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Bortezomib CombinationTherapy in Multiple Myeloma

Prashant Kapoor, Vijay Ramakrishnan, and S. Vincent Rajkumar

Bortezomib was approved for the treatment of multiple myeloma (MM) in 2003. Since then severalbortezomib-based combination therapies have emerged. Although some combinations have beenpreceded by preclinical investigations, most have followed the inevitable process in which active(or potentially active) drugs are combined with each other to create new treatment regimens.Regimens that have combined bortezomib with corticosteroids, alkylating agents, thalidomide,and/or lenalidomide have resulted in high response rates. Despite the higher and often deeperresponse rates and prolongation of progression-free survival with bortezomib-based multiagentregimens, an overall survival (OS) advantage has not been demonstrated with most combinationscompared to the sequential approach of using anti-myeloma agents, particularly in patients less than65 years of age with newly diagnosed myeloma. The unique properties of some of these regimenscan be taken into account when choosing a particular regimen based on the clinical scenario. Forexample, the combination of bortezomib, thalidomide, and dexamethasone (VTD) has particularvalue in renal failure since none of the drugs need dose modification. Similarly, the combinationchemotherapy regimen VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubi-cin, cyclophosphamide, and etoposide) is of particular value in patients presenting with aggressivedisease such as extramedullary plasmacytomas or plasma cell leukemia. Ongoing clinical trials aretesting combinations of bortezomib with several other classes of agents, including monoclonalantibodies, and inhibitors of deacetylases, heat shock proteins, phosphatidyl inositol 3-kinase/Akt/mammalian target of rapamycin pathway and farnesyl transferase.Semin Hematol 49:228–242. © 2012 Elsevier Inc. All rights reserved.

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Bortezomib is boronate-based dipeptide protea-some inhibitor (PI) that primarily targets thechymotrypsin-like activities of the intracellular

roteasome enzyme complex.1 It received acceleratedapproval by the US Food and Drug Administration in2003 based on a large multicenter phase II clinicaltrial.2 This trial demonstrated an overall response in

early a third of patients with advanced multiple my-loma (MM). Subsequent studies have attributed im-rovement in overall survival (OS) of MM patients inhe last decade to the use of bortezomib, as well asther agents such as thalidomide and lenalidomide thatre commonly referred to as immunomodulatory drugsIMiDs). However, most, if not all, patients inevitablyelapse. Each relapse requires salvage therapy, andhere is decreasing response duration with successive

Division of Hematology, Mayo Clinic, Rochester, MN.Conflicts of interest: none.Address correspondence to S. Vincent Rajkumar, MD, Professor of

Medicine, Division of Hematology, Mayo Clinic, 200 First Street SW,Rochester, MN 55905. E-mail: rajkumar.vincent@mayo.edu

0037-1963/$ - see front matter© 2012 Elsevier Inc. All rights reserved.

http://dx.doi.org/10.1053/j.seminhematol.2012.04.010

Sem228

ines of salvage therapies. Although the activity of bort-zomib has been demonstrated with retreatment inrior responders, the median OS of patients who be-ome refractory to bortezomib and IMiDs is disappoint-ngly short (�9 months).3

Bortezomib initially showed activity in a phase I trialin which clinical benefit was noted in all nine heavilypretreated MM patients.4 Subsequently, the phase IIUMMIT (Study of Uncontrolled Multiple Myelomaanaged with Proteasome Inhibition Therapy) andREST (Clinical Response and Efficacy Study of Bort-zomib in the Treatment of Relapsing MM) trials dem-nstrated meaningful benefit in relapsed refractory MMmedian time to progression 7–11 months and OS7–60 months).5,6 The phase III APEX (Assessment of

Proteasome Inhibition for Extending Remissions) trial,which led to the full approval of bortezomib in 2005 inpatients who have received at least one prior therapy,demonstrated a clear 6-month survival advantage withbortezomib (median OS 29.8 months) compared todexamethasone despite cross-over from the dexameth-asone arm.7 Here, we review bortezomib-based combi-nation strategies, other than bortezomib–steroid dou-

blets that have been effectively used for optimization of

inars in Hematology, Vol 49, No 3, July 2012, pp 228–242

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Bortezomib combination therapy in multiple myeloma 229

clinical response and disease control, particularly inrelapsed refractory MM patients who have exhaustedthe standard therapies or those who are unable toderive autologous stem cell transplantation (ASCT)-as-sociated survival benefit owing to their transplant inel-igibility status.

RATIONALE FOR USINGBORTEZOMIB-BASED COMBINATIONS

Although some combinations have been precededby preclinical investigations, most have followed theinevitable process in which active (or potentially ac-tive) drugs in a given malignancy are combined witheach other to create new treatment regimens. Never-theless, a review of possible biological mechanismsthrough which the activity of bortezomib can be influ-enced and targeted is worth some discussion. Bort-ezomib is a prototypical PI that reversibly inhibits theubiquitin proteasome pathway (UPP) leading to cell-cycle arrest and apoptosis.1 Combinations should ide-ally take into account the different mechanisms ofaction of bortezomib, drug resistance pathways, andincorporate strategies designed to improve sensitivityof myeloma cells to the drug. The molecular mecha-nisms of proteasome inhibition and the preclinical ac-tivity of bortezomib-based combinations have been elu-cidated in detail elsewhere in this issue of Seminars inHematology.

Compared to normal cells, neoplastic plasma cells aremore dependent on a functional unfolded protein re-sponse (UPR) for proper folding of abundantly synthe-sized immunoglobulins. Bortezomib and other PIs inhibitthe UPP, which results in the accumulation of misfoldedproteins leading to UPR-induced cell death.8 In addition,bortezomib inhibits plasma-cell adhesion to the mi-croenvironmental bone marrow stromal cells (BMSCs)and angiogenesis.1 The complementary and/or aug-

enting effects of various agents used in bortezomib-ased combinations have been demonstrated in pre-linical studies (Table 1). The most compellingationale for many of the combinations is from clinicalrials that have exploited the additive or synergisticnti-neoplastic effect that arises when one combinesrug classes with impressive independent single-agentctivity and unique non-overlapping toxicities. Bort-zomib lends itself to multi-drug combinations since itsyelosuppressive effect is typically mild, transient andon-cumulative. We have discussed below several bort-zomib-based combinations with promising clinical ac-ivities.

IMMUNOMODULATORY DRUGS—BORTEZOMIB-BASED COMBINATIONS

Lenalidomide–Bortezomib

The mechanism of anti-myeloma activity of lenalido-

mide is different from that of bortezomib although s

some degree of overlap exists. The value of this com-bination has been prospectively assessed in a clinicalphase I/II study of bortezomib–lenalidomide–dexam-ethasone (VRD) administered as 3-week cycle in newlydiagnosed patients.9 Sensory neuropathy (80%) and fa-igue (54%) were commonly seen, although the regi-en was not associated with any treatment-related

eaths. An unprecedented 100% overall response rateORR) was seen, with nearly three quarters of thehase II cohort achieving a very good partial responseVGPR) or better. Despite the impressive initial re-ponse rates, a quarter of the patients relapsed within8 months.9 This highly effective regimen has also beentudied in the relapsed-refractory setting (Table 2: notehat the dose is different in relapsed setting) in which4% patients achieved minimal response (MR) or betterith a median duration of response of 24 weeks (range,–81).10 The relatively small sample size of high-riskatients precludes one from drawing definite conclu-ions about the efficacy of this combination in patientsith adverse cytogenetics. The high response ratesith VRD have led to the premature adoption of this

egimen as a standard front-line treatment outside oflinical trials in the United States. For standard- andntermediate-risk patients with newly diagnosed my-loma, we do not recommend VRD since there are nohase III data to support such therapy. However, inewly diagnosed patients with high-risk features forhom attainment and maintenance of a complete re-

ponse (CR) is an important therapeutic goal, VRD is aeasonable alternative to other standard regimens. VRDs also of value in patients with relapsed refractory

yeloma.10

VRD has been compared with two other combinationsin the phase II EVOLUTION trial.11 This randomized studyoncurrently evaluated VRD, bortezomib–cyclophosph-mide–dexamethasone (VCD), and bortezomib–dexam-thasone–cyclophosphamide–lenaldiomide (VDCR). VCDas later substituted with a modified VCD schedule

hat added an extra dose of cyclophosphamide on day5. Initial treatment was followed by four 6-week cy-les of maintenance bortezomib in all arms. The bestesponse was noted in the modified VCD regimen (PRr better in 100%) with nearly half of the patientschieving CR, although the number of patients enrolledn this arm was small (n � 17). One-year OS was 92%or the four-drug VDCR arm, and 100% for the otherhree regimens.11 The study shows that VCD is aeasonable, much less expensive alternative to VRDn terms of highly active three-drug combinations.urther the study shows that the addition of cyclo-hosphamide to VRD (or lenalidomide to VCD) toreate a four-drug combination does not increasefficacy but results in higher toxicity rates. However,ore studies are needed.The ongoing phase III study (IFM/DFCI2009), de-

igned to evaluate the clinical benefit from VRD, with

ed inhib

230 P. Kapoor, V. Ramakrishnan, and S.V. Rajkumar

or without immediate ASCT followed by lenalidomidemaintenance, is an important trial attempting to ad-dress the usefulness of upfront transplantation in the

Table 1. Rationale for Novel Combinations With

Enzym

Class Drug(s) R

HSP inhibitors Tanespimycin Resla

Deacetylase inhibitors(DACI)

VorinostatPanabinostatBelinostatRomidepsin

SyniVdsam

AKT/mTOR inhibitors PerifosineTemsirolimus

TreMuir

Pan-Bcl inhibitors Obatoclax AnibMdM

Farnesyl transferaseinhibitors(FTIs)

TipifarnibLonafarnib

FTspi

Immuno modulatingagents (IMiDs)

ThalidomideLenalidomidePomalidomide

R,aabmw

DNA-damaging agents AlkylatorsAnthracyclinesBendamustine

Inefgds

Monoclonal antibodies ElotuzumabMapatumumabSiltuximab

V eM

Abbreviations: V, bortezomib; HSPI, heat shock protein inhibinhibitor; JNK, C-Jun N terminal kinase; UPR, unfolded proteimediated drug resistance; HDAC6, histone deacetylase 6; R,kappa B; IGF-1, insulin like growth factor; TNF-�, tumor necrobeta; NK, natural killer; DNA, deoxyribonucleic acid; X-linkcytotoxicity.

era of such potent regimens (NCT01208662).

Thalidomide–BortezomibA recent phase III study compared bortezomib–tha-

lidomide–dexamethasone (VTD) versus thalidomide–

zomib (V)

bitors

le for Combination Therapy With Bortezomib

to V is mediated via upregulation of HSPs. HSPIsMM cells to V by inhibiting HSP, which thenincreased accumulation of misfolded proteins

ther activation of endoplasmic stress response.ith V has been primarily attributed to the dualn of aggresomes and proteasomes by DACI andctively, thereby blocking protein degradation byt mechanisms. Upregulation of CDK inhibitorsp21 (vorinostat) or downregulation of anti-ic Bcl2 (romidepsin) are some specificisms that have been elucidated.t with V has been shown to upregulate pAkt inls and perifosine has been shown to inhibit theated pAkt. In addition, perifosine enhances V-cytotoxicity via activation of JNK (a stress-

e protein mediating apoptosis by UPR).st of BH3 binding groove of Bcl family proteins;apoptosis by interfering with the interaction

n pro- (eg, Bak) and anti-apoptotic proteins (eg,hich accumulates with V therapy a a result of PI)

trating augmented cytotoxic responses againstls.mbination with V overcome CAM-DR; induce ERlated MM cell apoptosis, downregulation ofnd disruption of aggresome complex vian of HDAC6.

icular, triggers caspase-8–dependent apoptosissitizes MM cells to death receptor, Fas-mediatedis; disrupts BMSC support, downregulates NF-�Bition of IGF-1 and TNF-� (in contrast to I�KBd downregulation by V); immunomodulationproved NK cell-mediated MM cell destruction.n to its proapoptotic effects through decreasedion of Bcl-2, XIAP and other anti-apoptoticV inhibits the protective cellular response toic stress thereby restoring the sensitivity to DNA-

ng agents. Anthracyclines further demonstrateby suppressing V-induced HSP expression.

es activity of monoclonal antibodies by renderingls more vulnerable to NK cell-mediated ADCC.

, multiple myeloma; IGs, immunoglobulins; PI, proteasomese; FTIs, farnesyl transferase inhibitors; CAM-DR, cell-adhesion

mide; BMSC, bone marrow stromal cells; NF-KB nuclear factorr alpha; IkKB, inhibitor of nuclear factor kappa B kinase subunititor of apoptosis protein; ADCC, antibody-dependent cellular

Borte

e Inhi

ationa

sistanceensitizeeads tond furergy w

nhibitio, respeifferenuch aspoptotechanatmenM cel

pregulnducedesponstagoninducesetweecl-1, w

emonsM cel

Is in cotress-reAKT, a

nhibitioin partnd senpoptosy inhibediateith im

additioxpressactors,enotoxamagiynergynhancM cel

itor; MMn responlenalidosis facto

dexamethasone (TD) as pretransplant induction ther-

Table 2. Selected Phase I/II Trials Incorporating Bortezomib � IMiDs and/or Cytotoxic Agents

Study Regimen Cohort N ORR >VGPR (%) MTD/Phase II Dose

Cycle

Days #

EVOLUTION Phase I56 VDCR NDMM�ASCT

25 96888575

100

56 V 1.3 mg/m2 IV d1,4,8,11D 40 mg PO d1,8,15R 15 mg (25 mg in VDR) PO d1–14C 500 mg/m2 PO d1,8 � d15 (mod)V maint. 1.3 mg/m2 IV d1,8,15,22

21 8EVOLUTION Phase II11 VDCR

VDRVDCVDC-modified

130 58515353 42 4

Phase II24,25 CyBorDCyBorD-modified

NDMM�ASCTTotal

333063

889390

616060

V 1.3 mg/m2 IV d1,4,8,11D 40 mg PO d1–4,9–12,17–20C 300 mg/m2 PO d1,8 15,22V 1.5 mg/m2 IV d1,8,15,22 (mod)D 40 mg d1,8,15,22 from cycle 3(mod)

28 4

Phase I/II9 RVD NDMM�ASCT

66 100 67 R 25 mg PO d1–14V 1.3 mg/m2 IV d1,4,8,11D 20 mg PO d1,2,4,5,8,9,11,12 cycles 1–4D 10 mg PO d1,2,4,5,8,9,11,12 cycles 5–8

21 8

Phase I/II57 RVDD NDMM�ASCT

74 96 67 R 25 mg PO d1–14V 1.3 mg/m2 IV d1,4,8,11D 20 mg PO d1,2,4,5,8,9,11,12 cycles 1–4D 10 mg PO d 1,2,4,5,8,9,11,12 cycles 5–8PLD 30 mg/m2 IV d4

21 8

DSSM XIPhase I58

VDC NDMM�ASCT

30 7792 @ MTD

NA V 1.3 mg/m2 IV d1,4,8,11D 40 mg PO d1,2,4,5,8,9,11,12C 900 mg/m2 IV d1

21 3

Phase II59 VDT(D, PLD)

NDMM�ASCT

40 78 35(CR�nCR) V 1.3 mg/m2 IV d1,4,15,18PLD 20 mg/m2 IV d1,15T 200 mg PO daily continuously

28 6 � 2

Phase II28 DVD NDMM 35 72 29 D 40 mg IV d1,4,8,11V 1 mg/m2 IV d1,4,8,11PLD 5 mg/m2 d1,4,8,11

28 8

Phase II29 VDD NDMM�ASCT

40 93 63 V 1.3 mg/m2 IV d1,4,8,11D 40 mg PO d1,2,4,5,8,9,11,12 cycle 1D 20 mg PO d1,2,4,5,8,9,11,12 cycles 2–8PLD 30 mg/m2 IV d4

21 6

Phase II60 DBdB, bortezomib

NDMM�ASCT

50 98�MR

27(CR�nCR) V 1.3 mg/m2 IV d1,4,8,11D 40 mg PO d1–4,8–11,15–18 cycle 1D 40 mg PO d1–4, cycles 2–4PLD 30 mg/m2 IV d4

21 3–4

Phase I/II30

Phase IIPAD1PAD2

NDMM�ASCT

2120

9589

6242

V 1.3 mg/m2 IV d1,4,8,11 (PAD1)V 1 mg/m2 IV d1,4,8,11 (PAD1)D 40 mg PO, d1–4,8–11,15–18 cycle 1D 40 mg PO, d1–4,cycle 2Dox 9 mg/m2 d1–4

21 4

Bortezomib

combination

therapyin

multiple

myelom

a231

Table 2. Continued

Study Regimen Cohort N ORR >VGPR (%) MTD/Phase II Dose

Cycle

Days #

Phase IITT3TT234

VDT-PACEVTD (1yr)TD (yr 2 & 3)VAD-DCEP-CAD-DCEPDPACE/Interferon�T

NDMM�tandem ASCT 303668

92*81 (�T)

79 (no T)

NA V 1 mg/m2/d IV d1,4,8,11D 40 mg PO, d1–4T 200 mg/d PO continuouslyP 10 mg/m2/d CIV 1–4A 10 mg/m2/d CIV 1–4C 400 mg/m2/d CIV 1–4E 40 mg/m2/d CIV 1–4(Interferon� D maintenance in TT2)

2 (I)2 (C)4 (I)4 (C)

Phase II36

TT3TT3B

VDT-PACEVTD (1yr)TD (yr 2 & 3)VDTPACEVRD (3 yrs)

NDMM� tandem ASCT 303177

59†61

NA V 1 mg/m2/d IV d1,4,8,11D 40 mg PO, d1–4T 200 mg/d PO continuouslyP 10 mg/m2/d CIV 1–4A 10 mg/m2/d CIV 1–4C 400 mg/m2/d CIV 1–4E 40 mg/m2/d CIV 1–4

28–42 4

Phase II10 VRD RR 64 84�MR

21 (CR/nCR) V 1 mg/m2 IV d1,4,8,11V d1,8 after cycle 8R 15 mg/d PO d1–14D 20–40 mg PO days of and after VD 10 mg d1,2,8,9 after cycle 8

21 8

Phase I/II61 VCP RR 37 95�MR

50 (CR/nCR) V 1.3 mg/m2 IV d1,4,8,11 orV 1.5 mg/m2 IV d1,8,15C 300 mg/m2 PO d1,8,15,22P 100 mg PO every other day

28 8

Phase II62 VDC RR 54 76 15 (CR) V 1.3 mg/m2 IV d1,4,8,11 cycle 1–8D 20 mg PO d1,2,4,5,8,9,11,12C 50 mg daily PO continuouslyV 1.3 mg/m2 d1,8,15,22 cycle 9–11

2135

83

Phase II63 PAd RR 64 67 25 V 1.3 mg/m2 IV d1,4,8,11D 40 mg d1–4Dox 30 mg/m2 IV d1

28 6

Phase II27 VDTVDT�PLD

RR 2842

3674

2152 (CR/nCR)

V 1 mg/m2 IV d1,4,8,11D 24 mg PO d1,2,4,5,8,9,11,12T 100 mg PO continuously

28 6

Phase I/II64 V�Bendamustine

RR 39 48 8 V 1 mg/m2 IV d1,4,8,11Benda 90 mg/m2 IV d1,4

28 8

Abbreviations: ORR, overall response rate; VGPR, very good partial response; MTD, maximum tolerated dose; V/Bor, bortezomib; D/d, dexamethasone; C/Cy, cyclophosphamide; R, Lenalidomide; T, thalidomide;PLD/D, pegylated liposomal doxorubicin; P, prednisone or cisplatin (in VDTPACE); E, etoposide; PAD, bortezomib, doxorubicin (adriamycin), dexamethasone; NDMM, newly diagnosed multiple myeloma; RR-,relapsed and/or refractory; ASCT, autologous stem cell transplantation; nCR, near complete remission; NA, not available; CIV, continuous intravenous; PO, oral; IV, intravenous.

*Two-year sustained CR rate: I, induction, C, consolidation.†Two-year CR estimate.

232P.

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andS.V.

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Bortezomib combination therapy in multiple myeloma 233

apy and post-double ASCT consolidation therapy (Table3).12 The study showed higher CR/near CR (nCR) ratesn the VTD arm (31% v 11% with TD; P � .0001). Thismprovement translated into a superior progressionree survival (PFS) rate (3-year PFS 68% v12%, respec-ively). No benefit was apparent in terms of OS.12 De-pite exclusion of patients with grade �2 neuropathy,he improvement in PFS came at a cost of significanteurotoxicity with VTD (10% grade 3 or higher periph-ral neuropathy [PN] similar to that in the Spanish trial14%]13 using VTD induction), a significant deterrent tots long-term use. We feel that the use of this potentegimen of two neurotoxic agents is best reserved forlinical scenarios requiring immediate cytoreductionuch as MM-induced acute renal failure. There are noandomized trials comparing VTD with either VCD orRD. In most circumstances, including renal failure,e prefer VCD over VTD.To improve on the safety profile of VTD while pre-

erving its marked efficacy (ie, to design a regimen withest efficacy/toxicity ratio), the Intergroupe Franco-hone du Myelome (IFM) conducted a phase III trialomparing reduced dose bortezomib (1 mg/m2 intrave-ously [IV] days 1, 4, 8, and 11 of a 3-week cycle),halidomide (100 mg/d), and dexamethasone (vtD) ver-us standard full-dose bortezomib–dexamethasoneVD).14 The dose of dexamethasone was similar in both

the arms. An increment in the dosage of bortezomiband thalidomide was permitted if less than PR wasachieved with two cycles of vtD. However, 90% ofpatients achieved a PR or better after just two cycles ofvtD. The incidence of grade 3–4 PN was 3% with vTDand 10% with VD. Although no difference in near CR orbetter responses were seen (31% v 22% with VD), asubstantial increase in CR�VGPR rates was noted withvtD prior to ASCT (49% v 36% with VD). The PFS andOS outcomes between the two groups have not shownany differences so far.14 This study shows that optimiz-ng the dose of bortezomib can alleviate the risk ofeuropathy without sacrificing efficacy.

COMBINATIONS OFBORTEZOMIB WITH CONVENTIONALCHEMOTHERAPEUTIC AGENTS

The magnitude of synergy between conventionalcytotoxic agents and bortezomib appears to be consid-erably high.15 Bortezomib-based combinations such as

CD and bortezomib, melphalan, prednisone (VMP)roduce high response rates. However, in most trials,espite significant improvement in the CR rates (con-idered a surrogate for OS), an improvement in OS hasot been seen.

Melphalan-Bortezomib–Based Combinations

The landmark, international VISTA (Velcade as Ini-

tial Standard Therapy in Multiple Myeloma: Assessment

ith melphalan and prednisone) trial established theuperiority of VMP (bortezomib–melphalan–predni-one) compared with MP in transplant-ineligible pa-ients with newly diagnosed myeloma.16,17 The VISTArial (Table 3) found a 13-month improvement in theedian OS with VMP compared with MP (56.4 v 43.1onths, respectively; hazard ratio 0.7, P � .0004).

However, the survival of patients with high-risk cyto-genetics (n � 46) did not improve with the addition of

ortezomib, a reminder of the continued poor out-ome in these patients despite several advances inyeloma therapy.17 No excess risk of second primary

malignancies (SPM) was seen between the two arms.18

A subsequent Spanish study (Table 3) compared VMPwith VTP (bortezomib–thalidomide–prednisone).19 Thistrial showed that the grade 3 or worse neurotoxicity ofVMP seen in the VISTA trial (13%) could be substan-tially reduced (�5%) with modification of the bort-ezomib dose from twice per week to the once-per-week schedule.19 Similar observations of significantlyreduced grade 3–4 nonhematologic adverse effects,including PN, without a compromise in efficacy werereported in an Italian study of 551 patients in which theschedule of bortezomib was modified from twiceweekly to once weekly after enrollment of the first 139patients (Table 3).20 A separate phase III trial con-

ucted by the IFM demonstrated that the risk of neu-otoxicity can be further reduced by subcutaneousosing.21 Unless there is need for rapid control foryeloma (eg, acute renal failure, extramedullary dis-

ase, or plasma cell leukemia) we prefer once-weeklyubcutaneous bortezomib as the standard schedulehen using bortezomib in both newly diagnosed and

elapsed settings.The importance of using a modified bortezomib

chedule to minimize neuropathy as much as possibleas recently highlighted by the results of a recent

ommunity-based phase III trial of elderly patients thatompared VD, VMP, and VTD. This trial found that theverall average quality of life (QOL) of patients withyeloma failed to improve above baseline in any of the

hree arms after 1 year of therapy.22,23

Cyclophosphamide-Bortezomib–BasedCombinations

Alkylators are particularly effective in MM. Owing tothe lack of cumulative stem cell damage, cyclophosph-amide, unlike melphalan, preserves the ability to har-vest stem cells during induction. The VCD regimen,which combines cyclophosphamide and bortezomib, isan excellent combination and has become our pre-ferred bortezomib-based combination regimen in thefrontline setting, as well as in the maintenance andrelapsed settings for selected patients. VCD has shownhigh response rates (61% �VGPR and nearly 40% CR/

nCR rates).24 A modified VCD regimen with weekly

Table 3. Phase III Trials With Bortezomib (V)-Based Combinations in Multiple Myeloma*Combination N Cohort ORR (%) PFS mo HR for PFS P Value for PFS OS mo HR for OS P Value for OS

1 GIMEMA12

VTD X 3 �ASCT x 2� VTD X 2TD X 3� ASCT x 2 � TD X 2

236238

NDMMASCT eligible

9689

(3-yr)68%56%

0.63 .006 (3-yr)86%84%

NA .30

2 IFM 2007–0214

VD � ASCTvtD�ASCT

99100

NDMM, ASCT eligible 8986

3026

NA .22 NA NA NS

3 PETHEMA19

VMP� VT or VP maintenanceVTP � VT or VP maintenance

130130

NDMM� 65 yrs

8180

3425

1.2 .1 (3-yr)74%65%

1.2 .3

4 PETHEMA/GEM05MEN0S6568

TDVTDVBMCP/VBAD/B

127130129

NDMM�66 ASCT eligible

NA 27NR

38

NA .006 4-yr76%‡

NA NS

5 VISTA16

VMPMP

327328

NDMMASCT ineligible

7135

2215

0.6 <.001 5643

0.7 <.001

6 UPFRONT22

VD� V maintenanceVTD� V maintenanceVMP� V maintenance

168167167

NDDMElderly, ASCTineligible

738069

141517

NA NS (1-yr)87%86%89%

NA NS

7 HOVON 65/GMMG-HD431

VAD with T maintenancePAD with V maintenance

305308

NDMM�ASCT

8792

3-yr42%48%

0.8 .047 3-yr71%78%

0.7 .048

8 VMPVMPT-VT20

257254

NDMM� 65 yrsASCT Ineligible

8189

27NR

0.6 .008 3-yr89%87%

0.9 .77

9 VANTAGE 08844

Bortezomib�VorinostatBortezomib�placebo

347320

RR† 5641

87

0.8 .01 NR28

0.9 .35

10 IFM-EBMT69

VTDTD

135132

RR afterASCT

9069

1913

NA .001 (2-yr)72%68%

NA .18

11 DOXIL-MMY-300126

VPLD�V

322324

RR 4144

97

0.6 <.001 (1.25-yr)65%76%

0.7 .03

Abbreviations: ORR, overall response rate; HR, hazard ratio; NDMM, newly diagnosed multiple myeloma; ASCT, autologous stem cell transplantation; PFS, progression-free survival; OS, overall survival; NA, notavailable; NR, not reached.

*Bortezomib-dexamethasone doublet excluded.†Patients with prior BTZ resistance excluded.‡No OS difference in three arms.

234P.

Kapoor,V.

Ramakrishnan,

andS.V.

Rajkumar

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Bortezomib combination therapy in multiple myeloma 235

bortezomib and low-dose dexamethasone (40 mgweekly) is equally effective compared with the originalVCD regimen that employed a twice weekly bort-ezomib schedule and high-dose dexamethasone, and isbetter tolerated.25 As suggested by the results of theVOLUTION trial,11 VCD produces comparable resultso VRD in newly diagnosed patients. Although theollow-up of patients in these trials is short to assess theurvival outcomes, the regimens incorporating bort-zomib and cyclophosphamide show rapid and deepesponses and appear to be promising.

Anthracyclines-Bortezomib–BasedCombinations

Anthracyclines, doxorubicin and pegylated lipo-somal preparation (PLD), have been shown to enhanceMM cell killing when combined with bortezomib inpreclinical studies (Table 1). Although statistically sig-nificant benefit has been seen with the use of anthra-cyclines in myeloma, the true clinical benefits havebeen modest at best. PLD has improved pharmacoki-netic and safety profile compared with doxorubicin butis more expensive and not easily available.

A phase III international study comparing bort-ezomib/PLD with bortezomib alone in relapsed, ad-vanced MM, demonstrated improved response quality(27% CR�VGPR v 19% with bortezomib alone; P �015), response duration (10.2 months v 7 months withortezomib alone, P � .0008), PFS, and OS (Table 3).26

The improved efficacy comes at a cost of greater tox-icity (grade 3–4 myelosuppression, fatigue, diarrhea,hand-foot syndrome), although bortezomib inducedneurotoxicity was not increased.26 Comparatively, anon-randomized study involving VDT � liposomaldoxorubicin (Table 2) showed further improvement inPFS with the four-drug regimen (15 vs. 8 months forVDT) again without any increment in the treatment-emergent neuropathy rate in the doxorubicin contain-ing arm compared to VDT alone. In addition, this studyregistered responses even in patients who were previ-ously anthracycline-refractory. The cycle length in thelatter study was 4 weeks instead of 3 weeks withbortezomib � PLD phase III study.27

In the frontline setting, three published phase IIstudies have reported on the efficacy and tolerability ofbortezomib combined with anthracyclines (Table 2).The recently reported outcome with an IV DVD regi-men demonstrated the advantages of using modifiedmetronomic dosing of PLD (5 mg/m2 along with dexa-

ethasone 40 mg and bortezomib 1 mg/m2 days 1, 4, 8,nd 11) in a longer 4-week schedule.28 This modified

regimen retained the high efficacy of a previously re-ported study of same combination by Jakubowiak etal29 with marked improvement in the side effect

rofile (reduced fatigue, PN myelosuppression, and

almar-plantar erythrodysesthesia).28 Similarly, Popat

et al reported that bortezomib dose reduction from 1.3mg/m2 to 1.0 mg/m2 improved the toxicity profileof this highly active regimen without adversely affect-ing the outcome measures.30 A randomized phase IIIHOVON65/GMMG-HD4 trial (Table 3) compared PADwith VAD (vincristine, doxorubicin, and dexametha-sone) induction regimen followed high-dose melphalan(HDM) therapy (in both arms) and post-transplantmaintenance therapy bortezomib (in the PAD arm) orthalidomide (VAD arm).31,32 Preliminary results suggesthat PAD results in a higher ORR compared with VAD80% for PAD v 64% post induction) and that thisifference is sustained post HDM (92% v 87% for VAD;� .01). Of the seven phase III trials of pretransplant

nduction therapy, the HOVON65/GMMG-HD4 trial ishe only one to show survival advantage of a bort-zomib-based regimen.31 However, the possible un-

availability of bortezomib-based salvage therapy at re-lapse for all patients in the non-bortezomib VAD arm inthis study could account for the survival difference.The investigators also analyzed the prognostic value ofchromosomal abnormalities in a subgroup of 354 MMpatients. Importantly, the patients with del 17p13 ap-peared to benefit the most from the bortezomib-con-taining regimen: the median PFS in VAD arm was 12.0months versus 26.2 months in PAD (P � .024); the 3year-OS for arm VAD was 17% versus was 69% (P �.028) for PAD. After multivariate analysis, del17p13was an independent predictor for PFS (P � .0001) andOS (P � .0001) in VAD arm, whereas no statisticallysignificant effect on PFS (P � .28) or OS (P � .12) wasseen with PAD.33

VDT-PACE

The multi-agent chemotherapy regimen VDT-PACE(bortezomib, high-dose dexamethasone, thalidomide,cisplatin, doxorubicin, cyclophosphamide, and etopo-side) has been tested as the standard induction therapyin the Total Therapy 3 (TT3) trials conducted by theMyeloma Institute for Research and Therapy in Arkan-sas. It is an extremely potent combination that buildsby combining the backbone of VTD therapy and the4-day continuous infusion of chemotherapy developedusing the components of CAD and DCEP regimens usedin earlier studies.34 With similar baseline prognosticfeatures, event-free survival (EFS) and CR durationwere markedly superior with TT3 versus Total Therapy2 (TT2) (Table 2), regardless of the addition of thalid-omide to one arm of TT2.34 A recently updated analysispredicted a 5-year OS of 86% (95% confidence interval[CI], 82.2–89.9) in patients with low-risk gene expressionprofile (GEP), no cytogenetic abnormalities, �2-micro-globulin (�2M) �5.5 mg/L and lactate dehydrogenaseLDH) �190 U/L versus only 11.18% (CI, 10.15–12.31)ith high-risk GEP, cytogenetic abnormalities, �2M

�5.5 mg/L, and LDH �190 U/L, highlighting the

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236 P. Kapoor, V. Ramakrishnan, and S.V. Rajkumar

poor prognosis of the very high-risk group despiteaggressive treatment.35 A recent trial (2006 – 66) re-placing VDT/TD consolidation/maintenance duringTT3 by VRD for 3 years demonstrated similar results(Table 2).36

Patients with t(4;14) on TT3 protocol had similar OScompared to the standard-risk patients, underscoringthe efficacy of bortezomib-based combination therapyand ASCT in this high-risk category. The GIMEMA andHOVON-65/GMMG-HD4 protocols using bortezomibwith VTD induction plus post-ASCT consolidation andPAD, respectively, also confirmed this effect seen withthe TT3 protocol on patients harboring t(4;14).

We use VDT-PACE in newly diagnosed patients pre-senting with agrressive extramedullary disease orplasma cell leukemia, and in selected patients withrelapsed refractory myeloma.

EXPERIMENTAL COMBINATIONS

The combinations listed here have some preclinicalrationale. However, most if not all of the agents that arebeing tested in combination with bortezomib havefailed to show significant single-agent activity in my-eloma in phase I/II studies, which is disappointing. Theproof of the efficacy of these combinations will need tocome from well-controlled phase III studies. Such dataare largely lacking at this juncture. Nevertheless wewill review the current status of these combinations indetail since they may provide insight into directions forthe future.

Bortezomib and Heat Shock Protein Inhibitors

Heat shock protein 90 (HSP90) is a molecular chap-erone for several oncoproteins that are crucial for thecancer cell growth, survival and drug resistance. Pre-clinical studies have demonstrated marked antitumoreffects of HSP90 inhibitors even in MM, a malignancythat is not critically dependent upon the HSP clientproteins.37 The upregulation of HSPs (for example,

SP90) by bortezomib is a cytoprotective response thateads to resistance to bortezomib. MM cells appear toe exquisitely sensitive to dual inhibition of the pro-easome and HSP90. The affinity of HSP90 inhibitor,anespimycin to tumor-related HSP90 is 100-fold higherompared to HSP from normal cells, making it an at-ractive therapeutic target. The early reports of clinicalfficacy of HSP90 inhibitor-bortezomib combinationre shown in Table 4. Interestingly, low rates of neu-ropenia, anorexia, and PN compared to historical dataith bortezomib monotherapy were noted, and hepa-

otoxicity was manageable. The low rates of severe PNay be related to the neuroprotective effect of tane-

pimycin.38 The TIME-2 randomized study comparingbortezomib plus three different doses of tanespimycin

in relapsed-refractory MM patients was truncated early w

for non-scientific reasons. Prior use of lenalidomide andbortezomib was a prerequisite for eligibility in thisstudy. The preliminary results suggest an ORR of 14% inthis heavily pretreated (median number of therapies �5) population (Table 4).39 A phase I/II trial evaluatinganother novel HSP inhibitor (HSPI), KW 2478, incombination with bortezomib is currently ongoing(NCT01063907). The results of a completed phase III,open-label trial (NCT00546780) for patients with MMin first relapse, comparing tanespimycin plus fixed-dose of bortezomib with bortezomib alone wouldhopefully shed light on the efficacy of this doublet,which has demonstrated modest activity to date.

Deacetylase Inhibitors With Bortezomib

In vitro data suggest that deacetylase inhibitors(DACIs) exhibit potent anti-myeloma activity in com-bination with bortezomib by inhibiting aggresomeformation, or by enhancing the histone acetylationproperties of bortezomib (Table 1). Deacetylases(DACs) are enzymes that remove the acetyl groupsfrom several target (both histone and non-histone) pro-teins, including HSP90, HIF-1a, BCL-6, and p53, in-volved in the DNA repair, gene expression, and cellgrowth. DACIs reverse the deacetylated status of MMcells and lead to persistent acetylation. This promotesexpression of genes that induce cell cycle arrest andapoptosis.40 Four clinical trials evaluating the efficacyof DACI in MM as monotherapy have demonstratedmodest activity but acceptable safety profiles. ThePANORAMA 2 study, a multicenter, phase II trial of panDACI, panabinostat-bortezomib and dexamethasone, inpatients who had to be bortezomib-refractory for en-rollment showed an ORR of nearly 25%.41 Anotherecently reported small phase I/II study evaluating theombination of bortezomib, dexamethasone, and ro-idepsin (an HDAC inhibitor, currently approved for

utaneous T-cell lymphoma) in the relapsed-refractoryM demonstrated a 60% PR rate.42 A retrospective

eview of nine patients, refractory to VRD who re-eived vorinostat (Z) additionally (VRDZ) demon-trated 89% disease-control rate (stable disease or bet-er), but disappointingly short median duration ofesponse of 3 months and median OS of 4 monthsrange, 3–21 months).43

The aforementioned results with bortezomib–DACI combinations (Table 4) while interesting needconfirmation in phase III trials to isolate what benefit,if any, is due to the addition of DACI. Two phase IIItrials, the VANTAGE 088 study44 (a randomized, dou-

le-blind, placebo-controlled phase III trial of bort-zomib versus vorinostat plus bortezomib) and theANORAMA 1 trial45 (panabinostat, bortezomib v bort-zomib) are addressing this. Prelimininary results ofANTAGE 088 have been reported and are sobering,

ith no clinically significant improvement in PFS (the

Table 4. Selected Phase I and II Trials of Combinations Involving Bortezomib (V) and Enzyme Inhibitors or Monoclonal Antibodies in Relapsedand/or Refractory Multiple Myeloma

Class/Agent(s) Phase N CBR % CR % PR % SD % PFS mo OS mo Comments

Heat Shock Protein 90 Inhibitori) Tanespimycin � VMTD: 340 mg/m2 IV38

1/2 72V naïveV pretreatedV refractory

27482213

3 12 33 NA7.23.71.6

18NR

17.713.8

Severe PN not noted possibly due to neuroprotectiveeffects of tanespimycin. Lower anorexia,constipation & neutropenia rates compared to Valone.

TIME 2 Tanespimycin�V39 2 22 14 0 9 45 NA NA Study prematurely terminated due to resource-related reasons

Deacetylase Inhibitorsi) VANTAGE 09565

Vorinostat�V � Dex after 4 cycles if SD2b 143 31 1 16 46 3 11 Activity shown in a heavily pre-treated

cohort.(median 4 lines); V refractory andrefractory, intolerant, or ineligible for IMiD-basedtherapy

ii) PANORAMA-241

Panabinostat�V�Dex2 55 49 0 20 NA NA NA A relatively low rate of PN (24%) seen. 2% grade

3/4 PN observed. Contrast romidepsin�VDiii) Panabinostat�V � Dex (San Miguel) 238 1B Escalation part 47

Expansion part 15V refractory

7666

13 40 15 NA NA Common GD3/4 AEs thrombocytopenia,neutropenia, asthenia and anemia

iv) Romidepsin �V� Dex42 1/2 25 72 8 52 8 7* 76% at 1-yr PN rates (76%) almost twice that reported in APEX(36%).

AKT/mTOR/Farnesyl Transferase or Serine/ThreonineKinase Inhibitors

i) Perifosine�V� Dex50 1/2 84V relapsed 20V refractory 53

416532

410

2

183511

413543

696

25NR

23

Overall well tolerated; side effects, including GItoxicities and fatigue were manageable.

ii) Temsirolimus�V48 12

2043

2047

05

519

6044

65

11NR

3 deaths noted during treatment. Cytopeniascommonly seen

iii) Tipifarnib�V52 1 16 13 NA 32 NA NA Commonest AE: Gd 2 diarrhea (24%)iv) Enzastaurin�V66 1 23 NA 0 17 39 8* NA Commonest AE: anemia (70%)

Monoclonal Antibodiesi) Elotuzumab �V55 1 28 63 7 41 NA 10* NA Elotuzumab related key toxicities: infusion reactionsii) Siltuximab�V67 2 21 NA 14 43 NA NA NA 33% discontinued therapy due to AE

Abbreviations: CBR, clinical benefit rate; CR, complete remission; PR, partial remission; SD, stable disease; PFS, progression-free survival; OS, overall survival; NA, not available; NR, not reached; Gd, grade; PN, peripheralneuropathy; AE, adverse effects; IMiDs, immunomodulatory drugs.

*Time to progression.

Bortezomib

combination

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238 P. Kapoor, V. Ramakrishnan, and S.V. Rajkumar

median improvement was 26 days), and no improve-ment in OS (Table 3). The results of the PANORAMA 1trial are awaited.16

AKT and mTOR Inhibitors Plus Bortezomib

The activated PI3-K/AKT/mammalian target of rapa-mycin (mTOR) pathway is a critical cytokine stimulatedpro-tumoral pathway46 that mediates growth and sur-ival of MM cells through their interaction with theMSCs. TORC1 complex of the downstream mTORinase is inhibited by rapalogs. However, TORC1 inhi-ition-associated feedback activation of the PI3K/AKTathway protects against apoptosis, and TORC1 inhib-

tors can only induce cell-cycle arrest without apopto-is. Dual TORC1/2 complex inhibitors may overcomehe activated AKT-mediated resistance seen with use ofORC1 inhibitors alone. In fact, a recent preclinicaltudy has shown that TORC1/2 knock-down signifi-antly inhibits the proliferative capacity of MM cells.47

However, the issue of the feedback activation of theMEK/ERK resistance pathway as a result of TORC1inhibition still remains. Therefore, mTOR inhibitors orAKT inhibitors in combination with inhibitors of theMEK/ERK pathway could potentially be more useful.

The postulation of synergy between PI3K/AKT/mTOR pathway inhibition and bortezomib formed thebasis of a recent phase I/II trial studying the steroid-sparing regimen of weekly temsirolimus (a rapalogwith anti-TORC1 activity) and bortezomib in heavily-pretreated relapsed and refractory MM patients. In thephase II portion, a third of patients (14 of 43) attaineda PR or better. Myelosuppression, particularly throm-bocytopenia, was the most common toxicity ob-served.48

Resistance to bortezomib-induced apoptosis has beendemonstrated to be associated with AKT, �-catenin, andurvivin (a member of inhibitor of apoptosis family) up-egulation. Perifosine is a novel, proapoptotic, signalransduction modulator that directly inhibits the constitu-ively phosphorylated AKT in MM cells. This well-toler-ted, oral agent has demonstrated activity in re-apsed/refractory MM in combination with both theonventional and novel anti-myeloma agents.49 Re-ently, a phase I/II study of perifosine in combinationith bortezomib with or without dexamethasone eval-ated a heavily pretreated cohort of 84 patients withelapsed and/or refractory MM (Table 4).50 An ORR of

41% (65% in bortezomib–relapsed and 32% in bort-ezomib refractory) was noted. Gastrointestinal toxici-ties, fatigue, and musculoskeletal pain were the predom-inant toxicities encountered. A phase III multicenter trialof testing the value of perifosine in relapsed/refractorypatients previously treated with bortezomib is ongoing

(NCT01002248).

Farnesyl Transferase Inhibitors

A phase II trial evaluating the efficacy of the single-agent farnesyl transferase inhibitor (FTI), tipifarnib,was conducted on the premise that MM patients withmutated Ras exhibit reduced chemosensitivity and tar-geting farnesylation of oncoprotein Ras would inhibitits membrane association and signaling activity.51 Thetudy involved 43 heavily pretreated patients with ad-anced MM and demonstrated disease stabilization in4% of patients independent of farnesyl inhibition. Therug was well tolerated (toxicities included fatigue,iarrhea, myelosuppression, and neuropathy) and 40atients with stable disease remained stable for 5onths or more.51 This study, along with the demon-

stration of preclinical synergistic activity of combina-tion therapy (Table 1), served as the basis for phase Itrial evaluating combination of bortezomib and FTI inrelapsed/refractory MM (Table 4). Again, so far onlystabilization of disease has been reported in nearly 50%of patients and the optimal dose is yet to be defined.52

The sequence of drug administration in the combina-tion is important and bortezomib followed by FTI isrecommended for optimal efficacy.52 The combinationppears to be effective, but more data are required.

Monoclonal Antibodies

Potential targets for monoclonal antibodies (MAbs)in MM include antigens predominantly expressed onMM cells, growth factors, their receptors, and signalingproteins although to date only modest clinical activityhas been observed with MAb monotherapy in MM.53

While meaningful responses have been noted withwell-tolerated bortezomib-based regimens incorporat-ing elotuzumab (humanized anti-CS1 antibody) or sil-tuximab, a chimeric anti–IL-6 MAb (Table 4), the resultsof a recent randomized phase II trial of bortezomibversus bortezomib � mapatumumab (a fully humangonistic antibody activating the tumor necrosis fac-or–related apoptosis-inducing ligand [TRAIL] recep-or-1) in relapsed refractory patients were largely dis-ppointing.54 A phase II trial of MPV with or without

siltuximab is currently underway (NCT00911859).Out of the many MAb combination therapies evalu-

ated so far, elotuzumab-based combinations with thenovel agents, bortezomib or Lenalidomide, appear tobe the most promising in relapsed refractory MM. In aphase I study of bortezomib and elotuzumab, nearlytwo thirds of patients achieved a clinically meaningfulresponse (� minor response) with nearly half of allevaluable patients achieving at least a PR.55 The medianime to progression was 9.5 months. Infusion-relatedoxicities and grade 3–4 lymphopenia (25%) were com-only encountered, although adverse effects were

argely manageable.55

The place of MAb therapy in the current treatment

paradigms for MM is still evolving. The results of ongo-

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Bortezomib combination therapy in multiple myeloma 239

ing trials with MAbs plus existing novel agent-basedtherapies will define the roles of these agents that havea relatively favorable toxicity profile.

CONCLUSIONS AND FUTURE DIRECTIONS

Implicit in our review is the development of numer-ous potent bortezomib-based combinations that havespawned during the past decade. Importantly, the eco-nomic implications of combining expensive agents de-serve to be factored into the clinical decision making.The UPFRONT22 and the PETHEMA trials19 comparinghe efficacy of different bortezomib-based combina-ions have been unable to establish the superiority ofne specific combination. Specifically, the high-riskatients continue to have a poor outcome, althoughome bortezomib-based regimens appear to be able tovercome the adverse prognostic effects of t(4;14)hen bortezomib-based induction and maintenance

herapy is incorporated into the treatment plan, partic-larly in the context of tandem transplantation. Withime, neoplastic plasma cells acquire a succession ofistinctive features that enable them to proliferate viactivation of alternative pathways notwithstanding thelethora of available combination therapies. Severalext-generation PIs with molecular characteristics dif-erent from bortezomib are being evaluated, and a fewhat target different proteasome subunits can some-hat overcome bortezomib resistance when used

lone or with other effective agents.While several combinations outlined in this re-

iew are frequently being used, ongoing trials allowne to envision an optimized approach to protea-ome inhibition that incorporates rational use ofortezomib as well as newer second-generation PIsuch as carfilzomib, marizomib, and MLN 9708. De-irable properties such as oral route of administra-ion and improved safety profile may make some PIsttractive agents if their clinical efficacy is con-rmed. The last decade has established a solid foun-ation upon which many rational bortezomib- andhe next-generation PI-based combination regimensan be developed to further improve the outcome ofatients afflicted with MM.

REFERENCES1. Rajkumar SV, Richardson PG, Hideshima T, Anderson

KC. Proteasome inhibition as a novel therapeutic targetin human cancer. J Clin Oncol. 2005;23:630–9.

2. Richardson PG, Barlogie B, Berenson J, et al. A phase 2study of bortezomib in relapsed, refractory myeloma.N Engl J Med. 2003;348:2609–17.

3. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progressionand survival in multiple myeloma relapsing after therapywith IMiDs and bortezomib: a multicenter InternationalMyeloma Working Group study. Leukemia. 2012;26:

149–57.

4. Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase Itrial of the proteasome inhibitor PS-341 in patients withrefractory hematologic malignancies. J Clin Oncol. 2002;20:4420–7.

5. Richardson PG, Barlogie B, Berenson J, et al. Extendedfollow-up of a phase II trial in relapsed, refractorymultiple myeloma: final time-to-event results from theSUMMIT trial. Cancer. 2006;106:1316 –9.

6. Jagannath S, Barlogie B, Berenson JR, et al. Updatedsurvival analyses after prolonged follow-up of the phase2, multicenter CREST study of bortezomib in relapsed orrefractory multiple myeloma. Br J Haematol. 2008;143:537–40.

7. Richardson PG, Sonneveld P, Schuster M, et al. Extendedfollow-up of a phase 3 trial in relapsed multiple my-eloma: final time-to-event results of the APEX trial. Blood.2007;110:3557–60.

8. Ling SC, Lau EK, Al-Shabeeb A, et al. Response of my-eloma to proteasome inhibitor bortezomib is correlatedwith unfolded protein response regulator XBP-1. Haema-tologica. 2012 Jan;97:64–72.

9. Richardson PG, Weller E, Lonial S, et al. Lenalidomide,bortezomib, and dexamethasone combination therapy inpatients with newly diagnosed multiple myeloma. Blood.2010;116:679–86.

0. Anderson KC, Jagannath S, Jakubowiak A, et al. Lenalido-mide, bortezomib, and dexamethasone in relapsed/re-fractory multiple myeloma (MM): encouraging outcomesand tolerability in a phase II study. ASCO Meeting Ab-stracts. 2009;27(15S):8536.

1. Kumar S, Flinn IW, Richardson PG, et al. Randomized,multicenter phase 2 study (EVOLUTION) of combina-tions of bortezomib, dexamethasone, cyclophosphamideand lenalidomide in previously untreated multiple my-eloma. Blood. 2012 Mar 17. Epub ahead of print.

2. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib withthalidomide plus dexamethasone compared with thalid-omide plus dexamethasone as induction therapy before,and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple my-eloma: a randomised phase 3 study. Lancet. 2010;376:2075–85.

3. Rosinol L, Cibeira MT, Martinez J, et al. Thalidomide/dexamethasone (TD) vs. bortezomib (Velcade)a/thalido-mide/dexamethasone (VTD) vs. VBMCP/VBAD/Velcadeaas induction regimens prior autologous stem cell trans-plantation (ASCT) in multiple myeloma (MM): results ofa phase III PETHEMA/GEM trial. ASH Annual MeetingAbstracts. 2009;114:130.

4. Moreau P, Avet-Loiseau H, Facon T, et al. Bortezomib plusdexamethasone versus reduced-dose bortezomib, thalido-mide plus dexamethasone as induction treatment prior toautologous stem cell transplantation in newly diagnosedmultiple myeloma. Blood. 2011;118:5752–8.

5. Mitsiades N, Mitsiades CS, Richardson PG, et al. Theproteasome inhibitor PS-341 potentiates sensitivity ofmultiple myeloma cells to conventional chemotherapeu-tic agents: therapeutic applications. Blood. 2003;101:2377–80.

6. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomibplus melphalan and prednisone for initial treatment of

multiple myeloma. N Engl J Med. 2008;359:906–17.

2

2

3

3

3

3

3

3

3

3

3

3

4

4

240 P. Kapoor, V. Ramakrishnan, and S.V. Rajkumar

17. Miguel JFS, Schlag R, Khuageva NK, et al. Continuedoverall survival benefit after 5 years’ follow-up with bort-ezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with previously untreatedmultiple myeloma, and no increased risk of second pri-mary malignancies: final results of the phase 3 VISTAtrial. ASH Annual Meeting Abstracts. 2011;118(21):476.

18. Miguel JFS, Richardson PG, Orlowski RZ, et al. Risk ofsecond primary malignancies (SPMs) following bort-ezomib (Btz)-based therapy: analysis of four phase 3randomized controlled trials in previously untreated orrelapsed multiple myeloma (MM). ASH Annual MeetingAbstracts. 2011;118:2933.

19. Mateos MV, Oriol A, Martinez-Lopez J, et al. Bortezomib,melphalan, and prednisone versus bortezomib, thalido-mide, and prednisone as induction therapy followed bymaintenance treatment with bortezomib and thalidomideversus bortezomib and prednisone in elderly patients withuntreated multiple myeloma: a randomised trial. LancetOncol. 2010;11:934–41.

20. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-mel-phalan-prednisone-thalidomide followed by mainte-nance with bortezomib-thalidomide compared withbortezomib-melphalan-prednisone for initial treatmentof multiple myeloma: a randomized controlled trial.J Clin Oncol. 2010;28:5101–9.

21. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneousversus intravenous administration of bortezomib in pa-tients with relapsed multiple myeloma: a randomised,phase 3, non-inferiority study. Lancet Oncol. 2011;12:431–40.

22. Niesvizky R, Flinn IW, Rifkin R, et al. Efficacy and safetyof three bortezomib-based combinations in elderly,newly diagnosed multiple myeloma patients: resultsfrom all randomized patients in the community-based,phase 3b UPFRONT study. ASH Annual Meeting Ab-stracts. 2011;118:478.

23. Niesvizky R, Flinn IW, Rifkin R, et al. Patient-reportedquality of life (QoL) in elderly, newly diagnosed multiplemyeloma (MM) patients receiving bortezomib-basedcombinations: results from all randomized patients in thecommunity-based, phase 3b UPFRONT study. ASH An-nual Meeting Abstracts. 2011;118:1864.

24. Reeder CB, Reece DE, Kukreti V, et al. Cyclophosph-amide, bortezomib and dexamethasone induction fornewly diagnosed multiple myeloma: high response ratesin a phase II clinical trial. Leukemia. 2009;23:1337–41.

25. Reeder CB, Reece DE, Kukreti V, et al. Once- versustwice-weekly bortezomib induction therapy with Cy-BorD in newly diagnosed multiple myeloma. Blood.2010;115:3416–7.

26. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomizedphase III study of pegylated liposomal doxorubicin plusbortezomib compared with bortezomib alone in re-lapsed or refractory multiple myeloma: combinationtherapy improves time to progression. J Clin Oncol.2007;25:3892–901.

27. Ciolli S, Leoni F, Casini C, Breschi C, Santini V, Bosi A.The addition of liposomal doxorubicin to bortezomib,thalidomide and dexamethasone significantly improvesclinical outcome of advanced multiple myeloma. Br J

Haematol. 2008;141:814–9.

8. Berenson JR, Yellin O, Chen CS, et al. A modified regi-men of pegylated liposomal doxorubicin, bortezomiband dexamethasone (DVD) is effective and well toleratedfor previously untreated multiple myeloma patients. Br JHaematol. 2011;155:580–7.

9. Jakubowiak AJ, Kendall T, Al-Zoubi A, et al. Phase II trialof combination therapy with bortezomib, pegylated li-posomal doxorubicin, and dexamethasone in patientswith newly diagnosed myeloma. J Clin Oncol. 2009;27:5015–22.

0. Popat R, Oakervee HE, Hallam S, et al. Bortezomib,doxorubicin and dexamethasone (PAD) front-line treat-ment of multiple myeloma: updated results after long-term follow-up. Br J Haematol. 2008;141:512–6.

1. Sonneveld P, Schmidt-Wolf I, van der Holt B, et al. HO-VON-65/GMMG-HD4 randomized phase III trial compar-ing bortezomib, doxorubicin, dexamethasone (PAD) vsVAD followed by high-dose melphalan (HDM) and main-tenance with bortezomib or thalidomide in patients withnewly diagnosed multiple myeloma (MM). ASH AnnualMeeting Abstracts. 2010;116:40.

2. Sonneveld P, van der Holt B, Schmidt-Wolf IGH, et al.First analysis of HOVON-65/GMMG-HD4 randomizedphase III Trial comparing bortezomib, adriamycine,dexamethasone (PAD) vs VAD as induction treatmentprior to high dose melphalan (HDM) in patients withnewly diagnosed multiple myeloma (MM). ASH AnnualMeeting Abstracts. 2008;112:653.

3. Neben K, Lokhorst HM, Jauch A, et al. Administration ofbortezomib before and after autologous stem cell trans-plantation improves outcome in multiple myeloma pa-tients with deletion 17p. Blood. 2012;119:940–8.

4. Pineda-Roman M, Zangari M, Haessler J, et al. Sustainedcomplete remissions in multiple myeloma linked to bort-ezomib in total therapy 3: comparison with total therapy2. Br J Haematol. 2008;140:625–34.

5. Hoering A, Mitchell A, Sexton R, Crowley J, Barlogie B.Prognostic index for predicting overall survival andevent-free survival in Total Therapy 3 patients. ASH An-nual Meeting Abstracts. 2010;116:1342.

6. Nair B, van Rhee F, Shaughnessy JD Jr, et al. Superiorresults of Total Therapy 3 (2003–33) in gene expressionprofiling-defined low-risk multiple myeloma confirmedin subsequent trial 2006–66 with VRD maintenance.Blood. 2010;115:4168–73.

7. Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Antimy-eloma activity of heat shock protein-90 inhibition. Blood.2006;107:1092–100.

8. Richardson PG, Chanan-Khan AA, Lonial S, et al. Tane-spimycin and bortezomib combination treatment in pa-tients with relapsed or relapsed and refractory multiplemyeloma: results of a phase 1/2 study. Br J Haematol.2011;153:729–40.

9. Richardson PG, Badros AZ, Jagannath S, et al. Tanespi-mycin with bortezomib: activity in relapsed/refractorypatients with multiple myeloma. Br J Haematol. 2010;150:428–37.

0. McConkey D. Proteasome and HDAC: who’s zoomingwho? Blood. 2010;116:308–9.

1. Richardson PG, Alsina M, Weber DM, et al. Phase IIstudy of the pan-deacetylase inhibitor panobinostat in

combination with bortezomib and dexamethasone in

Bortezomib combination therapy in multiple myeloma 241

relapsed and bortezomib-refractory multiple myeloma(PANORAMA 2). ASH Annual Meeting Abstracts.2011;118:814.

42. Harrison SJ, Quach H, Link E, et al. A high rate of durableresponses with romidepsin, bortezomib, and dexameth-asone in relapsed or refractory multiple myeloma. Blood.2011;118:6274–83.

43. Siegel D, Bilotti E, McBride L, et al. Vorinostat overcomesresistance in patients with multiple myeloma refractoryto bortezomib, lenalidonide and dexamethasone. Hema-tologica. 2011;96(s1):S94.

44. Dimopoulos MA, Jagannath S, Yoon S-S, et al. Vantage088: vorinostat in combination with bortezomib in pa-tients with relapsed/refractory multiple myeloma: resultsof a global, randomized phase 3 trial. ASH Annual Meet-ing Abstracts. 2011;118:811.

45. San-Miguel JF, de Moraes Hungria VT, Yoon S-S, et al.Update on a phase III study of panobinostat with bort-ezomib and dexamethasone in patients with relapsedmultiple myeloma: PANORAMA 1. ASH Annual MeetingAbstracts. 2011;118:3976.

46. Hidalgo M. From node to pathway blockade: lessonslearned from targeting mammalian target of rapamycin.J Clin Oncol. 2012;30:85–7.

47. Maiso P, Liu Y, Morgan B, et al. Defining the role ofTORC1/2 in multiple myeloma. Blood. 2011;118:6860 –70.

48. Ghobrial IM, Weller E, Vij R, et al. Weekly bortezomib incombination with temsirolimus in relapsed or relapsedand refractory multiple myeloma: a multicentre, phase1/2, open-label, dose-escalation study. Lancet Oncol.2011;12:263–72.

49. Hideshima T, Catley L, Yasui H, et al. Perifosine, an oralbioactive novel alkylphospholipid, inhibits Akt and in-duces in vitro and in vivo cytotoxicity in human multiplemyeloma cells. Blood. 2006;107:4053–62.

50. Richardson PG, Wolf J, Jakubowiak A, et al. Perifosineplus bortezomib and dexamethasone in patients withrelapsed/refractory multiple myeloma previously treatedwith bortezomib: results of a multicenter phase I/II trial.J Clin Oncol. 2011;29:4243–9.

51. Alsina M, Fonseca R, Wilson EF, et al. Farnesyltransferaseinhibitor tipifarnib is well tolerated, induces stabilizationof disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced mul-tiple myeloma. Blood. 2004;103:3271–7.

52. Lonial S, Francis D, Karanes C, et al. A phase I MMRCclinical trial testing the combination of bortezomib andtipifarnib in relapsed/refractory multiple myeloma. ASHAnnual Meeting Abstracts. 2008;112:3706.

53. Richardson PG, Lonial S, Jakubowiak AJ, Harousseau JL,Anderson KC. Monoclonal antibodies in the treatment ofmultiple myeloma. Br J Haematol. 2011;154:745–54.

54. Belch A, Sharma A, Spencer A, et al. A multicenterrandomized phase II trial of mapatumumab, aTRAIL-R1 agonist monoclonal antibody, in combina-tion with bortezomib in patients with relapsed/refrac-tory multiple myeloma (MM). ASH Annual MeetingAbstracts. 2010;116:5031.

55. Jakubowiak AJ, Benson DM Jr, Bensinger W, et al. Elotu-

zumab in combination with bortezomib in patients with

relapsed/refractory multiple myeloma: updated resultsof a phase I study. ASH Annual Meeting Abstracts.2010;116:3023.

56. Kumar SK, Flinn I, Noga SJ, et al. Bortezomib, dexameth-asone, cyclophosphamide and lenalidomide combina-tion for newly diagnosed multiple myeloma: phase Iresults from the multicenter EVOLUTION study. Leuke-mia. 2010;24:1350–6.

57. Jakubowiak AJ, Griffith KA, Reece DE, et al. Lenalido-mide, bortezomib, pegylated liposomal doxorubicin, anddexamethasone in newly diagnosed multiple myeloma: aphase 1/2 Multiple Myeloma Research Consortium trial.Blood. 2011;118:535–43.

58. Kropff M, Liebisch P, Knop S, et al. DSMM XI study: dosedefinition for intravenous cyclophosphamide in combi-nation with bortezomib/dexamethasone for remissioninduction in patients with newly diagnosed myeloma.Ann Hematol. 2009;88:1125–30.

59. Sher T, Ailawadhi S, Miller KC, et al. A steroid-indepen-dent regimen of bortezomib, liposomal doxorubicin andthalidomide demonstrate high response rates in newlydiagnosed multiple myeloma patients. Br J Haematol.2011;154:104–10.

60. Belch A, Reece DE, Bahlis NJ, et al. Bortezomib[VELCADE], pegylated liposomal doxorubicin[DOXIL/CAELYX] and dexamethasone in the treat-ment of previously untreated multiple myeloma pa-tients: impact on quality-of-life. ASH Annual MeetingAbstracts. 2007;110:3618.

61. Reece DE, Rodriguez GP, Chen C, et al. Phase I-II trial ofbortezomib plus oral cyclophosphamide and prednisonein relapsed and refractory multiple myeloma. J Clin On-col. 2008;26:4777–83.

62. Kropff M, Bisping G, Schuck E, et al. Bortezomib incombination with intermediate-dose dexamethasoneand continuous low-dose oral cyclophosphamide forrelapsed multiple myeloma. Br J Haematol. 2007;138:330 –7.

63. Palumbo A, Gay F, Bringhen S, et al. Bortezomib, doxo-rubicin and dexamethasone in advanced multiple my-eloma. Ann Oncol. 2008;19:1160–5.

64. Berenson JR, Yellin O, Bessudo A, et al. Bendamustinecombined with bortezomib has efficacy in patientswith relapsed or refractory multiple myeloma: a phase1/2 study. ASH Annual Meeting Abstracts. 2011;118:1857.

65. Siegel DS, Dimopoulos MA, Yoon S-S, et al. Vantage 095:vorinostat in combination with bortezomib in salvagemultiple myeloma patients: final study results of a globalphase 2b trial. ASH Annual Meeting Abstracts. 2011;118:480.

66. Ghobrial IM, Munshi NC, Harris BN, et al. A phase Isafety study of enzastaurin plus bortezomib in the treat-ment of relapsed or refractory multiple myeloma. Am JHematol. 2011;86:573–8.

67. Rossi J-F, Manges RF, Sutherland HJ, et al. PreliminaryResults of CNTO 328, an anti-interleukin-6 monoclonalantibody, in combination with bortezomib in the treat-ment of relapsed or refractory multiple myeloma. ASH

Annual Meeting Abstracts. 2008;112:867.

242 P. Kapoor, V. Ramakrishnan, and S.V. Rajkumar

68. Rosinol L, Cibeira MT, Mateos MV, et al. Results of pre- andpost- autologous stem cell transplantation (ASCT) withthree induction regimens in multiple myeloma (MM): supe-riority of VTD (bortezomib/thalidomide/dexamethasone)over TD and VBMCP/VBAD plus bortezomib (VBMCP/

VBAD/V). Hematologica. 2011; 96(S1):S69.

69. Garderet L, Iacobelli S, Moreau P, et al. Bortezomib(Velcade)-thalidomide-dexaemthasone (VTD) is superiorto thalidomide-dexaemthasone (TD) in patients withmultiple myeloma (MM) progressing or relapsing afterautologous transplantation. Hematologica. 2011; 96(s1):

S72–3.