Is autologous stem cell transplant the best consolidation after initial therapy?

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1 Is autologous stem cell transplant the best consolidation after initial therapy? William Bensinger, MD Professor of Medicine, Division of Oncology University of Washington School of Medicine Director, Autologous Stem Cell Transplant Program Fred Hutchinson Cancer Research Center Seattle, Washington

2 Managing myeloma: the components Transplant Eligible Patients Transplant Ineligible patients Initial Therapy Consolidation Auto Tx Maintenance Consolidation/ Maintenance/ Continued therapy Treatment of Relapsed disease Supportive Care

3 Theoretical results in MM Ineffective treatment Dexamethasone Tumor Volume Alkylators High-Dose Therapy Limit of detection Goal of newer therapy options Time Ultimate goal: Cure

4 2009 OptumHealth Education

5 2009 OptumHealth Education

6 Influence of Post Transplant Responses on Outcome 632 patients treated with VMCP/VBAD, ASCT, IFN/Pred Maint SD PR CR ncr 6 Lahuerta et al. ASH 2008, abstract #161

7 Arguments against Transplant Complete Response is a marker for survival BUT Retrospective Studies suggest patients in CR after induction DO NOT BENEFIT from ASCT High risk patients clearly have less benefit from ASCT Novel Drugs may eliminate hi-risk cells that lead to relapse making ASCT superfluous At least 1 randomized study of patients with MR or better after initial therapy shows no benefit of ASCT Tandem ASCT does not benefit VGPR or better patients Delaying ASCT until relapse does not have an adverse effect on survival 7

8 Complete Response and Survival in MM Should CR be a surrogate marker for long-term survival? 758 newly diagnosed patients with MM from 1987 to 2007 Response by European Group for Blood and Marrow Transplantation criteria Survival by Transplant and Response No Transplant Transplant Living (%) 50 CR 25 (9%) PR 170 (58%) P<0.01 Living (%) 50 CR 32 (9%) NR 96 (33%) P< Years NR=not reported. Wang. ASCO (abstr 8523). 0 NR 98 (26%) PR 245 (65%) Years P<0.01

9 PFS and OS Patients Who Achieve CR Before and After ASCT Freedom From Progression N=103 CR achieved before CR achieved after Fraction Surviving N= Months Months 9 Dingli D et al. J Clin Oncol. 2007;25:4933.

10 ASCT v. CC in MM patients responding to initial therapy PFS OS Blade, Blood, 2005

11 IFM 94: Single vs Double Transplant OS by Response to First Transplant < VGPR VGPR OS (%) Double Transplant Single Transplant Months After First Transplantation Months After First Transplantation 11 Attal M et al. N Engl J Med. 2003;349:2495.

12 BOLOGNA 96 CLINICAL TRIAL N=228 SURVIVAL AFTER Tx-1 vs Tx-2 ACCORDING TO FINAL RESPONSE PR CR + ncr 1,0 1,0,9,9,8,7 Tx-2 (67%),8,7 Tx-1 (85 mos),6,6,5 Tx-1 (59 mos),5 Tx-2 (73 mos),4,4,3,3,2,2,1 0,0 0 P= months ,1 0,0 0 P= months Courtesy of Drs. Tosi & Cavo Seràgnoli Institute -Bologna, Italy

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14 IFM Analysis of Cytogenetics/β 2 m on Survival After Tandem ASCT 1.00 Probability of Survival FISH, β 2 m < del13, β 2 m <4 FISH, β 2 m >4 4;14,17p, β 2 m <4 del13, β 2 m > ;14,17p, β 2 m > Months Avet-Loiseau H et al. Blood. 2007;109:3489

15 Bortezomib/Thal/Dex vs Thal/Dex as Induction Therapy MM: Efficacy in Hi Risk Groups P= % P= % P< % P= % % CR/nCR % 32% Del(13) t4;14 VTD 8% 4% Del(13) t4;14 TD 15 Cavo. ASH (abstr 73).

16 Drugs for MM Steroids Alkylators Class Vinca alkyloids Anthracyclines IMiDs Proteasome inhibitors Histone Deacetylase Inhibitors Drugs dexamethasone, prednisone cyclophosphamide, melphalan, bendamustine vincristine doxorubicin, PEG-DOX thalidomide, lenalidomide pomalidomide Bortezomib, carfilzomib panobinostat

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18 Stewart et al, Combinations in the Upfront Treatment of MM

19 Treatment schedule l 402 patients (younger than 65 years) randomized from 62 centers l Patients: Symptomatic disease, organ damage, measurable disease *Randomisation (2x2 design) Rd four 28-day courses MPR six 28-day courses MPR six 28-day courses MEL 200 Two courses # MEL 200 Two courses # R MAINTENANCE 28-day courses until PD NO MAINTENANCE R MAINTENANCE 28-day courses until PD NO MAINTENANCE * MPR vs MEL 200; R maintenance vs no maintenance; Anti-thrombotic substudy: Aspirin vs Low molecular weight heparin Rd (R: 25 mg/d, days 1-21; d: 40 mg/d, days 1,8,15,22); MPR (M: 0.18 mg/kg/d, days 1-4; P: 2 mg/kg/d, days 1-4; R: 25 mg, d 1-21), MEL 200 (M: 200 mg/m2 day -2); R maint (R: 10 mg/day, days 1-21); # One course MEL 200 if patients achieves VGPR after cycle 1 R: lenalidomide; MEL200: melphalan 200 mg/m2 and autologous stem cell transplant; MPR: melphalan-prednisone-lenalidomide; NDMM: newly diagnosed multiple myeloma.

20 MPR vs MEL200: Response Rate MPR (N=130) MEL200 (N=143) P value CR 20% 25% 0.49 > VGPR 60% 58% MPR 70 MEL200 Patients (%) CR VGPR PR 5 1 Patients (%) CR VGPR PR 4 1 SD PD SD PD

21 2009 OptumHealth Education

22 2009 OptumHealth Education

23 2009 OptumHealth Education

24 IFM 2008 Newly Diagnosed MM n VRD x3 -> HDM200 x1 -> VTD x2 -> Maint n N=31 n Major Response Rates CR n VRD x3-> 23% Increase n HDM x1-> 42% 83% n VRD x2-> 48% 14% Roussel ASH 2011 #1872

25 V(bortezomib)RD v. C(carfilzomib)RD in Upfront Treatment Combinations 36 mg/m2 36 mg/m2 Richardson, Blood, 2010, Jakubowiak Blood, 2012.

26 CRd in Newly Diagnosed MM: Efficacy and Durability Patients (%) Best Response PR VGPR ncr scr N = 53; median 12 cycles (range: 1-25) JakubJakubowiak AJ, et al. Blood owiak AJ, et al. ASCO Abstract Patients (%) Overall (n = 52; median 12 cycles; range: 1-25) ncr Cycles (n = 49; median 13 cycles; range: 4-25) PFS 97% at 12 mos PFS 92% at 24 mos scr Cycles (n = 49; median 16 cycles; range: 8-25)

27 Correlation of MRD neg Disease with PFS after C(carfilzomib)RD Induction N=16, MRD neg=6, MRD pos =10 Jasielec, ASH 2014, #

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29 Strategy to test the Value of Consolidation after Novel Drugs Newly Diagnosed, Symptomatic MM Carfilzomib + Lenalidomide + Dex 28 day cycles to Best response CR Est 70% C C= stem cell collection R A N D O M I Z E C <CR R A N D O M I Z E Consolidation?VPD Melphalan 200/m 2 + PBSCT Maintenance Maintenance CR Rate Ind + Consolid v. Ind + Tx EFS Ind + Consolid + maint v. Ind + Tx + Maint v. Ind + Maint

30 Conclusions n Complete Response, stringent CR, and MRD negativity are associated with better outcomes n Novel drug combinations for newly diagnosed MM result in high rates of CR, ncr n These patients likely will not benefit from ASCT consolidation n Treat your patient to their best response, NOT a fixed number of cycles of therapy n Novel drugs and combinations may turn myeloma into a chronic condition without the need for ASCT n But how are we going to pay the costs of all these newly developed drugs?

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33 ASCT + len Maint MPR + len Maint P=ns