1. 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

2. 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

3. 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

4. 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”

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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: , 2012 11

12. 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

15. 15

16. 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

17. Len maintenance (10 mg/d)a
Continuous Lenalidomide Therapy in Transplant-Eligible Patients CALGB –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
CR, PR, SD
Len maintenance (10 mg/d)a
Placebo
Randomization
The CALGB 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 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 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

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

19. Continuous Lenalidomide Therapy in Transplant-Eligible Patients CALGB 100104–Study Design
CALGB , 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

20. 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

21. 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

22. 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