consolidation, and maintenance phases of

ASCT have helped in reaching five5-year overall survival (OS) and event-free survival (EFS)

rates of 70% [13,14]. Recent studies have shown that a second ASCT is a feasible and safe

option for salvage therapy in MM patients who have undergone a front-line single ASCT

[15,16]. Michaelis et al., reported the outcomes of 187 patients who underwent a second ASCT

(ASCT2) for the treatment of relapsed/progressive MM at a median age of 59 years (range: 28−-

72), and were followed up for a median of 47 months (range: 3−-97). Non-relapse mortality was

2% one 1 year after ASCT2 and 4% after three 3 years. The median interval from ASCT1 to

relapse/progression was 18 months, and the median interval between transplantations was 32

months. After ASCT2, the one- and three-year incidence of relapse/progression was 51% and

82%, respectively 51% and 82%. Three years after ASCT2, progression-free survival was 13%,

and OS was 46%. Multivariate analyses showed that the patients relapsing 36 months after

ASCT1 had better progression-free (p P= 0.045) and overall survivalOS (p P= 0.019) [17]. These

data support the use of a late second ASCT in patients with relapsed/progressive MM but, with

the aim of verifying the timing of the second ASCT, researchers of the European Group for

Blood and Marrow Transplantation reviewed the cases of 7,452 patients, of whom 2,655

underwent a planned ASCT2 and 4,797 an unplanned ASCT2 between 1993 and 2002. They

found that outcomes were better when the ASCT2 was performed before relapse (within 6−-12

months of ASCT1) [18].

Myeloablative or non-myeloablative allogeneic stem cell transplantation (allo-SCT) is

considered potentially curative for myeloma, but offers only a limited clinical benefit in the case

6

of relapsed/refractory MM [12].

<H2>Immunomodulatory drugs

(IMIDs)

<H3>Thalidomide

Thalidomide (α-N-phthalimido-glutarimide) is a synthetic derivative of glutamic acid that was

initially introduced in 1956 as a sedative hypnotic. An important part of its in vivo efficacy is

attributablilitye to its immunomodulatory properties as it potentiates the immune response by

restoring dendritic cell function and inhibiting T cell regulatory activity. This leads to the

activation of T lymphocytes and natural killer T (NKT) cells by increasing the production of

interleukin 2 (IL-2) and interferon gamma (IFN-γ) and activating natural killer (NK) cells.

IMIDs are characterizsed by their anti-tumoral activity, which disrupts the interactions between

neoplastic clones and the bone marrow micro-environment. Another important mechanism is

their anti-angiogenic activity [19, 20].

Thalidomide induces the apoptosis of neoplastic cells by down-regulating anti-apoptotic proteins

via the caspase 8-mediated pathway [19]. It has been reported that thalidomide alone induces

partial remission in 50% of newly diagnosed patients, and that its combination with oral

dexamethasone increases this to 60−-70% [19,20]. Thalidomide was the first novel agent

evaluated in patients with relapsed/refractory MM, and a number of studies have demonstrated

that, alone, it leads to response rates of 25−-35% [5,21]. Similarly, Mothy et al., found that

thalidomide salvage therapy is also feasible and beneficial in a significant proportion of patients

with progressive MM after allo-SCT [22]. Taken together, these studies show that thalidomide

monotherapy can induce at least a PR in 30% of patients with relapsed/refractory disease, with a

1-year OS rate of 60% and a median OS of 14 months.

The addition of dexamethasone leads to higher response rates than those obtained using

thalidomide alone, and the addition of cyclophosphamide to thalidomide and dexamethasone

leads to even higher response rates [23]. Thalidomide has also been combined with conventional

7

cytotoxic drugs (alkylating agents and anthracyclines), and other novel agents such as

bortezomib. Trials have shown that a combination of thalidomide and conventional

chemotherapy is clearly active, leading to overall response rates (ORR) of 60−-75%, with CR

rates of approximately 20% in a number of early pPhase I/II studies [24,25]. TABLEable 2II

summariszes the main clinical trials of thalidomide in MM patients refractory or relapsing after

different front-line therapies.

<H2>Lenalidomide

Lenalidomide (Revlimid®; Celgene, NJ, USA) is an oral immunomodulatory derivative of

thalidomide that has a different toxicity profile, different pleiotropic (immunomodulatory, anti-

angiogenic and anti-neoplastic) activity, and different anti-inflammatory effects. These properties

have led to the drug being investigated in other hematological malignancies, such as aggressive

non-Hodgkin lymphomas and myelodysplastic syndromes [26−-31]. Lenalidomide is the most

recent agent approved for relapsed/refractory myeloma in the USAnited States and Europe. The

approval was based on the results of two parallel trials (MM-009 and MM-010) in which

lenalidomide plus dexamethasone was compared with dexamethasone alone in patients with

progressive myeloma who had received 1−-3 previous regimens. The dose of lenalidomide was

25 mg on days 1− to 21 of a 28-day schedule, whereas pulsed dexamethasone was given on days

1−-4, 9−-12 and 17−-20 for the first four cycles, with the dose being reduced for subsequent

cycles [10,32]. The results of these two trials demonstrated that continuing treatment with

lenalidomide plus dexamethasone led to the best responses, the absence of disease progression

and toxicity, and provided deeper remissions and greater clinical advantages. All of the patients

in the thalidomide-exposed subgroup (including those who had relapsed on or had been

refractory to thalidomide) also significantly benefited from the combination of lenalidomide and

dexamethasone. Further trials confirmed the efficacy of lenalidomide in relapsed/refractory MM

(TABLEable 3III).

<H2>Pomalidomide

8

The third IMID is pomalidomide (CC4047), a new drug with a high degree of in vitro activity

that was developed to improve the clinical efficacy and reduce the toxicity of its parent molecule

thalidomide. Pomalidomide has a good toxicity profile, with neutropenia being its most frequent

adverse effect. Thromboembolic complications are as frequent as with the other IMIDs, whereas

other side effects such as neuropathy are rare [28]. In vitro studies have demonstrated that

pomalidomide is more effective than thalidomide in inhibiting the proliferation of malignant B

cells, and preclinical studies have shown that pomalidomide significantly increases the serum

levels of IL-2 receptors and IL-12, and may promote the switch to an effector T-cell phenotype.

In addition, some evidence suggests that pomalidomide may inhibit the destructive effects of

MM in the bone microenvironment by inhibiting osteoclast differentiation. [7]

As pomalidomide is the latest IMID undergoing development, it has so far only been

investigated in pPhase I and pPhase II trials involving heavily pre-treated patients. The results of

the Phase I trials show that the maximum tolerated dose (MTD) is 1−-5 mg/day, and that both

daily and alternate day dosing regimens lead to encouraging ORR overall response rates of 50%

[33−-35].

Two pPhase II trials have been carried out. The first enrolled 60 patients who had received 1−-3

previous treatments, and administered pomalidomide (2 mg/day continuously) and

dexamethasone. The ORR overall response rate of 60% included 33% VGPRs and CRs. The

median PFS was 11.6 months without any significant differences between the patients with high-

risk disease and those with standard-risk disease [36]. Interestingly, pomalidomide proved to be

active in a subgroup of patients who were refractory to lenalidomide, in whom the ORR overall

response rate was almost 50%. In the second pPhase II trial, 70 patients were randomizsed to

receive pomalidomide 2 mg/day or 4 mg/day in combination with dexamethasone. The results

showed a small advantage in the 2 mg arm, thus suggesting that responses are not dose related

[37].

<H1>Proteasome inhibitors

9

<H2>Bortezomib

Bortezomib (PS-341) was the prototype proteasome inhibitor. It has potent anti-myeloma activity

as a single agent (TABLEable 4IV) and in combination with other drugs (TABLE 5able V).

The ubiquitin proteasome system is a multi-catalytic proteinase complex that degrades a wide

variety of protein substrates in normal and transformed cells in order to maintain cell

homeostasis. Consequently proteasome inhibition affects a wide range of cell functions such as

cell cycle regulation and apoptosis. Cancer (and especially MM) cells seem to be highly

dependent on proteasome-homeostatic pathways. In addition to anti-MM activity, bortezomib

stabilises the nuclear factor kappa light chain-enhancer of activated B cells (NF kappa B) and

up-regulates anti-apoptotic factors in tubular cells.

The large randomizsed APEX (Assessment of Proteasome Inhibition for Extending Remissions)

trial demonstrated the superiority of bortezomib given intravenously on days 1, 4, 8 and 11 of a

21-day cycle over pulse dexamethasone in patients with relapsed/refractory myeloma, who had

received no more than three previous treatment regimens. The ORR overall response rate was

38%, and the median time to progression (TTP) was 6.2 months, as against only 18% and 3.5

months with dexamethasone at the time of the first analysis [38]. Bortezomib combinations have

been evaluated in a number of different settings and are being widely tested due to their minimal

marrow toxicity, ease of use in the case of renal failure, and absence of thrombogenicity. Various

studies have demonstrated the activity of bortezomib in patients with MM and renal

insufficiency [39, 40]. Bortezomib does not undergo renal clearance, and therefore allows prompt

therapy without the need for dose adjustments. Retrospective analyses of pPhase III trials have

shown that bortezomib can overcome the poor prognosis of patients with unfavourable

chromosomal abnormalities, such as the del(13q14) and t(4:14) mutations. There are also initial

data suggesting that bortezomib-based treatment may be effective in patients with the del(17p)

mutation, which is usually associated with refractoriness and a dismal prognosis [41−-43].

<H3>Carfilzomib

10

The second-generation proteasome inhibitor PR-171 (carfilzomib) is now available and has

different functional capacities, such as the irreversible inhibition of the chymotryptic activity of

the proteasome, the same site as that of bortezomib-induced inhibition. Clinical studies

(TABLEable 6VI) have shown that carfilzomib has long-lasting anti-cancer activity in patients

with relapsed/refractory MM, including those previously treated with bortezomib. Ongoing

Phase II trials evaluating the efficacy of carfilzomib have shown an ORR overall response rate of

23.7% with a median duration of response of 7.8 months, and a median overall survivalOS of

15.6 months. Adverse events have been manageable without giving rise to cumulative toxicities.

The lasting responses of this heavily pre-treated population and the drug‟s acceptable tolerability

profile demonstrate the potential of carfilzomib to offer a significant clinical benefit [44].

In an open-label,. single-arm, multicentere pilot pPhase II study of carfilzomib involving 46

patients with relapsed and refractory MM after ≥2 previous therapies, the best ORR overall

response rate was 16.7%, with a median duration of response of 7.2 months [45]. In 2012, the US

FDAood and Drug Administration approved carfilzomib for the treatment of patients with MM who

have received at least 2 prior therapies, including bortezomib and IMIDs, and have demonstrated

disease progression on or within 60 days of the completion of the last therapy.

Other proteasome inhibitors are being developed with different spectrums of activity (e.g., pan-

proteasome inhibition with NPI-0052) and with oral formulation.

<H3>IMIDs combined with bortezomib

Recent discoveries concerning the fundamental molecular mechanisms underlying MM cell

growth and survival have led to the introduction of new combinations of an IMID and

bortezomib. Both have significant activity against MM when used as single agents, and so the

challenge is to demonstrate whether their combination increases their activity. The rationale for

combining an IMID and bortezomib is their complementary mechanisms of action, which would

theoretically reduce the risk of the emergence of resistant clones. However, as cumulative

toxicity is a concern, various groups are evaluating the impact of other bortezomib-based

combination therapies, including the association with thalidomide and dexamethasone (BTD). In

11

one study [46], Wang et al., administered 38 patients with newly diagnosed myeloma

dexamethasone 20 mg/m2/day on days 1−-4, 9−-12, 17−-20; bortezomib 1.3 mg/m2 on days 1, 4,

8 and 11, associated with thalidomide 100 mg daily, which was increased to 200 mg after one

week if tolerated. The therapy was repeated every four 4 weeks for a maximum of three cycles.

Although the study population was small, some of the results were remarkable [46]. Eleven

patients could proceed to ASCT after only one cycle because the regimen induced rapid and

significant tumour cytoreduction, and an objective response was observed in 87%, with a low

incidence of neuropathy. This regimen may also be attractive in patients with acute renal failure

due to myeloma kidney, when a rapid reduction in monoclonal protein production is important in

order to restore renal function [47].

The combination of bortezomib (Velecade), thalidomide and dexamethasone (VTD) was

compared with that of TD in a prospective multicenter pPhase III study of patients with MM

progressing or relapsing after ASCT [47]. In this study, 269 patients were randomly assigned to

receive bortezomib (1.3 mg/m2 intravenous bolus) or no bortezomib for 1 year, in combination

with thalidomide (200 mg/ per day orally) and dexamethasone (40 mg orally once a day on 4

days once every 3 weeks). Bortezomib was administered on days 1, 4, 8, and 11 with a 10-day

rest period (day 12 to day 21) for eight cycles (6 months), and then on days 1, 8, 15, and 22 with

a 20-day rest period (day 23 to day 42) for four cycles (6 months). They found that VTD was

more effective than TD in the treatment of patients with MM with progressive or relapsing

disease post-ASCT (the median time to progressionTTP was 19.5 months for VTD and 13.8 for

TD) but was associated with a higher incidence of grade 3 neurotoxicity (29% for VTD and 12%

for TD).

Morabito et al., assessed efficacy, safety, and the reversal of renal impairment (RI) in previously

untreated MM patients who received a combination of bortezomib, melphalan, prednisone and

thalidomide followed by maintenance treatment with bortezomib an thalidomide (VMPT-VT) or

bortezomib, melphalan and prednisone (VMP). There were statistically significant improvements

12

in ORR overall response rates and progression-free survival in the VMPT-VT arms across the

renal cohorts, except in the group of patients with severe RI. In the VMPT group, severe RI

reduced OS. RI was reversed in 16/63 patients receiving VMPT-VT (25.4%) and 31/77 receiving

VMP (40.3%). VMPT-VT was superior to VMP in the patients with normal renal function or

moderate RI, but failed to outperform VMP in patients with severe renal insufficiency. Although

the relatively small number of cases precludes any definite conclusions, it seems that VMPT-VT

had no advantage over VMP in terms of renal insufficiency reversal [48]. TABLEable 5V shows

the trials of bortezomib combined with novel agents for the treatment of relapsed refractory MM

<H2>Histone deacetylase inhibitors

Histone deacetylase (HDAC) inhibitors represent a new class of anti-myeloma agents that

includes panobinostat (LBH589) and vorinostat. Inhibiting HDAC leads to histone

hyperacetylation and structural alterations in chromatin which cause growth arrest differentiation

and/or apoptosis in a number of tumour cells. Microarray-based studies have shown that HDAC

inhibitors induce transcriptional modulations in 7−-10% of the genes in malignant cell lines by

acetylating histone and non-histone proteins, and HDAC inhibitor-induced cell death is one of

the main mechanisms of inhibiting the survival of myeloma cells. Extrinsic and intrinsic

apoptotic pathways, as well as non-apoptotic cell death such as autophagy, have been reported in

myeloma cells treated with an HDAC inhibitor. The intrinsic apoptotic pathway is mediated by

the mitochondria, and the pro-apoptotic signals result in the release of mitochondrial inter-

membrane proteins such as cytochrome c (cyto-c), apoptosis-inducing factors (AIF) and the

second mitochondria-derived activator of caspase (Smac). HDAC inhibitors induce cell cycle

arrest in the G1/S phase. The events in the G1 phase are coordinated by the three early G1 D

cyclins (1, 2 and 3) and their associated cyclin-dependent kinases (CDKs) 4/6 (G1 progression)

and CDK 2 (G1/S transition).

A number of clinical trials of HDAC inhibitors alone or in combination with other anti-myeloma

agents are ongoing. Phase I trials have shown that HDAC inhibitors are well tolerated by

13

myeloma patients, but pPhase II trials have found that the activity of HDAC inhibitors as single

agents is limited. However, when combined with dexamethasone and/or bortezomib, the results

are more promising, even in patients with refractory and/or relapsed MM [49]. Panobinostat

(LBH589) and vorinostat have shown promise as adjuncts to current treatment options, and

panobinostat is currently being tested in a large, randomizsed pPhase III trial. Panobinostat and

vorinostat are the oral HDAC inhibitors that are farthest along the clinical development pathway

[6].

<H2>Immune-based therapies

Monoclonal antibody therapy for MM patients has entered clinical testing. Elotuzumab is a

humanized monoclonal IgG1 antibody directed against a cell surface glycoprotein named CS-1,

which is highly and uniformly expressed in MM. Elotuzumab induces significant antibody-

dependent cytotoxicity against primary MM cells in the presence of peripheral lymphocytes and,

in combination with lenalidomide and low-dose dexamethasone has led to promising results.

Two other agents in the same class have also showed promise: lorvotuzumab (anti-CD56) in

combination with lenalidomide and dexamethasone, and mapatumumab (anti-Trail-R1) in

combination with bortezomib [50].

<H2>Alkylators

Bendamustine is an agent that is structurally similar to alkylating agents and purine analogues,

and it has been found to be active in MM patients. Lentzsch et al. have recently published the

final results of a pPhase I/II study of bendamustine combined with lenalidomide and

dexamethasone in patients with refractory or relapsed MM, and the combination of

bendamustine, bortezomib and dexamethasone has anti-myeloma activity with relatively little

toxicity in previously treated MM patients. [51,52].

<H2>Toxicity of the new anti-myeloma agents

The frequency and severity of IMID side -effects are dose related and time dependent, and

should be graded using the National Cancer Institute Common Toxicity Criteria for Adverse

14

Events. Venous thromboembolism (VTE) and occasional thrombotic events have been reported

in patients treated with thalidomide, especially when thalidomide and pulsed dexamethasone

(TD) are combined [53]. The thrombogenic effects seem to be due to a transient reduction in

soluble thrombomodulin levels during the first month of therapy and the restoration of

endothelial cell PAR-1 expression after damage by cytotoxic agents such as doxorubicin.

Furthermore, thalidomide leads to the phosphatylserine-induced activation of pro-coagulant

tissue factor (TF) on the apoptotic cell membrane, thus increasing the thrombogenic risk [54−-

56].

Lenalidomide and pomalidomide are structurally related to thalidomide, but relatively more

potent and have a different toxicity profile. The sedation, constipation and neuropathy associated

with thalidomide are not commonly seen, but the risk of developing thromboembolic events

seems to be similar to that attributed to thalidomide combinations. There are data suggesting that

the combination of lenalidomide and dexamethasone increases the risk of thromboembolic

complications [56]. Myelosuppression (grade 3−-4 neutropenia and thrombocytopenia), the

dose-limiting side effect in Phase I studies of lenalidomide, is the most frequent adverse event,

but can be effectively managed by means of dose reductions or discontinuations, although

granulocyte colony- stimulating factor (G-CSF) or erythropoietin may be needed in more severe

cases [57].

Although some concerns have been raised regarding the incidence of second primary

malignancies (SPMs) among patients treated with lenalidomide, including two cases of

myelodisplastic syndrome, Adès et al. [58] found no significant differences from a historical

series. Similarly, Palumbo et al. [59] have recently stated that the PFS benefit obtained using

lenalidomide maintenance treatment outweighs the increased risk of SPM; moreover, in patients

with relapsing/refractory MM, the number and types of SPM do not seem to affect the drug‟s

risk/benefit profile.

15

The toxicity of bortezomib has been well characterised, and includes nausea, diarrhea, cyclic

reversible thrombocytopenia, fatigue, and peripheral neuropathy. The last occurs in about one-

third of patients and may have a painful component, and requires dose modification or

discontinuation; the neuropathy improves or resolves in a high proportion of patients, although

recovery often takes several months. An increased incidence of herpes zoster reactivation has

been reported, and so acyclovir prophylaxis is recommended for all patients receiving

bortezomib [60].

Clinical trial data show that histone deacetylaseHDAC inhibitors are generally well tolerated, but

there have been reports of cardiac, metabolic and hematological toxicities, consisting of

reversible QT prolongation, pericardial effusion, hypokalemia and thrombocytopenia [62,63].

<H2>Supportive care

Patients with MM not only require treatment for the disease itself, but also a wide range of

supportive and palliative measures to optimizse their quality of life at all stages of the disease.

Considerable progress has been made in terms of supportive care for patients with MM and this

can benefit them when integrated with conventional medical treatment.

Approximately 85% develop bone disease due to osteopenia, osteolytic lesions and related

complications, which reduces their performance status and quality of life [63]. The first step in

the treatment of bone pain should be to consider a non-opioid analgesic such as acetaminophene;

non steroidal anti-inflammatory drugs should be avoided because of their potential

nephrotoxicity, and opioids should only be considered when patients fail to respond to first-step

therapy. Local radiotherapy can also relieve the pain of skeletal disease and may palliate soft

tissue disease. Mill and Griffith [64] treated 128 patients using a wide dose range, and observed

pain relief in 91% at a median dose of 10−-15 Gy divided into 2−-3 Gy fractions. Only 6% of the

sites required re-treatment, and this was unrelated to the initial dose.

A number of clinical trials have shown that bisphosphonates can help in the management of bone

pain in MM patients by reducing the incidence of new bone lesions and pathological fractures

16

[65,66]. It has also been shown that zoledronic acid extends median OS by 5.5 months and PFS

by two months [66]. It is generally accepted that biphosphonate therapy should be offered to

MM patients with symptomatic bone disease for no more than two years in order to limit the

development of jaw osteonecrosis, but it is possible to keep offering them further forms of

treatment aimed at reducing bone marrow plasma cell activity and the consequent expression of

symptoms.

Even when a patient is approaching the terminal stage of the disease and specific anti-cancer

treatments have been withdrawn, blood and platelet transfusions can help maintain the quality of

life by relieving exertional dyspnea and preventing bleeding. In patients with renal insufficiency,

the deterioration of renal function and tumour lysis syndrome can be prevented by appropriate

hydration, urine alkalinizsation, and the treatment of hypercalcemia, hyperuricemia, and

infections. In some patients, managing symptomatic hyperviscosity by means of regular plasma

exchanges may be reasonable.

<H1>Therapeutic strategies

Although substantial progress has been made, MM remains incurable in most cases due to

multiple relapses. The clinical picture of relapsed MM ranges from an asymptomatic form that

can only be identified by means of laboratory tests to very aggressive disease. Relapsing patients

with MM should be treated at the appearance of the typical clinical manifestations of MM which

are summarized by the CRAB symptoms (elevated Ccalcium, Rrenal impairment, Aanemia, and

Bbone lesions), or when monoclonal protein in serum or urine has a significant growth (M spike

>1 g/dlL, Bence Jones protein >500 mg/day, or serum free light chain >200 mg/dlL).

There are still no standard therapies for relapsed MM, and treatment remains a challenge

especially in the case of patients who already received several lines of therapy. The first

remission is likely to be the period during which patients enjoy the best quality of life, and so the

goal should be that of achieving the longest remission possible by using the most effective drugs.

The most effective strategy for almost all patients, regardless of whether or not they are eligible

17

for stem cell transplantation, is to use the new agents. Patients with indolent relapse can be

treated first with two-drug or three-drug combinations, Patients with more aggressive relapse

often require therapy with a combination of active agents, for example,e.g., VCD, VTD, VRd, or

VDT-PACE or ASCT .

The message coming from the trials reviewed in this article, although the population of patients

may be heterogeneous due to the differences in prior treatments over the years, is that these

drugs (i.e., IMIDs and proteasome inhibitors) can be used to treat relapsed/refractory disease

with encouraging results and that the crucial factor is their sequencing. In patients who have

relapsed and are refractory to a particular drug, a change in drug class of agent is indicated

because they are likely to have become resistant. Various disease- and patient-related factors

should be considered when selecting a treatment option.

The disease-related factors include the quality and duration of response to previous therapies

administered for purposes of induction or because of a previous relapse, and the aggressiveness

of the relapse. Deep and prolonged responses are more likely in patients with a late relapse (after

a remission of >12 months) than in those relapsing early (a remission of <6 months). The

duration of first remission and the timing of relapse are key points in the treatment strategy. If

the relapse occurs after a long remission and treatment-free period, it is possible to consider

repeating the same treatment [67] but, if it occurs earlier (6−-12 months) or while the patient is

still undergoing treatment (which indicates aggressive, relapsed and refractory disease), the use

of an alternative regimen should be considered. In addition, the presence of clinical risk factors

such as cytogenetic abnormalities may indicate high-risk disease, which requires a different

approach from that used in „slowly‟ relapsing patients.

The patient-related factors include pre-existing toxicities, comorbidities, the quality of life, age

and performance status. Nearly 50% of MM patients develop some degree of renal impairment

during the course of their disease and, as many therapeutic agents are renally excreted, this may

affect drug pharmacokinetics and limit the choice. Among the new drugs, bortezomib and

18

thalidomide are not excreted renally, which makes them better for patients with renal impairment

than lenalidomide, which is renally excreted and therefore requires dose adjustments. A number

of trials have shown the beneficial effects of bortezomib in patients with MM and renal

insufficiency [39,40], thus making its use (alone or in combination with dexamethasone) the

drug of choice in such patients as it rapidly reduces light chain production and provides an

opportunity for renal recovery. On the contrary, as neither lenalidomide nor thalidomide are

metabolizsed by the liver, they are more suitable for patients with impaired liver function than

bortezomib.

The use of thalidomide and bortezomib can lead to neuropathy in up to 80% of previously

treated patients, whereas neuropathy is less frequent in patients treated with lenalidomide-based

regimens, thus making them a reasonable choice in patients with pre-existing neuropathies.

Diabetes is a frequent comorbidity, particularly among the elderly, and may be exacerbated by

the frequent use of corticosteroids to treat of MM; in this case, the corticosteroid-sparing

combination of bortezomib and pegylated liposomal doxorubicin (PLD) may well be suitable.

Bortezomib alone has not been associated with any increase in VTE, and is therefore a good

choice for patients with a history of thromboembolic events which, although it does not per se

exclude treatment with thalidomide or lenalidomide, requires appropriate anti-thrombotic

prophylaxis. It is generally accepted that acetylsalicylic acid (ASA) is suitable for

thromboprophylaxis in patients without a previous history of thrombotic events and with no

thrombotic risk factors, whereas anti-coagulant prophylaxis is mandatory for those who have

previously experienced a thromboembolic event or who are at high thrombotic risk [68]. The

thromboprophylaxis should be performed almost for three months with low molecular weight

heparin before switching to asprin, in fact thromoembolic events are more likely in the first three

3 months of IMIDs treatment.

One-third of MM patients are 75- years- old or older at diagnosis, which raises more concerns

about treatment tolerability and toxicity than in the case of younger patients. Although age

19

should not be considered an exclusion criterion, only a few clinical trials have investigated the

safety and efficacy of drugs in old and/or frail patients. Modified treatment regimens and dose

reductions should be used to improve tolerability. New protocols for elderly patients that also

include a global geriatric evaluation should be encouraged in order to guide clinicians in

everyday clinical practice.

In the case of transplant-eligible patients, it is feasible to consider „retransplantation‟ at the time

of relapse if an adequate stem cell graft is available. In order to be eligible for a second salvage

ASCT at the time of relapse, patients need to have enjoyed a reasonable response duration

following the first ASCT. As a relapse occurring within 12−-18 months of a first ASCT is

associated with a poor outcome, alternative treatments should be considered, preferably

incorporating novel approaches. In the case of a disease relapse that is refractory to treatment

with IMIDs and proteasome inhibitors, eligible patents should be enrolled in clinical trials of

experimental agents, and those who do not qualify for inclusion in a trial should receive

treatment aimed at alleviating their symptoms and maintaining their quality of life while

stabilizsing the disease as much as possible. Palliative treatment can include alkylating agents in

combination with corticosteroids (i.e., oral cyclophosphamide and prednisone), or cisplatin-

containing regimens such as continuous infusions of dexamethasone, cyclophosphamide,

etoposide and cisplatin [67].

<H1>Expert commentary

Emerging evidence indicates that, in addition to the pharmacological characteristics of anti-

myeloma drugs, disease- and patient-related factors should be considered when selecting a

treatment option for relapsed/refractory MM. However, optimal treatment and its duration has

still not been fully defined. On the basis of the natural history of the disease, the duration of

responses is relatively long early in the disease course and becomes progressively shorter with

each relapse.

20

Novel agents targeting the tumour and its microenvironment such as thalidomide, lenalidomide

and bortezomib have improved outcomes and extended survival in patients with relapsed and/or

refractory MM. Outcomes are significantly better when they are used at the time of a first relapse

rather than as salvage treatment after two or more previous therapies. Combination therapy using

agents with different mechanisms of action is becoming an attractive means of increasing

efficacy and/or overcoming resistance to standard treatment regimens.

When treating indolent or slow relapse, the treatment options may be different. Lenalidomide

based salvage therapy is preferred if the patient has been previously exposed to bortezomib

therapy, has a history of polyneuropathy or has cytogenetic standard risk. Bortezomib based

salvage therapy is used if the patient has been exposed to IMIDs, has renal failure or unfavorable

chromosomal abnormalities. Thalidomide based salvage therapies are indicated in presence of a

previous treatment with bortezomib or lenalidomide, when the patient has never been treated

with IMIDs or when the patient is cytopenic. Stem- cell transplantation may be considered if

deferred in first line therapy. Aggressive and rapid relapse requires an immediate treatment,

which is likely a combination therapy including treatment with chemotherapy based regimens,

chemotherapy in combination with novel agents (lenalidomide or bortezomib) or transplant

based regimen.

Other new agents are in clinical development. Pomalidomide has led to encouraging results in

heavily pre-treated patients. The oral histone deacetylaseHDAC inhibitors panobinostat and

vorinostat can synergistically enhance the cytotoxic activity of lenalidomide and bortezomib, and

overcome possible resistance. The second-generation proteasome inhibitor carfilzomib can be

used as monotherapy and in combination with lenalidomide plus low-dose dexamethasone.

Consolidation and maintenance strategies are being evaluated in order to verify whether they

guarantee longer survival without evidence of disease.

<H1>Five-year view

One important future research goal is to use molecular studies to guide therapeutic strategies at

21

the time of diagnosis and at the time of relapse. MM is a clonal disease, and a number of sub-

clones have been described. Myeloma therapies profoundly change the bone marrow

microenvironment, and this creates new selective pressures on different sub-clones. Recent

results suggest that the patterns of clonal evolution are different. In patients treated with

conventional chemotherapy and those treated with new drugs, such as the proteasome pathways,

the technical means of detecting and defining tumour sub-clones may become clinically relevant.

It could be proposed that therapeutic options should be chosen on the basis of the results of serial

clonal evaluations comparing the disease genome at the time of diagnosis and at relapse [69,70].

Clinical studies of monoclonal antibody therapy in combination with lenalidomide or bortezomib

have led to promising early results [50]. Ongoing and future research is and will be aimed at

using oncogenomics to develop personalizsed therapies, next-generation agents targeting tumour

cells and their microenvironment, and rationally based combinations of targeted therapies. These

approaches will lead to a more tailored therapeutic strategy for MM patients.

<H1>Key POINTS issues

Multiple myeloma (MM) is a clonal disorder of plasma cells that still cannot be cured

using conventional treatments because of frequent relapses.

The introduction of thalidomide, lenalidomide, and bortezomib has changed the treatment

paradigm for patients with relapsed/refractory disease by improving clinical outcomes in

comparison with conventional chemotherapy alone.

Relapsing patients with multiple myeloma should be treated at the appearance of the

typical clinical manifestations of MM which are summarized by the CRAB symptoms

(elevated Ccalcium, Renal impairment, Aanemia, and Bbone lesions), or when

monoclonal protein in serum or urine has a significant growth.

Treatments for patients with relapsed/refractory MM include hematopoietic cell

transplantation, a rechallenge using a previous chemotherapy regimen, or a trial of a new

regimen.

22

At the time of a relapse, the challenge is to select the optimal treatment for each patient

while balancing efficacy and toxicity. The decision will depend on disease- and patient-

related factors, as well as the pharmacological characteristics of the anti-myeloma agents.

Patients with indolent relapse can be treated first with two-drug or three-drug

combinations. Patients with more aggressive relapse often require therapy with a

combination of multiple active agents, consider ASCT as salvage therapy at first relapse

for patients who have cryopreserved stem cells early in the disease course.

Outcomes are significantly better when novel agents are used at first relapse, rather than

as salvage treatment after two or more previous therapies

Combined therapy can be used to prevent or overcome treatment resistance, and increase

the efficacy of standard treatment regimens.

<H1>Financial and & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity

with a financial interest in or financial conflict with the subject matter or materials discussed in

the manuscript. This includes employment, consultancies, honoraria, stock ownership or options,

expert

testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

23

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http://www.ncbi.nlm.nih.gov/pubmed?term=Lokhorst%20HM%5BAuthor%5D&cauthor=true&cauthor_uid=2644970

http://www.ncbi.nlm.nih.gov/pubmed?term=Meuwissen%20OJ%5BAuthor%5D&cauthor=true&cauthor_uid=2644970

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http://www.ncbi.nlm.nih.gov/pubmed?term=Avvisati%20G%5BAuthor%5D&cauthor=true&cauthor_uid=2924885

http://www.ncbi.nlm.nih.gov/pubmed?term=Tribalto%20M%5BAuthor%5D&cauthor=true&cauthor_uid=2924885


http://www.ncbi.nlm.nih.gov/pubmed?term=Delain%20M%5BAuthor%5D&cauthor=true&cauthor_uid=7989948

http://www.ncbi.nlm.nih.gov/pubmed?term=Linassier%20C%5BAuthor%5D&cauthor=true&cauthor_uid=7989948

http://www.ncbi.nlm.nih.gov/pubmed?term=Petitdidier%20C%5BAuthor%5D&cauthor=true&cauthor_uid=7989948


http://www.ncbi.nlm.nih.gov/pubmed?term=Foss%C3%A5%20A%5BAuthor%5D&cauthor=true&cauthor_uid=9529138

http://www.ncbi.nlm.nih.gov/pubmed?term=Muer%20M%5BAuthor%5D&cauthor=true&cauthor_uid=9529138

http://www.ncbi.nlm.nih.gov/pubmed?term=Kasper%20C%5BAuthor%5D&cauthor=true&cauthor_uid=9529138



http://www.ncbi.nlm.nih.gov/pubmed?term=Boots%20M%5BAuthor%5D&cauthor=true&cauthor_uid=10886206



http://www.ncbi.nlm.nih.gov/pubmed?term=Kneller%20A%5BAuthor%5D&cauthor=true&cauthor_uid=10691870

http://www.ncbi.nlm.nih.gov/pubmed?term=Raanani%20P%5BAuthor%5D&cauthor=true&cauthor_uid=10691870

http://www.ncbi.nlm.nih.gov/pubmed?term=Hardan%20I%5BAuthor%5D&cauthor=true&cauthor_uid=10691870


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30

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96.94. Vij R, Siegel DS, Jagannath S, et al. An open-label, single-arm, phase 2 study of

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http://www.ncbi.nlm.nih.gov/pubmed?term=Berenson%20J%5BAuthor%5D&cauthor=true&cauthor_uid=12826635






http://www.ncbi.nlm.nih.gov/pubmed?term=Bringhen%20S%5BAuthor%5D&cauthor=true&cauthor_uid=18326520


31

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(2012).

97. Jagannath S, Vij R, Stewart AK, Trudel S et al. An open-label single-arm pilot phase II

study (PX-171-003-A0) of low-dose, single-agent carfilzomib in patients with relapsed

and refractory multiple myeloma Clin Lymphoma Myeloma Leuk.;12(5):310–8 (2012).

Table 1I:. Conventional chemotherapeutic regimens for relapsing/refractory multiple

myeloma.

Chemotherapy ORR (%) Median survival

(months)

Median duration of

response (months)

Ref.

M2 PROTOCOL (vincristine,

cyclophosphamide, carmustine, melphalan and

steroids) [71]

47% NA 7

[71]

VAMP (continuous infusions of vincristine, adriamycin,

high-dose methylprednisolone) [72]

36% 20 11

[72]

VAD (continuous infusions of vincristine, adriamycin, pulsed

high-dose dexamethasone)

[73]

60% 12 9

[73]

Intermediate-dose (25 mg/m2) melphalan [74]

35% 8 16 [74]

VAD-PECC (alternating vincristine, doxorubicin and dexamethasone/prednisone, vindesine, carmustine, and cyclophosphamide) [75]

54% 18 NA

[75]

VECD (vincristine, epirubicin, cyclophosphamide and oral

dexamethasone) [76]

44% 13 NA

[76]

CIDEX (lomustine, idarubicin and dexamethasone) [77]

49% NA NA [77]

ORR: oOverall response rate; NA: nNot available. Table 2II. Thalidomide-based clinical trials.

32

AuthorsStud

y (year)

No. of

ptsPatient

s (n).

Regimen Dose/day Response (%)

Mean duration of

response/survival

rates

Singhal S et al. (1999) [78]

84 T T: 200−-800 mg/day R: 32% CR: 2%

EFS: 22 ± 5% OS: 58 ± 5%

Kneller A et al. (2000) [79]

17 T T: 200−-800 mg/day

R: 64% VGPR: 29%

PR: 29% MR: 6%

NR

Lee CK et al. (2003) [80]

229 DTPACE

D: 40 mg p.o. daily x 4 days; T: 400 mg p.o. at night, days

1−-28; Cis: 10 mg/m2/day x 4 days,

CIV; Dox: 10 mg/m2/day x 4 days,

CIV; C: 400 mg/m2/day x 4 days,

CIV; E: 40 mg/m2/day x 4 days,

CIV;

CR: 7% nCR: 9% PR: 16%

NR

Anagno-stopoulos A et al. (2003) [81]

47 TD

T: 200−-600 mg p.o. at night, days 1−-28;

D: 20 mg/m2 p.o., days 1−-5 and repeated every 15 days

R: 47% CR: 13%

Median OS: 38 months

Garcia-Sanz R et al. (2004)

[24] 71 CTD

T: 200-−800 mg p.o. at night, days 1−-28;

C: 50 mg/day p.o., days 1−-28; D: 40 mg/day p.o., days 1−-4

every three 3 weeks

CR: 2% PR: 55%

PFS: 57% OS: 66%

≥

33

Kyriakou C et al. (2005) [82]

52 CTD

C: 300 mg/m2 p.o. once weekly;

D: 40 mg/day p.o., days 1−-4 once monthly;

T: 50−-300 mg/day p.o. at individually escalated doses

based on mg/day p.o. on days 1−-28

CR: 17% PR: 61.5% MR: 11.5%

PFS: 34% OS: 73%

Hovenga S et al. (2005) [83]

38 CT T: 100−-400 mg/day p.o.; C: 100−-150 mg/day p.o.

.

PR: 53% CR: 11%

Median PFS: 20 months

Median OS: months 30

Palumbo A et al. (2006) [84]

24 MPT

M: 20 mg/m2, day 1 every 4th month;

T: 50−-100 mg/day, days 1−-28;

Pp: 50 mg/day p.o. every other day

nCR: 12.5% PR: 29% MR: 17%


C: cCyclophosphamide; CR: Complete response; CIV: Continuous intravenous infusion; D: dexamethasoneDexamethasone; EFS: Event-free survival; M: Mmelphalan; MR: Minimal response; nCR: Near-complete response; OS: Overall survival; P: Pprednisone; PFS: Progression-free survival; PR: Partial response. CR: complete response; nCR: near-complete response; PR: partial response; MR: minimal

response; EFS: event-free survival; OS: overall survival; PFS: progression-free survival.

CIV: continuous intravenous infusion

Table 3III. Lenalidomide-based clinical trials.

Authors

ReferenceStudy

(year)

No. of

pts.Patient

s (n)

Regimen

Previous

treatment

(%)

Dosage/day Response

(%)

Mean duration

response/survival

rate

MM-009; Weber DM et al. (2007) [85]

177 LD Thal 41.8%; Bort 10.7%; stem-cell transplantation 61.6%

L: 25 mg/day, days 1−-21 of a 28−-day cycle D: 40 mg/day, days 1−-4, 9−-12, 17−-20 for the first 4 four cycles, thereafter 40 mg/day, days 1−-4

CR: 14.1% nCR: 10.2% PR: 36.7%

Median TTP:months Median OS:months

34

MM-010; Dimo-poulos M et al. (2007) [86]

176 LD Thal 30%; Bort 4.5%; stem-cell transplantation 55 %

L: 25 mg/day, days 1−-21 of a28-day cycle; D: 40 mg/day, days 1−-4, 9−-12, 17−-20 for the first 4 four cycles, thereafter 40 mg/day, days 1−-4

CR: 15.9% nCR: 8.5% PR: 35.8%

Median TTP:months Median OS:reached

Knop S et al. (2009) [87]

69 RAD Thal 20% Bort 57% Len 0%

DL1: Len 10 mg/day, days 1−-21; ADR 4 mg/m2, day 1; Dex 40 mg, days 1−-4 and 17−-20. DL2: Len 10 mg/day, days 1−-21; ADR 6 mg/m2, day 1; Dex 40 Mmg/day, days 1−-4 and 17−-20. DL3: Len 10 mg/day, days 1−-21; ADR 9 mg/m2, day 1; Dex 40 mMg/day, days 1−-4 and 17−-20. DL4: Len 15 mg/day, days 1−-21; ADR 9 mg/m2, day 1; Dex 40 Mmg/day, days 1−-4 and 17−-20. DL5: Len 25 mg/day, days 1−-21; ADR 9 mg/m2, day 1; Dex 40 Mmg/day, days 1−-4 and 17−-20 + G-CSF .[(Knop, Blood 2009)].

ORR: 73% CR: 15% VGPR: 45%

Median TTP:months

35

Schey S 2010 [88]

31 RCD Thal 90% Bort 26% Len 0%

RCD1: Cyc 300 mg/day, days 1−-8 of a 28 cycle; lenalidomide 25 mg/day, days 1−-21; dexamethasone 20 mg/day, days 1−-4, 8−-11. RCD2: Cyc 400 mg/day, days 1−-8 of a 28 cycle; lenalidomide 25 mg/day, days 1−-21; dexamethasone 20 mg/day, days 1-4, 8−-11. RCD3: Cyc 500 mg/day, days 1−-8 of a 28 cycle; lenalidomide 25 mg/day, days 1−-21; dexamethasone 20 mg/day, days 1−-4, 8−-11. RCD4: Cyc 600 mg/day, days 1−-8 of a 28 cycle; lenalidomide 25 mg/day, days 1−-21; dexamethasone 20 mg/day, days 1−-4, 8−-11 RCD5: Cyc 700 mg/day, days 1−-8 of a 28 cycle; lenalidomide 25 mg/day, days 1−-21; dexamethasone 20 mg/day, days 1−-4, 8−-11

CR: 29% VGPR: 7% PR: 45% ORR:. 81%

2-year PFS: 56%30-month OS:80%

−

−

Lentzsch et al. [50]

25 BLD Thal 48% Bort NA Len 79%

Len 10 mg day on days 1−-21; Bendamustine 75 mg/m2, days 1 and 2; Dex 40 mg/day, days 1, 8, 15, 22

VGPR: 24% PR: 52%

PFS: 6.1 mont

A: Adriamycin; ASCT: aAutologous stem cell transplantation; C: cCyclophophamide; D: Ddexamethasone; L: lLenalidomide. VGPR: vVery good partial remission; TTP: tTime to progression. Table 4IV. Bortezomib-based clinical trials (single agent).

AuthorsStud

y (year)

No. of

pts.Patient

s (n)

Regimen Previous

treatment Dose/day

Response

(%)

Me

of

36

AuthorsStud

y (year)

No. of

pts.Patient

s (n)

Regimen Previous

treatment Dose/day

Response

(%)

Me

of

Richardson et al.. (SUMMIT study, 2003)

[89]

202 Bortezomib-

dexamethasone

Corticosteroids; alkylating

agents, anthracyclines

stem-cell transplant

B: 1.3 mg/m2, days 1, 4, 8, 11 of a 21-day cycle;

D: 20 mg/day, days 1, 2, 4, 5, 8, 9, 11, 12

ORR: 27% CR/nCR:

10%

Jagannath et al. (CREST study, 2008)

[90]

54 Bortezomib +

dexamethasone




B: 1 mg/m2, days 1, 4, 8, 11 of a 21-day cycle;

B: 1.3 mg/m2, days 1, 4, 8, 11 of a 21-day cycle;

D: 20 mg/day, days 1, 2, 4, 5, 8, 9, 11, 12

ORR: 30% ORR: 38%

DO

OS:

TTP:

Richardson et al. (APEX

study, 2007) [38]

333 336

Bortezomib single agent

vs dexamethasone




B: 1.3 mg/m2, days 1, 4, 8, 11 of cycles 1−-8 (21-day

cycles), and on days 1, 8, 15, 22 of cycles 9−-11 (35-day

cycles); D: 40 mg/day, days 1−-4, 9−-12, 17−-20 of

cycles 1−-4 (35-day cycles), and on days 1−-4 of cycles

5−-9 (28-day cycles)

ORR: 43 % CR/nCR: 15

% ORR: 18%

CR/nCR: 2%

DOTTP:OS:DOTTP:OS:

B: Bbortezomib; CR: Complete response; D: Ddexamethasone; DOR: Duration of response; nCR: Near-complete response; ORR: Ooverall response rate; OS: Overall survival; PN: Peripheral neuropath; TTP: Time to progression. CR: complete response; nCR: near-complete response; DOR: duration of response; TTP: time

to progression; OS: overall survival; PN peripheral neuropathy; Table 5V. Bortezomib-based clinical trials (combinations).

Authors

Study

(year)

No. of

pts.Patie

nts (n)

Regimen Previous treatment Dose/day Response

(%)

Mean duration of

response/survival

rates

Berenson et

al.(2006) [91]

35 B M

Glucocorticoids; melphalan-based regimen; thalidomide; lenalidomide;

VAD; bortezomib; autologous stem-cell transplantationASCT

B: 1 mg/m2, days 1, 4, 8, 11 of a 28-day

cycle; M: 0.10 mg/kg p.o.,

days 1−-4

ORR: 47% CR: 6%


37

Authors

Study

(year)

No. of

pts.Patie

nts (n)

Regimen Previous treatment Dose/day Response

(%)

Mean duration of

response/survival

rates

Orlowski et al.

(2007) [92]

324 322

B-PLD B

Corticosteroids; alkylating agents;

thalidomide/lenalidomide; anthracycline; stem-cell

transplantation

B: 1.3 mg/m2, days 1, 4, 8, 11 of a 21-

day cycle; PLD: 30 mg/m2,

day 4 B: 1.3 mg/m2, days 1, 4, 8, 11 of a21-day cycle

ORR: 44% CR: 4%

ORR: 41% CR: 2%

Median TTP: 9.3 months

15-months OS: 76%

Median TTP: 6.5 months

15-month OS: 65%

Kropff et al.

(2007) [93]

54 B C D NR

B: 1.3 mg/m2, days 1, 4, 8, 11 of a 21-day cycle for the

first 8 cycles, followed by 1.3

mg/m2, days 1, 8, 15, 22 for three 5-

week cycles; C: 50 mg p.o. daily; D: 20 mg on days of B and day after

ORR: 82% CR: 16%

Median EFS: 12 months


Palumbo et al.

(2008) [94]

64 B Dx D Autologous transplantation; bortezomib; anthracyclines

B: 1.3 mg/m2, days 1, 4, 8, 11 of a 28-

day cycle; PLD: 20 mg/m2, days 1, 4 or 30 mg/m2, day 1;

D: 40 mg/day, days 1−-4

ORR: 67% CR: 9%

1-year EFS: 34%1-year OS: 66%

Popat et al.

(2009) [95]

53 B M D

Corticosteroids; alkylating agents; thalidomide;

anthracyclines; radiotherapy; bortezomib;

autologous ASCT or allogeneic stem-cell

transplantation

B: 1.3 mg/m2, days 1, 4, 8, 11 of a 28-

day cycle M: 7.5 mg/m2 i.v.,

day 2; D: 20 mg/day, days 1, 2, 4, 5, 8, 9, 11, 12 in the case of progressive or

stable disease after respectively two2 or four4 cycles,

respectively

ORR: 68% CR: 19%



ASCT: Autologous stem-cell transplantation; B: bBortezomib; C: Cyclophosphamide; CR: Complete response; D: dDexamethasone; Dx: dDoxorubicin; EFS: Event-free survival; C: cyclophosphamide; M: mMelphalan; NR: Not reported; ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival; PLD: Pegylated liposomal doxorubicin; PN: Peripheral neuropathy. ORR: overall response rate; CR: complete response; OS: overall survival; PFS: progression-

free survival; EFS: event-free survival; PN peripheral neuropathy; PLD: pegylated liposomal

38

doxorubicin. NR not reported

Table 6VI. Carfilzomib based clinical trials.

AuthorsStud

y (year)

No. of

pts.Patient

s (n)

Regimen Previous

treatment Dose/day

Response

(%)

Mean duration

of response Side

Vij et al. (2012) [96]

35 Carfilzomib single agent

Bortezomib

Cfz 20 mg/m2, days 1, 2, 8, 9, 15, 16 of 28-day cycles

ORR: 17% ORR + minimal

response : 31.4%

TTP: 4.6 months

Hematolog

Ppne; fF

Hematolog

pPne

Jagannath et al. (2009) [97]


NR

Cfz 20 mg/m2, days 1, 2, 8, 9, 15, 16 of 28-day cycles

ORR: 17%

DOR: 7.2 months

AneThromboc

LeucopoeFa

Upper rinfe

DyspnRenal fa

Siegel et al. (2012) [44]


NR

Cfz 20−-27 mg/m2, days 1, 2, 8, 9, 15, 16 of 28-day

cycles

ORR: 24% > VGPR: 5%

DOR: 7.8 months

Hematolog

PneFa

Cfz: cCarfilzomib; DOR: Duration of response; NR: Not reported; ORR: oOverall response rate; PFS: Progression-free survival; TTP: Time to progression; DOR: duration of response; VGPR: vVery good partial response.; PFS: progression-free survival; TTP: time to progression; NR: not reported.. Table 7[R3]VII. Conditions influencing the selection of treatment options for patients with relapsed/refractory myeloma and suggested regimens.

Condition

Disease- related

Duration of response to front-line therapy If relapse occursame treatment used If relapse occur –while the patient ian alternative re

FISH or cytogenetic profile (patients with non-hyperdiploid t(4:14), del(17p), and del(13q14) mutations have high-risk disease due to

poor response to the treatment)

For patients at hibortezomib- or

Regimen- related

Previous drug exposure (new vs classic agents) Consider treatmA change in thewhose disease hdrug.

39

Previous autologous stem cell transplantationASCT Consider second ASCT for salva

Patient- related

Age and performance status Consider aggre

Neuropathy Consider lenali

Neutropenia or cytopenia Avoid or reduc

Renal impairment Consider bortez

Recent thromboembolic or cardiovascular events Consider bortez

ASCT: Autologous stem cell transplantation

Choosing treatment options for patients with relapsed/refractory multiple myeloma

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