To Transplant or Not to Transplant, That is the Question for Multiple Myeloma Patients James R. Berenson, MD Medical & Scientific Director Institute for Myeloma & Bone Cancer Research Los Angeles, CA

Myeloma in 2013 Survival has greatly improved BUT it remains incurable in most cases (>95%)! Median survival has more than doubled since 2000 to more than 7 years (11 years in our recently published study)! Myeloma is not a “100 yard dash” disease anymore a marathon! Thus, It’s better to run 10 minute miles and run all 26 miles in the marathon than 4 minute miles and last only 5 miles! Berenson et al. Am J Hematol 2010

Treatment Choices for Myeloma Patients in 2013 The number of choices is growing rapidly! More new combinations involving already approved drugs Clinical trials of drugs recently and not yet approved Thus, it is becoming clear that patients have MANY more options today! Patients need to be able to avail themselves of the opportunity to receive different therapies Reducing that ability with too much prior treatment is detrimental

Establish the Goals of Therapy for the Individual Myeloma Patient Patient wants the longest life possible with therapy and a disease that has the least impact on their life! That does not necessarily mean they want the regimen w/ the highest % of CRs Remember that CRs in myeloma are based on paraprotein NOT really molecular CRs Very little difference in tumor burden between stable disease and “CR”

Arguments for Transplant in Myeloma Highest CR rates Higher CR associated w/ delay in time to progression (TTP) prolonged progression free survival (PFS) Older randomized trials show PFS/TTP and in some cases an overall survival advantage No additional therapy required following the transplant 5

Arguments for Transplant in Myeloma Highest CR rates Higher CR associated w/ delay in TTP prolonged PFS Older randomized trials show PFS/TTP and in some cases an overall survival advantage No additional therapy required following the transplant 6

Now the Highest CR Rates are w/o HDT: Frontline Carfilzomib, Lenalidomide and Dexamethasone Jakubowiak AJ, et al. ASCO 2012., Blood 2012; 120(9):1801-9 7

Why does CR compared to < CR delay TTP/PFS but effects on OS are mixed? These are not real CRs based on M-protein becoming undetectable PCR-based molecular CRs are only as sensitive as the assay Why CR consistently delays TTP Tumor Burden Easy to detect this relapse Patient 3 M-protein detectable Patient 2 CR! Patient 1 True CR

Arguments for Transplant in Myeloma Highest CR rates Higher CR associated w/ delay in TTP prolonged PFS Older randomized trials show PFS/TTP and in some cases an overall survival advantage No additional therapy required following the transplant 9

Transplants: Results from Randomized Trials and Meta-analyses No consistent advantage to overall survival (OS) from randomized Phase III trials EVEN PRIOR to the availability of new drugs (IMiDs, PIs) French & MRC trials- Yes! PETHEMA trial- No! Meta-analyses show PFS BUT not OS advantage Early vs Late (at time of progressive disease) No difference in overall survival from French and US Intergroup trials Attal et al. N Engl J Med 1996; Child et al. N Engl J Med 2003; Blade et al. Blood 2006; Fermand et al. 1998; Barlogie et al. J Clin Oncol 2006

Role of Transplant in the New Drug Era Early versus delayed transplant for IMiD-treated patients at Mayo Clinic: A Retrospective Study 290 previously untreated MM patients Pre-transplant induction treatment 167- Thalidomide+Dexamethasone 123- Lenalidomide+Dexamethasone Timing of transplant 173- early (w/i 12 months of diagnosis) 112- late (> 12 months from diagnosis) Results: No difference in either PFS or OS between early vs late transplanted patients! Kumar et al. Cancer 118:1585-1592, 2012 11

Upfront Len+Dex & then Randomized to MPL(R) versus ASCT x 2 402 patients (younger than 65 years) randomized from 62 centers l Patients: Symptomatic disease, organ damage, measurable disease l R A N D O M I Z T 1° 2° R A N D O M I Z T MPL six 28-day courses M: 0.18 mg/Kg/d, days 1-4 P: 2 mg/Kg/d, days 1-4 L: 10 mg/d, days 1-21 NO MAINTENANCE Ld* four 28-day courses L: 25 mg/d, days 1-21 d: 40 mg/d, days 1,8,15,22 MEL200 two courses M: 200 mg/m2 day -2 Stem cell support day 0 MAINTENANCE 28-day courses until relapse L: 10 mg/day, days 1-21 *Thromboprophylaxis randomization: aspirin vs low molecular weight heparin L, lenalidomide; d, low-dose dexamethasone; M, melphalan; P, prednisone; MEL200, melphalan 200 mg/m2 Palumbo, et al ASH 2011

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Arguments for Transplant in Myeloma Highest CR rates Higher CR associated w/ delay in TTP prolonged PFS Older randomized trials show PFS/TTP and in some cases an overall survival advantage No additional therapy required following the transplant 16

Len maintenance (10 mg/d)a Continuous Lenalidomide Therapy in Transplant-Eligible Patients CALGB 100104–Study Design Patients < 70 years of age ≤ 1 year from start of therapy Stratified by β2-microglobulin and Thal and Len use during induction Mel200 ASCT Restaging Days 90-100 CR, PR, SD Len maintenance (10 mg/d)a Placebo Randomization The CALGB 100104 trial is a phase 3 randomized, double-blind study evaluating lenalidomide maintenance vs placebo following autologous stem cell transplant (ASCT) in patients with multiple myeloma A total of 568 patients were registered across 46 centers in North America Key inclusion criteria: Stage 1-3 Durie-Salmon disease Aged < 70 years Achieving at least stable disease following at least 2 cycles of induction therapy Availability of 2 × 106 CD34+ cells/kg for ASCT Patients underwent ASCT with 200 mg/m2 melphalan conditioning Patients were restaged 90-100 days following ASCT and prior to randomization Patients with progressive disease were removed from the study Patients who achieved at least stable disease were randomly assigned to receive lenalidomide or placebo maintenance until progression The primary endpoints that were examined included the efficacy of prolonging time to progression (TTP) The study was powered to determine TTP improvement prolongation from 24 months to 33.6 months (a difference of 9.6 months) Secondary endpoints: complete response rate, progression-free survival, overall survival, and feasibility of long-term lenalidomide use Reference McCarthy PL, Owzar K, Anderson K, et al. Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant (ASCT) for multiple myeloma (MM): CALGB ECOG BMT-CTN 100104. Haematologica. 2011;96:S23-S24. [abstract]. Primary objective: efficacy of Len in prolonging TTP in MM patients after ASCT Secondary objectives: CR rate post-ASCT, PFS, OS, and feasibility of long-term Len administration a Dose adjustments between 5-15 mg/d of Len permitted. ASCT, autologous stem cell transplant; CR, complete response; Len, lenalidomide; Mel200, melphalan 200 mg/m2; MM, multiple myeloma; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease; Thal, thalidomide; TTP, time to progression. McCarthy P, et al. N Engl J Med 2012 17 17

Continuous Lenalidomide Therapy in Transplant-Eligible Patients CALGB 100104–Study Design CALGB 100104, NEJM 2012 follow up to 10/31/2011 ITT Analysis with a median follow-up from transplant of 34 months. P < 0.001 Estimated HR=0.48 (95% CI = 0.36 to 0.63), Median TTP: 46 months versus 27 months.

Continuous Lenalidomide Therapy in Transplant-Eligible Patients CALGB 100104–Study Design CALGB 100104, NEJM 2012 follow up to 10/31/2011 Median follow-up of 34 months There are 35 deaths in the lenalidomide arm and 53 deaths in the placebo arm. P = 0.028

Ongoing Phase III Trial for Previously Untreated MM: LBD Induction ± AutoTx + LBD Consolidation + L Maintenance Randomized, international, phase III trial in previously untreated MM patients who are candidates for HDT-PBSCT Patients: Symptomatic MM with measurable disease <65 yrs and transplant-eligible; ECOG <2 (KPS ≥60%) Arm A (LBD 8) LBD Cycles 2-3 HD Cytoxan and SC collection LBD Cycles 4-8 Maintenance Lenalidomide for 12 months (HD Melphalan + SCT at relapse) R A N D O M I Z E Primary Endpoint: PFS Secondary Endpoints: RR, TTP, OS, toxicity, quality of life, pharmacoeconomics, define genetic prognostic groups and best treatment for each group Initial Therapy LBD Cycle 1 Arm B (LBD 5) LBD Cycles 2-3 HD Cytoxan and SC collection HD Melphalan + PBSCT LBD for additional 2 cycles Maintenance Lenalidomide for 12 months *Randomization within 1st cycle 20 20

Transplants in 2013 for Myeloma: Con No consistent overall survival (OS) advantage from older or newer randomized trials Highest CR rates are w/o transplant (i.e. CLD) All patients now receive ongoing therapy Treatment options are rapidly increasing Thus, compromising a patient’s ability to receive these options because of toxicity from HDT is important to consider Also be careful interpreting results (especially OS) from trials where treatment options are limited As MM patients are living longer, optimizing QOL becomes of increasing importance 21

Treatment of Myeloma in 2013 It’s no longer about MORE It’s about being MORE SPECIFIC Transplants are only about MORE It’s time to focus on MORE SPECIFIC! More tumor specific treatments Therapies tailored to each MM patient’s disease, co-morbid conditions & lifestyle 22