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2 CME Information LEARNING OBJECTIVES Integrate emerging research information on the use of proteasome inhibitors and immunomodulatory agents to individualize induction treatment recommendations and maintenance therapeutic approaches for elderly patients with multiple myeloma. Compare and contrast the benefits and risks of lenalidomide- and bortezomibbased induction therapy, and consider the role of combined immunomodulatory and proteasome-inhibitor regimens for elderly patients with multiple myeloma. Communicate the benefits and risks of postinduction maintenance therapy with lenalidomide- and bortezomib-based therapies to elderly patients with multiple myeloma. Weigh the benefit of continuous therapy with lenalidomide against the risk of development of second primary cancer for patients who receive lenalidomide with alkylating agents. CREDIT DESIGNATION STATEMENT Research To Practice designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

3 CME Information (Continued) HOW TO USE THIS CME ACTIVITY This CME activity contains slides and edited commentary. To receive credit, the participant should review the slide presentations, read the commentary, complete the Post-test with a score of 75% or better and fill out the Educational Assessment and Credit Form located at ResearchToPractice.com/5MJCASH2012/7/CME. FACULTY DISCLOSURES The following faculty (and their spouses/partners) reported real or apparent conflicts of interest, which have been resolved through a conflict of interest resolution process: Sagar Lonial, MD Professor Vice Chair of Clinical Affairs Director of Translational Research, B-Cell Malignancy Program Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, Georgia Advisory Committee: Bristol-Myers Squibb Company, Celgene Corporation, Merck and Company Inc, Millennium: The Takeda Oncology Company, Novartis Pharmaceuticals Corporation, Onyx Pharmaceuticals Inc.

4 CME Information (Continued) Paul G Richardson, MD Associate Professor of Medicine Harvard Medical School Clinical Director of the Jerome Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute Boston, Massachusetts Advisory Committee: Bristol-Myers Squibb Company, Celgene Corporation, Keryx Biopharmaceuticals Inc, Millennium: The Takeda Oncology Company, Nereus Pharmaceuticals Inc, Novartis Pharmaceuticals Corporation.

5 A Phase 3 Study Evaluating the Efficacy and Safety of Lenalidomide Combined with Melphalan and Prednisone Followed by Continuous Lenalidomide Maintenance (MPR-R) in Patients (Pts) 65 Years (Yrs) with Newly Diagnosed Multiple Myeloma (MDMM): Updated Results for Pts Aged Yrs Enrolled in MM-015 Palumbo A et al. Proc ASH 2011;Abstract 475.

6 Background Interim results from the randomized placebo-controlled Phase III trial MM-015 showed unprecedented reduction in the risk of disease progression with induction melphalan (M), prednisone (P) and Len (R) followed by Len maintenance therapy (MPR-R) (Proc ASH 2010;Abstract 622). Overall, MPR-R reduced the risk of disease progression by 58% compared to MP Objective: Report updated efficacy and safety results with a focus on a subpopulation of elderly patients, aged 65 to 75 years, from the MM-015 trial. Palumbo A et al. Proc ASH 2011;Abstract 475.

7 MM-015 Study Design (N = 459) RANDOMIZATION MPR-R MPR MP Double-Blind Treatment Phase Cycles (28-day) 1-9 Cycles 10+ M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1-21 M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1-21 M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 Placebo (PBO): days 1-21 Maintenance Lenalidomide 10 mg/day Days 1-21 Placebo (PBO) Placebo (PBO) Disease Progression Open-Label Extension Phase Lenalidomide (25 mg/day) +/- Dexamethasone Stratified by age ( 75 vs >75 years) and stage (ISS I/II vs III) Primary comparison: MPR-R vs MP With permission from Palumbo A et al. Proc ASH 2011;Abstract 475.

8 Second Primary Malignancies (SPMs) and Survival in All Patients SPM, n (IR per 100 per year) MPR-R (n = 150) MPR (n = 152) MP (n = 153) Total invasive SPMs 12 (3.04) 10 (2.57) 4 (0.98) Hematologic 7 (1.75) 6 (1.54) 1 (0.24) Solid tumors 5 (1.26) 5 (1.28) 3 (0.74) Nonmelanoma skin cancer 2 (0.50) 5 (1.29) 6 (1.50) Survival MPR-R MPR MP Median PFS* 31 mo 14 mo 13 mo Four-year OS rate 59% 58% 58% IR = incidence rate; OS = overall survival * Hazard ratio (HR) MPR-R vs MP: (p < 0.001); HR MPR vs MP: (p = 0.135) Palumbo A et al. Proc ASH 2011;Abstract 475.

9 Response Rates: Intention-to-Treat Population (65-75 Years) Best response MPR-R (n = 116) MPR (n = 116) MP (n = 116) ORR 79.3% 73.3% 47.4% VGPR 35.3% 35.3% 11.2% PR 44.0% 37.9% 36.2% SD 15.5% 23.3% 50.0% PD 0 0.9% 0 NE 5.2% 2.6% 2.6% Median time to response 2 mo 2 mo 3 mo ORR = overall response rate; PR = partial response; VGPR = very good PR; SD = stable disease; PD = progressive disease; NE = not evaluable Palumbo A et al. Proc ASH 2011;Abstract 475.

10 Time to PR and VGPR: MPR-R versus MP (65-75 Years) Patients 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% MPR-R PR MP PR MPR-R VGPR MP VGPR Cycle With permission from Palumbo A et al. Proc ASH 2011;Abstract 475.

11 PFS and OS (65-75 Years) Survival MPR-R MPR MP Median PFS* 31 mo 15 mo 12 mo 4-year OS 69% 61% 58% * MPR-R vs MP: (p < 0.001); HR MPR vs MP: (p = 0.006) HR MPR-R vs MP: (p = 0.133); HR MPR vs MP: (p = 0.639) Preplanned landmark analysis of PFS from maintenance entry showed a greater reduction in the risk of disease progression with MPR-R versus MPR (HR: 0.349; p < 0.001). Palumbo A et al. Proc ASH 2011;Abstract 475.

12 Grade 4 Hematologic Adverse Events (65-75 Years) Induction (MPR vs MP) Maintenance (Len vs PBO) MPR MP MPR-R MPR Neutropenia Neutropenia Thrombocytopenia Thrombocytopenia Anemia Anemia Febrile neutropenia Febrile neutropenia Patients (%) Patients (%) With permission from Palumbo A et al. Proc ASH 2011;Abstract 475.

13 Grade 3/4 Nonhematologic Adverse Events (65-75 Years) Induction (MPR vs MP) Maintenance (Len vs PBO) MPR MP MPR-R MPR Infections Bone pain Fatigue Rash DVT Infections Bone pain Fatigue Rash DVT PE Peripheral neuropathy Peripheral neuropathy Patients (%) Patients (%) DVT = deep vein thrombosis; PE = pulmonary embolism With permission from Palumbo A et al. Proc ASH 2011;Abstract 475. PE

14 Author Conclusions Independent of age, lenalidomide maintenance reduced the risk of progression by 65% (hazard ratio: 0.34). Induction therapy with MPR reduced the risk of disease progression by 39% in patients aged years with newly diagnosed MM (hazard ratio: 0.61). The continuous Len treatment with MPR-R in patients aged years decreased the risk of disease progression by 70% (hazard ratio: 0.30). MPR-R treatment regimen demonstrated a trend toward a survival benefit in patients aged years (hazard ratio: 0.70). Palumbo A et al. Proc ASH 2011;Abstract 475.

15 Investigator Commentary: Continuous Lenalidomide Treatment in Patients Age 65 to 75 with Newly Diagnosed Multiple Myeloma (NDMM) This trial validates a continuous treatment approach in the studied patient population and clearly demonstrates a maintenance effect from Len. Although MPR improved PFS, greater benefit was observed with continuous Len treatment after induction therapy. In my view MPR is a challenging combination to use because it is associated with myelosuppression and forces the use of a lower Len dose. For example, even though the study administered a low dose of Len (10 mg/d) for induction and maintenance, I tend to use a higher Len range of 15 to 20 mg for my patients during induction therapy when I use other agents such as bortezomib. This notwithstanding, these data are exciting and clearly demonstrate that Len is important in elderly populations with NDMM. Interview with Paul G Richardson, MD, January 24, 2012 This study clearly demonstrates that Len maintenance therapy has a major impact in terms of PFS in elderly patients with NDMM. However, whether MPR is better than MP is less clear. Maintenance therapy is important in elderly patients age 75 or older because there may not be a second chance for treatment if relapse occurs after stopping the initial therapy. Interview with Sagar Lonial, MD, January 25, 2012

16 Second Primary Malignancies in Newly Diagnosed Multiple Myeloma Patients Treated with Lenalidomide: Analysis of Pooled Data in 2459 Patients Palumbo A et al. Proc ASH 2011;Abstract 996.

17 Background The observation of an 8-fold increased incidence of AML/MDS in MGUS (monoclonal gammopathy of undetermined significance) compared to that of the general population supports a role of nontreatment-related factors in the development of AML/MDS in plasma cell dyscrasias (Blood 2011:118, 4086). In patients with multiple myeloma (MM), the risk of second primary malignancy (SPM) is influenced by age and the use of alkylating agents. Current study objective: Post hoc analysis to assess the risk of development of SPMs in patients with newly diagnosed MM who were enrolled in 9 studies of the European Myeloma Network Palumbo A et al. Proc ASH 2011;Abstract 996.

18 Study Method SPM incidence rates per 100 person-years were examined from 9 trials: RVMM EMN01; RVMMEMN 441; RVMM PI 026; RVMM PI 302; RVMM PI 209; GIMEMA MM 03 05, GIMEMA MM 04 05, GISMM 2001; HOVON 87. Treatment received in the examined trials: Cyclophosphamide-lenalidomide-corticosteroids (CRC), n = 326 Melphalan-prednisone-lenalidomide (MPR), n = 668 Autologous stem cell transplant followed by lenalidomide maintenance (ASCT-R), n = 484 Melphalan-prednisone (MP), n = 164 MP-thalidomide (MPT), n = 384 MP-bortezomib (VMP), n = 257 MPV-thalidomide (VMPT), n = 254 Lenalidomide-low-dose dexamethasone (Rd), n = 147 Palumbo A et al. Proc ASH 2011;Abstract 996.

19 Incidence of SPMs per 100 per year* Treatment received Median follow-up (mo) Incidence (%) All patients (n = 2,283) Dex/cyclo-lenalidomide (n = 351) Melphalan-lenalidomide (n = 972) Melphalan-thalidomide (n = 539) Melphalan no IMiDs (n = 421) Dex = dexamethasone; Cyclo = cyclophosphamide * Post hoc analysis was restricted to pooled data from 2,283 patients with at least 1 year of follow-up. Palumbo A et al. Proc ASH 2011;Abstract 996.

20 SPM Cases SPMs (%) Treatment received Total Solid tumors Hematologic cancer All patients (n = 2,283) Dex/cyclo-lenalidomide (n = 351) Melphalan-lenalidomide (n = 972) Melphalan-thalidomide (n = 539) Melphalan no IMiDs (n = 421) Dex = dexamethasone; Cyclo = cyclophosphamide Post hoc analysis was restricted to pooled data from 2,283 patients with at least 1 year of follow-up. Palumbo A et al. Proc ASH 2011;Abstract 996.

21 Incidence of SPMs per 100 per Year Subgroup Analysis According to Therapy SPMs = second primary malignancies; Dex = dexamethasone; Cyclo = cyclophosphamide With permission, Palumbo A et al. Proc ASH 2011;Abstract 996.

22 SPMs and Risk of Death Dex/cyclo - Lenalidomine Melphalan - Lenalidomine Melphalan - Thalidomide Melphalan - no IMiDs Death Solid SPMs Hematologic SPMs Months Months Risk of death is greater than the risk of SPMs With permission, Palumbo A et al. Proc ASH 2011;Abstract 996.

23 Author Conclusions With a short follow-up time as a study limitation, the data currently support a role for nontreatment-related factors as causes of SPMs. SPM incidence was lower than expected in all treatment groups, and the observed and expected rates of SPMs were similar (data not shown). The benefits of continuous therapy with lenalidomide outweigh the potential risk of SPMs: The risk of death is greater than the risk of SPM. Longer follow-up is needed to assess the risks of SPMs in patients receiving lenalidomide with alkylating agents. Palumbo A et al. Proc ASH 2011;Abstract 996.

24 Investigator Commentary: Assessment of SPM Risk in MM This study from the European Myeloma Network clearly noted no reported cases of SPM in patients receiving cyclophosphamide and lenalidomide as a combination therapy. By contrast, melphalan, which is more genotoxic than cyclophosphamide, is associated with a small but observable rate of increased acute leukemia/mds in particular. I am aware from my own practice, and from historical data with melphalan, that there is a real signal in terms of secondary leukemia from treatment with melphalan. In a number of trials in the relapsed setting, in which patients have been receiving lenalidomide-based therapy for prolonged periods of time either lenalidomide alone or lenalidomide with dexamethasone the signals for a secondary malignancy related to lenalidomide use have been minimal. Based on the data from the IFM trial, I would say that the risk of SPM from maintenance lenalidomide after transplant is low, but if patients have not received much genotoxic therapy, they are much less likely to develop SPMs. Given the survival benefit now seen in the CALGB trial with the use of lenalidomide maintenance after SCT, these data must be kept very much in perspective, and certainly in our group the enthusiasm for continued therapy with lenalidomide in the appropriate clinical context remains high. Interview with Paul G Richardson, MD, January 24, 2012

25 Efficacy and Safety of Three Bortezomib-Based Combinations in Elderly, Newly Diagnosed Multiple Myeloma Patients: Results from All Randomized Patients in the Community-Based, Phase 3b UPFRONT Study Niesvizky R et al. Proc ASH 2011;Abstract 478.

26 Background Often elderly patients with multiple myeloma (MM) are not eligible for high-dose therapy and stem cell transplant (HDT- SCT) because of age and comorbidities. Bortezomib-based therapies have demonstrated activity in patients with newly diagnosed MM in several Phase II and III trials (JCO 2010;28:4621; Lancet 2010;376:2075). However, the efficacy and safety of different bortezomibbased treatment regimens have not been directly compared. Objective: Compare the efficacy and safety of bortezomib-based treatment regimens in patients with newly diagnosed MM who are not eligible for HDT-SCT, and evaluate its use as maintenance therapy. Niesvizky R et al. Proc ASH 2011;Abstract 478.

27 UPFRONT Trial Design Induction therapy (IT)* Eligibility (n = 502) Previously untreated symptomatic MM Ineligibility for HDT- SCT due to age, comorbidities or patient preference Measurable MM requiring systemic therapy R VD (8 cycles) (n = 168) V 1.3 mg/m 2, d1,4,8,11 x 8 cycles D 20 mg, d1,2,4,5,8,9,11,12, cycles 1-4; d1,2,4,5, cycles 5-8 VTD (8 cycles) (n = 167) V 1.3 mg/m 2, d1,4,8,11 x 8 cycles T 100 mg d1-21 x 8 cycles D 20 mg, d1,2,4,5,8,9,11,12, cycles 1-4; d1,2,4,5, cycles 5-8 VMP (8 cycles) (n = 167) V 1.3 mg/m 2, d1,4,8,11 x 8 cycles M 9 mg/m 2, d1,2,3,4 every other cycle P 60 mg/m 2, d1,2,3,4 every other cycle V = bortezomib; T = thalidomide; D = dexamethasone; M = melphalan; P = prednisone * Followed by maintenance therapy (MT): V 1.6 mg/m 2, d1,8,15,22 x 5 cycles Niesvizky R et al. Proc ASH 2011;Abstract 478.

28 Best Confirmed Response Rates (RRs) During Induction and Maintenance PR = partial response; VGPR = very good PR; CR = complete response; ncr = near CR With permission from Niesvizky R et al. Proc ASH 2011;Abstract 478.

29 Progression-Free Survival (PFS) in the Intention-to-Treat Population Proportion of patients Median follow-up period: 26 months VD (N = 168, 51% PFS events) VTD (N = 167, 42% PFS events) VMP (N = 167, 49% PFS events) Time (months) 1-year PFS estimates (n = 502): 57.4% (VD), 63.8% (VTD), 67.3% (VMP) There were no statistically significant differences among treatment arms With permission from Niesvizky R et al. Proc ASH 2011;Abstract 478.

30 Overall Survival (OS) in the Intention-to-Treat Population Proportion of patients 1.0 Median follow-up period: 26 months VD (N = 168, 27% OS events) 0.3 VTD (N = 167, 27% OS events) 0.2 VMP (N = 167, 25% OS events) Time (months) 1-year OS estimates (n = 502): 87.4% (VD), 86.1% (VTD), 88.3% (VMP) 2-year OS estimates: 73.7% (VD), 73.6% (VTD), 77.6% (VMP) There were no statistically significant differences among treatment arms With permission from Niesvizky R et al. Proc ASH 2011;Abstract 478.

31 Selected Adverse Events (AEs) VD VTD VMP IT MT IT MT IT MT Event (n = 165) (n = 82) (n = 158) (n = 60) (n = 163) (n = 69) At least 1 Grade 3 AE PN Fatigue Diarrhea Pneumonia Neutropenia 74% 19% 10% 9% 10% 2% 9% 6% 2% 4% 1% 0% 84% 24% 12% 3% 6% 3% 8% 7% 0% 5% 0% 0% 82% 19% 8% 7% 5% 18% 3% 3% 0% 6% 3% 0% 1 serious AE 48% 11% 53% 12% 47% 9% Discontinuation 29% 37% 34% IT = induction therapy; MT = maintenance therapy Quality of life (QoL) trend: Poorer in VTD versus VD and VMP treatment arms Niesvizky R et al. Proc ASH 2011;Abstract 478.

32 Peripheral Neuropathy Any grade PN Grade 3 PN Any grade causing discontinuation Grade 3 PN causing discontinuation Median time to PN onset IT (n = 165) 47% 19% 10% 7% VD 70 days MT (n = 82) 6% 1% 6% 6% IT (n = 158) 57% 24% 16% 12% IT = induction therapy; MT = maintenance therapy VTD 42 days MT (n = 60) 7% 5% 0% 0% VMP IT MT (n = 163) (n = 69) 44% 4% 19% 3% 17% 1% 13% 1% 63 days Niesvizky R et al. Proc ASH 2011;Abstract 478.

33 Author Conclusions VD, VTD and VMP were active in the treatment of elderly patients with newly diagnosed MM. After MT, VGPR rates were significantly higher for VTD than VD. PFS and OS appeared to be similar among the treatment arms in the intention-to-treat population at the studied follow-up period. The rates of Grade 3 AEs, serious AEs, discontinuations and PN were highest with VTD treatment. Maintenance with single-agent bortezomib was well tolerated with limited additional toxicity as compared to induction therapy. Triplet therapy with VTD or VMP appears to offer little advantage over doublet therapy with VD for improving RRs and survival in elderly patients with newly diagnosed, HDT-SCTineligible MM. Because alternative VMP regimens based on less intensive bortezomib dosing have showed activity in this patient population (JCO 2010;28:5101), weekly dosing may be preferable in the community-based setting. Niesvizky R et al. Proc ASH 2011;Abstract 478.

34 Investigator Commentary: Efficacy and Safety of 3 Bortezomib Combinations in Elderly Patients with Newly Diagnosed MM: Phase IIIb UPFRONT Study Results These results help in our understanding of the impact of weekly maintenance therapy with bortezomib. In general bortezomib is well tolerated and a viable option when offered as doublet therapy (such as VD) for elderly patients. In this randomized study VD was as effective as VTD and VMP in terms of long-term outcome. This should make clinicians comfortable with administering VD. At this point, the administration of VD subcutaneously is also a good option for elderly patients, especially for patients with underlying neuropathy, but one that must be approached with some caution. For example, I would start up-front therapy with VD by IV for a patient with aggressive newly diagnosed myeloma with high-risk features, in addition to perhaps considering a third agent, and then proceed with subcutaneous administration if PN developed. This is not only because bortezomib-induced PN is reversible and typically manageable, but also because in some patients with more advanced disease responsiveness can be lost with subcutaneous administration. This can be restored with IV therapy, suggesting that C max (which is the key difference between the 2 routes of administration) may matter in certain settings. Interview with Paul G Richardson, MD, January 24, 2012

35 Continued Overall Survival Benefit After 5 Years Follow-Up with Bortezomib-Melphalan-Prednisone (VMP) versus Melphalan-Prednisone (MP) in Patients with Previously Untreated Multiple Myeloma, and No Increased Risk of Second Primary Malignancies: Final Results of the Phase 3 VISTA Trial San Miguel JF et al. Proc ASH 2011;Abstract 476.

36 Background The initial report of VISTA with a median follow-up of 16.3 months demonstrated that VMP was superior to MP in response rates, time to progression and overall survival (OS) (NEJM 2008;359:906). Demonstrations of OS improvement are difficult as a result of availability of highly effective treatments for subsequent therapy and lack of longer-term follow-up. Some MM therapeutic agents are associated with increased risk of second primary malignancies (SPMs). Current Study Aim: Final updated OS analysis after a median follow-up of 60.1 months with analysis of impact of subsequent therapy Exploratory analysis of SPMs with long-term bortezomib use in VMP vs MP San Miguel JF et al. Proc ASH 2011;Abstract 476.

37 VISTA Study Design Eligibility (N = 682) Newly diagnosed, untreated, symptomatic, measurable myeloma ineligible for high-dose therapy + SCT due to age ( 65) or coexisting conditions R1:1 VMP (n = 344) nine 6-week cycles MP (n = 338) nine 6-week cycles Primary endpoint: Time to disease progression Patients are evaluated at least every 12 weeks for survival and subsequent therapy use. Data on SPMs were collected from 655 patients (96%) by individual patient queries at all study sites during February San Miguel JF et al. Proc ASH 2011;Abstract 476.

38 OS Analyses Patient group MP VMP Hazard ratio p-value Intent-to-treat (n = 338, 344) 43.1 mo 56.4 mo High-risk cytogenetics* (n = 20, 26) 50.6 mo 44.1 mo Age <75 (n = 237, 258) 47.7 mo 58.6 mo 0.68 Age 75 (n = 101, 115) 32.9 mo 50.7 mo 0.71 ISS Stage I (n = 64, 67) NA NA 0.8 ISS Stage II (n = 159, 176) 43.3 mo 56.4 mo 0.69 ISS Stage III (n=115, 130) 30.5 mo 42.1 mo 0.67 Creatinine Clr 60 ml/min (n = 154, 175) 52.7 mo 56.2 mo 0.72 Creatinine Clr <60 ml/min (n = 184, 198) 36.7 mo 56.8 mo 0.70 * Any of t(4;14), t(14;16), del(17p) San Miguel JF et al. Proc ASH 2011;Abstract 476.

39 OS Analyses According to Subsequent Therapies MP VMP Hazard ratio p-value OS from start of subsequent therapy mo 28.1 mo NR NR OS of all patients receiving subsequent therapy mo 55.7 mo OS of patients who have not relapsed or received salvage bortezomib mo 56.4 mo VMP does not induce more resistant relapses. 2 Bias against VMP resulting from omission of higher proportion of VMP versus MP patients who experienced the most benefit from treatment (ie, those who had not yet required subsequent therapy 35% versus 23%). 3 Analysis includes all VMP patients versus MP patients who have not received second-line therapy (as a result of not having relapsed or because of death) and those who received salvage bortezomib. San Miguel JF et al. Proc ASH 2011;Abstract 476.

40 SPMs: Exposure-Adjusted Incidence Rate SPM incidence rate, n per 100 patient-years VMP (N = 327) MP (N = 328) RR Exposure, patient-years 1,167 1,004 Hematologic SPMs Fatal Nonhematologic SPMs Fatal Overall rate Background rate, all cancers, general US population aged years, No increased risk of SPMs with addition of bortezomib to MP Overall incidence rates in both arms consistent with background rate of all cancers in the general US population aged years (SEER Cancer Statistics Review ). San Miguel JF et al. Proc ASH 2011;Abstract 476.

41 Author Conclusions Persistent significant OS benefit was observed after a median of 60.1 months of follow-up (13.3-month improvement) with VMP vs MP. Seen across multiple prespecified subgroups Maintained after 5 years follow-up and despite substantial use of novel agent-based salvage therapies OS subanalyses in patients receiving subsequent therapy demonstrate importance of providing optimal first-line treatment incorporating bortezomib rather than reserving bortezomib for salvage therapy and using conventional first-line treatment. No emerging safety signal for SPMs following VMP. Thorough data collection, with <5% of patients lost to follow-up San Miguel JF et al. Proc ASH 2011;Abstract 476.

42 Investigator Commentary: Continued OS Benefit After 5 Years Follow-Up with VMP versus MP in Patients with Previously Untreated Multiple Myeloma: Final Phase III VISTA Trial Results This study provides the longest follow-up that has been performed in a large international, randomized, Phase III trial. As shown in this study, with 5 years of follow-up the VMP treatment arm continues to demonstrate improved survival in comparison to MP. This reinforces the concept that the type of treatment administered at the initial stage of the disease can affect the entire natural history in an older patient. I would argue that a similar trend will probably occur in younger patients. However, because younger patients live much longer than older patients, such a trend would be harder to see than it is in this trial. Overall, I strongly believe that choosing the right treatment regimen early on is, in fact, critically important to changing the natural history of the disease. Interview with Sagar Lonial, MD, January 25, 2012

43 Maintenance Therapy with Bortezomib plus Thalidomide (VT) or Bortezomib plus Prednisone (VP) in Elderly Myeloma Patients Included in the GEM2005MAS65 Spanish Randomized Trial Mateos MV et al. Proc ASH 2011;Abstract 477.

44 Background In 2005 the Spanish Myeloma Group (GEM/PETHEMA) activated a 2-stage randomized trial in patients with untreated myeloma. No significant differences were observed in ORR or CR rate between patients receiving induction therapy with bortezomib/ melphalan/prednisone (VMP) and those receiving bortezomib/thalidomide/prednisone (VTP) in the first stage of this trial (Lancet Oncol 2010;11:934). In the second stage, patients were randomly assigned to maintenance therapy with bortezomib in combination with prednisone (VP) or thalidomide (VT). Current study objective: Compare the efficacy and safety of maintenance therapy with VT versus VP in the second stage of the trial. Mateos MV et al. Proc ASH 2011;Abstract 477.

45 GEM2005MAS65 Study Design VT Eligibility (N = 260) Elderly, untreated MM R VMP VTP R R VP VT VP Bortezomib was administered once a week for induction. Patients completing 6 induction cycles without disease progression or toxicity were moved to the second stage of maintenance. Mateos MV et al. Proc ASH 2011;Abstract 477. First stage Second stage Induction Maintenance

46 Dosing Schedule for Maintenance Therapy Bortezomib 1.3 mg/m 2 VT (n = 91) Day Rest period Thalidomide, 50 mg daily up to 3 years Bortezomib 1.3 mg/m 2 VP (n = 87) Day Rest period Prednisone, 50 mg every 48 h up to 3 years Bortezomib was administered every 3 months up to 3 years. With permission from Mateos MV et al. Proc ASH 2011;Abstract 477.

47 Response to Maintenance Therapy Premaintenance VT (n = 91) VP (n = 87) IF-CR 24% 46% 39% IF+CR 10% 10% 11% PR 47% 39% 47% MR 8% 3% 1% SD 10% 1% 1% IF = immunofixation; CR = complete response; PR = partial response; MR = minimal response; SD = stable disease After a median of 20 months of maintenance therapy, no significant difference in response was observed between the VT and VP arms. Mateos MV et al. Proc ASH 2011;Abstract 477.

48 Progression-Free Survival (PFS) and Overall Survival (OS) According to the Maintenance Arm PFS OS Proportion of pts VP: 32 m VT: 39 m Proportion of pts VP: 60 m VT: Not reached 5-y OS: 69% 0.0 p = 0.1 p = Time in months from 1 st randomization Time in months from 1 st randomization Median follow-up: 46 months PFS and OS: n = 178 With permission from Mateos MV et al. Proc ASH 2011;Abstract 477.

49 Selected Adverse Events Adverse event VT (n = 91) VP (n = 87) Grade 1/2 Grade 3/4 Grade 1/2 Anemia 1% Thrombocytopenia 2% Neutropenia 3% 1% GI symptoms 7% 4% 2% Grade 3/4 1% Peripheral neuropathy 37% 9% 17% 3% Cardiac events 5% 2% 1% Second primary malignancies: VT (n = 3), VP (n = 1) Deaths: VT (total: 26%, disease progression: 20%, toxicity: 6%) VP (total: 35%, disease progression: 30%, toxicity: 5%) Mateos MV et al. Proc ASH 2011;Abstract 477.

50 Author Conclusions Maintenance therapy with VT or VP improved the ORR and CR rate after soft induction therapy. No significant differences were observed between the maintenance arms, but a trend to better outcome was evident for VT. The toxicity profile was acceptable and slightly higher for the VT arm. Both maintenance regimens do not overcome the poor prognosis of high-risk cytogenetic abnormalities (data not shown). These bortezomib-based maintenance regimens represent an attractive platform for further optimization. Mateos MV et al. Proc ASH 2011;Abstract 477.

51 Investigator Commentary: Maintenance with Bortezomib in Combination with Thalidomide or Prednisone in Elderly Patients with Myeloma This update of the Spanish GEM2005MAS65 trial provides strong supportive data for bortezomib-based therapy as maintenance because an improvement in response was reported in both arms with its use, and interestingly, there was a trend toward a better outcome for the VT group. What is also exciting is that the PFS approached 40 months, which is remarkable, although the VT arm had more toxicity. In my view this is a nice proof-of-principle trial showing that the IMiD/proteasome inhibitor platform is effective in this setting, but care regarding side effects is important. Thus, this study opens the door to combining bortezomib with lenalidomide for maintenance therapy with less neurotoxicity and better tolerability. Interview with Paul G Richardson, MD, January 24, 2012