1 Changing Patient Care in Multiple Myeloma: The IMF Nurse Leadership Board’s Long-Term Survivorship Care Plan Accredited by Medical Education Resources Supported by The International Myeloma Foundation Grant Funding Provided by Celgene Corporation and Millennium – The Takeda Oncology Company May 13, 2010 San Diego

2 TimeDiscussion TopicPresenter 12: :10 PM Welcome/Introductions and Multiple Myeloma Overview Elizabeth Bilotti 12: :30 PM Update on Current Therapies for the Treatment of Multiple Myeloma Beth Faiman 12: :45 PM The NLB’s Long-Term Survivorship Care PlanJoseph Tariman Impact of Myeloma Disease, Treatments, Long-Term Effects and Patient-Specific Characteristics on: 12:45 - 1:00 PM ○Bone Disease and Bone Health ○Functional Mobility Teresa Miceli 1:00 - 1:15 PM ○Renal Complications ○Sexuality and Sexual Dysfunctions Tiffany Richards 1:15 - 1:30 PM ○Health Maintenance Elizabeth Bilotti 1:30 PM Closing RemarksElizabeth Bilotti Agenda

3 Update on Current Therapies for the Treatment of Multiple Myeloma Beth Faiman, MSN, APRN-BC, AOCN ® Cleveland Clinic Taussig Cancer Institute Cleveland, OH

4 NCCN Review Categories Transplant NCCN Category Non Transplant NCCN Category Bortezomib/Dexamethasone*1Bortezomib/Melphalan/Prednisone (VMP)1 Bortezomib/Thalidomide/ Dexamethasone (VTD)* 1Melphalan/Prednisone/Thalidomide (MPT)1 Lenalidomide/Dexamethasone*1Lenalidomide/low Dexamethasone*1 Bortezomib/Doxorubicin/ Dexamethasone* 1Melphalan/Prednisone (MP)2A Dexamethasone*2BVincristine/Doxorubicin/Dexamethasone (VAD)*2B L-Doxorubicin/Vincristine/ Dexamethasone (DVD)* 2BThalidomide/Dexamethasone*2B Thalidomide/Dexamethasone*2BDexamethasone*2B Bortezomib/Lenalidomide/ Dexamethasone (VRD) 2BL-Doxorubicin/Vincristine/Dexamethasone (DVD) 2B NCCN Clinical Practice Guidelines in Oncology, v Generic NameTrade Name BortezomibVelcade LenalidomideRevlimid ThalidomideThalomid *Combinations recently reviewed by NCCN NCCN Categories of Evidence and Consensus: 1 High-level evidence, uniform consensus 2A Lower-level evidence, uniform consensus 2B Lower-level evidence, non-uniform consensus

5 Revised Categories of Evidence and Consensus – NCCN Guidelines, 2010 Multiple Myeloma Therapy Previous Category New Category Bortezomib/Dexamethasone 2B1 Bortezomib/Thalidomide/Dexamethasone (VTD) 2B1 Lenalidomide/Dexamethasone 2B1 Bortezomib/Doxorubicin/Dexamethasone 2B1 Lenalidomide/low Dexamethasone 2B1 Thalidomide/Dexamethasone 2A2B Dexamethasone 2A2B Vincristine/Doxorubicin/Dexamethasone (VAD) 2A2B L-Doxorubicin/Vincristine/Dexamethasone (DVD) 2A2B NCCN Clinical Practice Guidelines in Oncology, v NCCN Categories of Evidence and Consensus: 1 High-level evidence, uniform consensus 2A Lower-level evidence, uniform consensus 2B Lower-level evidence, non-uniform consensus

6 NCCN: Changing Categories of Consensus Change is a natural process secondary to constant stream of data from recent clinical studies Categories 2A and 2B are not indicative of inferiority of the treatment: …non-uniform consensus does not represent a major disagreement, rather it recognizes that given imperfect information, institutions may adopt different approaches. A Category 2B designation should signal to the user that more than one approach can be inferred from the existing data… NCCN, “Categories of Evidence and Consensus”, 2010

7 Future of MM Therapy: Recent and Ongoing Clinical Studies Patient Treatment Largely Determined by Transplant Status Transplant-ineligible patients –Bortezomib/Melphalan/Prednisone – Bortezomib/Thalidomide vs. Bortezomib/Thalidomide/Prednisone – Bortezomib/Prednisone –Bortezomib/Melphalan/Prednisone/Thalidomide – Bortezomib/Thalidomide vs. Bortezomib/Melphalan/Prednisone –Melphalan/Prednisone vs. Melphalan/Prednisone/Thalidomide –Melphalan/Prednisone vs. Melphalan/Prednisone/Lenalidomide vs. Melphalan/Prednisone/Lenalidomide (continued Lenalidomide) Transplant-eligible patients –Lenalidomide after ASCT –Melphalan/Prednisone/Lenalidomide (MPR) vs. high dose Melphalan Lenalidomide/Dexamethasone in Smoldering Myeloma –QUIREDEX Study New combinations and early studies –EVOLUTION Study –Pomalidomide/low Dexamethasone –Carfilzomib –Carfilzomib/Lenalidomide/Dexamethasone –Elotuzumab/Lenalidomide/Dexamethasone Point about transplant-ineligible studies Point about transplant eligible studies Point about early studies Beth – Could you add short comments for each cat or should we reomove

8 VMP vs. VTP Followed by VT vs. VP (ASH PLENARY SESSION) Mateos et al, Blood 114, Abstract 3, 2009 Study Objective: –Testing an alkylating agent (Melphalan) and an immunomodulatory drug (Thalidomide) as a partner for Bortezomib Study Design: –Prospective, multicenter, randomized –Induction: patients randomized to 6 cycles of VMP vs. VTP –Maintenance: patients randomized to VT vs. VP for up to 3 years A Phase III Study of Bortezomib/Melphalan/Prednisone (VMP) vs. Bortezomib/Thalidomide/Prednisone (VTP) Followed by Bortezomib/Thalidomide (VT) vs. Bortezomib/Prednisone (VP) in Elderly NDMM Patients

9 Conclusions from VMP – VT vs. VTP – VP Both induction schedules are highly effective with similar ORR and CR –More neutropenia but less cardiac toxicity and peripheral neuropathy with VMP Both maintenance therapies markedly improve responses Combination of these induction and maintenance regimens tend to overcome the poor prognosis of high-risk cytogenic abnormalities (CA) in elderly MM patients Induction≥PR, %CR, %CR/nCR, %TTP, %PFS, %OS, % VMP VTP MaintenanceCR, %1Y TTP, %1Y OS, % VT VP p-ValueNS0.05NS Mateos et al, Blood 114, Abstract 3, 2009

10 Bortezomib/Melphalan/Prednisone/Thalidomide – Bortezomib/Thalidomide Palumbo et al, Blood 114, Abstract 128, 2009 Study Objective: –Compare VMPT with a maintenance regimen including Bortezomib and Thalidomide with VMP without a maintenance regimen Study Design: –Prospective, randomized –Both regimens amended to 9 5-week cycles –Bortezomib modified to weekly administration (days 1,8,15,22) A Phase III Study of VMPT Followed by Maintenance with Bortezomib and Thalidomide for Initial Treatment of Elderly Multiple Myeloma Patients Bortezomib 1.3 mg/m 2 Melphalan 9 mg/m 2 Days 1-4 Prednisone 60 mg/m 2 Days 1-4 Thalidomide 50 mg Days 1-42 Bortezomib 1.3 mg/m 2 Melphalan 9 mg/m 2 Days 1-4 Prednisone 60 mg/m 2 Days 1-4 No Maintenance Bortezomib 1.3 mg/m 2 Days 1, 15 Thalidomide 50 mg/daycontinuously

11 Conclusions from VMPT – VT vs. VMP VMPT followed by VT was superior to VMP for response rates and PFS The weekly infusion of Bortezomib significantly reduced the incidence of grade 3-4 peripheral neuropathy –From 18% to 4% (p=0.0002) in VMPT arm –From 13% to 2% (p=0.0003) in VMP arm This is the first report showing the superiority of a 4- drug regimen followed by maintenance compared to standard therapy (VMP) Study ArmPR, %VGPR, %CR, %2Y PFS, %2Y OS, % VMPT-VT VMP p-Value Palumboet al, Blood 114, Abstract 128, 2009

12 Melphalan/Prednisone vs. Melphalan/Prednisone/Thalidomide Kapoor et al, Blood 114, Abstract 615, 2009 MP vs. MPT as Initial Therapy for Previously Untreated Elderly and/or Transplant Ineligible Patients with Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials Study Objective: –Systemic review of randomized controlled trials to compare efficacy of MP with MP+T –Clinical endpoints are Response Rate (RR), Progression-Free Survival (PFS) and Overall Survival (OS) Study Design –Comprehensive search of database to identify randomized controlled trials –Meta-analysis by pooling results on clinical endpoints

13 Conclusions from MP vs. MPT Five prospective randomized controlled trials were identified –1571 patients were evaluable in the studies The pooled odds ratio of responding to treatment indicated that MPT was better than MP in achieving at least a partial response The pooled hazards ratios for PFS and OS were in favor of MPT Analyses suggest that MPT is superior to MP in terms of response and survival Kapoor et al, Blood 114, Abstract 615, 2009

14 MP vs. MPR vs. MPR – R Palumbo et al, Blood 114, Abstract 613, 2009 Study Objective: –In previous studies Lenalidomide was efficacious in relapsed/refractory MM –Compare safety and efficacy of MPR in NDMM patients Study Design: A Phase III Study to Determine the Efficacy and Safety of Lenalidomide in Combination with Melphalan and Prednisone (MPR) in Elderly Patients with Newly Diagnosed Multiple Myeloma Melphalan 0.18 mg/kg Days 1-4 Prednisone 2 mg/kg Days 1-4 Lenalidomide 10 mg QD PODays 1-21 Melphalan 0.18 mg/kg Days 1-4 Prednisone 2 mg/kg Days 1-4 Lenalidomide 10 mg QD PODays 1-21 Melphalan 0.18 mg/kg Days 1-4 Prednisone 2 mg/kg Days 1-4 Placebo Days 1-21 Lenalidomide Placebo Lenalidomide Progression Placebo 9 28-day cycles Cycles 10+

15 Conclusions from MP vs. MPR vs. MPR – R MPR – R regimen reduced risk of progression by 50% vs. MP alone MPR followed by Lenalidomide maintenance is a new therapeutic option and can be considered a new standard for elderly patients Study Arm (patients)ORR, %CR, %≥ VGPR, %PR, % MPR-R (152) MPR (153) MP (154) Palumbo et al, Blood 114, Abstract 613, 2009

16 Lenalidomide after ASCT Attal et al, Blood 114, Abstract 529, 2009 First Analysis of a Phase III Study of the Intergroupe Francophone Du Myelome (IFM ) Study objective –Controlling the residual disease after high-dose therapy Neuropathy a major limiting factor in previous study –Lenalidomide evaluated as a newer agent without neurological toxicity Study design –Prospective, randomized, placebo controlled –1 st line ASCT less than 6 months before enrollment –Consolidation with Lenalidomide, 25 mg/day, po, 21 days/month, 2 months –Maintenance till relapse: Lenalidomide, mg/day

17 2 month consolidation with Lenalidomide: –80% of patients were able to receive the planned 2 cycles of consolidation –Significantly improved the sCR/CR rate Conclusions from Lenalidomide after ASCT Attal et al, Blood 114, Abstract 529, 2009 Post-consolidation category improvement CR to sCR VGPR to CR/sCR PR to VGPR/CR/sCR n, patients52925 Patient StatussCR/CR Ratep-Value Pre-consolidation Post-consolidation0.144

18 Melphalan/Prednisone/Lenalidomide vs. High Dose Melphalan MPR vs. Melphalan (200 mg/m 2 ) and Autologous Transplantation in Newly Diagnosed Myeloma Patients: An Interim Analysis Palumbo et al, Blood 114, Abstract 350, 2009 Study objective: –To compare Melphalan/Prednisone/Lenalidomide (MPR) with tandem Melphalan (200 mg/m 2 ) in patients younger than 65 years Study design: –Induction, 4 28-day cycles Lenalidomide 25 mg days 1-21 Low-dose Dexamethasone 40 mg days 1,8,15,22 –Consolidation: MPR arm: 6 28-days cycles –Melphalan 0.18 mg/kg days 1-4 –Prednisone 2 mg/kg days 1-4 –Lenalidomide 10 mg days 1-21 Melphalan arm: tandem melphalan 200 mg/m 2 with stem cell support

19 Conclusions from MPR vs. MEL200 Rd InductionPRVGPRCR Response, at least, %84275 Consolidation Arm 1 Year PFS, % 1 Year OS, % Neutro- penia, % Thrombo- cytopenia, % Infections % GI % MPR MEL p-Valuen/a <0.001 Rd is an effective and safe induction regimen Both MPR and MEL200 improved the quality of response –At 1 year follow-up, PFS and OS are similar in both groups –Longer follow-up is needed Palumbo et al, Blood 114, Abstract 350, 2009

20 Lenalidomide/Dexamethasone in Smoldering Myeloma Study objective –To investigate whether early treatment prolongs the time to progression (TTP) in sMM patients at high risk Study design –Multicenter, randomized, open-label –High risk population defined by Plasma Cells ≥10% and M-component ≥3g/dL –Len/Dex arm, 9 4-week cycles: Lenalidomide: 25 mg/daily, days 1-21 Dexamethasone: 20 mg/daily, days 1-4 and (total dose 160 mg) Maintenance with Lenalidomide, 10 mg on days 1-21 evert 2 months until progression Phase III trial of Lenalidomide/Dexamethasone vs. therapeutic abstention in Smoldering Multiple Myeloma (sMM) at high risk of progression to symptomatic MM Mateos et al, Blood 114, Abstract 614, 2009

21 In sMM patients, lack of treatment is associated with early progression (17.5 months) with bone disease Lenalidomide/Dexamethasone treatment prolonged TTP and induced CRs with a manageable and acceptable toxicity profile Conclusions From Lenalidomide/Dexamethasone in Smoldering Myeloma Interim AnalysesPatientsPR % VGPR % CR % sCR % ORR % Evaluable patients Completed 9 cycles Mateos et al, Blood 114, Abstract 614, 2009

22 Emerging New Treatments in Early Development ASCO 2009; Kumar et al, Blood 114, Abstract 127, 2009; Lonial et al, Blood 114, Abstract 432, 2009; Richardson et al, Blood 114, Abstract 301, 2009; Siegel et al, Blood 114, Abstract 303, 2009; Wang et al, Blood 114, Abstract 302, 2009; Niesvizky et al, Blood 114, Abstract 304, 2009 EVOLUTION Ph II Study –Novel 3- and 4-drug combinations: VDR, VDC, VDCR –Exploring the combination of Bortezomib and Dexamethasone with Lenalidomide and Cyclophosphamide in NDMM patients Development of a novel proteosome inhibitor, Carfilzomib –Appears to work in patients that are resistant to Bortezomib –Prior therapy with Bortezomib doesn’t preclude a good response –Minimal neuropathy and myelosuppression Development of Pomalidomide, an immunomodulatory drug –Evidence of efficacy in heavily pretreated patients with relapsed disease –Acceptable safety profile Development of Elotuzumab, a monoclonal antibody against a glycoprotein that is highly and uniformly expressed in MM –Manageable toxicity profile in combinations with other agents –Promising preliminary efficacy data

23 2 new clinical paradigms are shaping out: –Control Option Careful use of drugs, using agents sequentially –Cure Option Aggressive treatment in hope for cure for some patients Future Direction of New Therapy Combinations & Protocols of Novel Therapies ASCO 2009; ASH 2009 Treatment of Smoldering MM patients provided first evidence of efficacy in preventing progression Evolving role of the new drug combinations for transplant eligible and ineligible patients –New 4-drug aggressive regimen (VMPT) –New strategy for Bortezomib: weekly dose with much better tolerability

24 Conclusions Novel combination therapies exhibit great potentials in improving response rate, time to progression, progression-free survival, and overall survival outcomes Randomized clinical trials are underway to compare which of these novel combinations will offer patients better OS balanced with a good quality of life