What is the Best Induction Therapy in Transplant-Eligible Patients What is the Best Induction Therapy in Transplant-Eligible Patients? Combination Therapy   Ajai Chari, MD Attending Physician Multiple Myeloma Program Mount Sinai Medical Center

Classes of Agents with Anti-MM Activity: What Is the Best Combination? off label ― Steroids ImIDs Proteasome Inhibitors Conventional Chemo Prednisone Thalidomide Bortezomib Melphalan Dexamethasone Lenalidomide Carfilzomib Cyclophosphamide Pomalidomide Doxil DCEP/D-PACE BCNU Bendamustine

Clinical Features at Presentation of Symptomatic MM Increased plasma cells in the bone marrow (96%) Monoclonal (M) protein (93%) Anemia (normochromic normocytic; 73%) Lytic bone lesions (67%) Renal failure, serum creatinine >2.0 (19%) Hypercalcemia (corrected calcium >11) (13%) Infection Kyle RA. Mayo Clin Proc 2003;78:21-33

Elements of Risk Stratification for MM

Doublet Induction Regimens Responses <?xml version="1.0"?><AllQuestions /> <?xml version="1.0"?><AllResponses /> Doublet Induction Regimens Responses <?xml version="1.0"?><Settings><answerBulletFormat>Numeric</answerBulletFormat><answerNowAutoInsert>No</answerNowAutoInsert><answerNowStyle>Explosion</answerNowStyle><answerNowText>Answer Now</answerNowText><chartColors>Use PowerPoint Color Scheme</chartColors><chartType>Horizontal</chartType><correctAnswerIndicator>Checkmark</correctAnswerIndicator><countdownAutoInsert>No</countdownAutoInsert><countdownSeconds>10</countdownSeconds><countdownSound>TicToc.wav</countdownSound><countdownStyle>Box</countdownStyle><gridAutoInsert>No</gridAutoInsert><gridFillStyle>Answered</gridFillStyle><gridFillColor>255,255,0</gridFillColor><gridOpacity>50%</gridOpacity><gridTextStyle>Keypad #</gridTextStyle><inputSource>Response Devices</inputSource><multipleResponseDivisor># of Responses</multipleResponseDivisor><participantsLeaderBoard>5</participantsLeaderBoard><percentageDecimalPlaces>0</percentageDecimalPlaces><responseCounterAutoInsert>No</responseCounterAutoInsert><responseCounterStyle>Oval</responseCounterStyle><responseCounterDisplayValue># of Votes Received</responseCounterDisplayValue><insertObjectUsingColor>Red</insertObjectUsingColor><showResults>Yes</showResults><teamColors>Use PowerPoint Color Scheme</teamColors><teamIdentificationType>None</teamIdentificationType><teamScoringType>Voting pads only</teamScoringType><teamScoringDecimalPlaces>1</teamScoringDecimalPlaces><teamIdentificationItem></teamIdentificationItem><teamsLeaderBoard>5</teamsLeaderBoard><teamName1></teamName1><teamName2></teamName2><teamName3></teamName3><teamName4></teamName4><teamName5></teamName5><teamName6></teamName6><teamName7></teamName7><teamName8></teamName8><teamName9></teamName9><teamName10></teamName10><showControlBar>All Slides</showControlBar><defaultCorrectPointValue>0</defaultCorrectPointValue><defaultIncorrectPointValue>0</defaultIncorrectPointValue><chartColor1>187,224,227</chartColor1><chartColor2>51,51,153</chartColor2><chartColor3>0,153,153</chartColor3><chartColor4>153,204,0</chartColor4><chartColor5>128,128,128</chartColor5><chartColor6>0,0,0</chartColor6><chartColor7>0,102,204</chartColor7><chartColor8>204,204,255</chartColor8><chartColor9>255,0,0</chartColor9><chartColor10>255,255,0</chartColor10><teamColor1>187,224,227</teamColor1><teamColor2>51,51,153</teamColor2><teamColor3>0,153,153</teamColor3><teamColor4>153,204,0</teamColor4><teamColor5>128,128,128</teamColor5><teamColor6>0,0,0</teamColor6><teamColor7>0,102,204</teamColor7><teamColor8>204,204,255</teamColor8><teamColor9>255,0,0</teamColor9><teamColor10>255,255,0</teamColor10><displayAnswerImagesDuringVote>Yes</displayAnswerImagesDuringVote><displayAnswerImagesWithResponses>Yes</displayAnswerImagesWithResponses><displayAnswerTextDuringVote>Yes</displayAnswerTextDuringVote><displayAnswerTextWithResponses>Yes</displayAnswerTextWithResponses><questionSlideID></questionSlideID><controlBarState>Expanded</controlBarState><isGridColorKnownColor>True</isGridColorKnownColor><gridColorName>Yellow</gridColorName><AutoRec></AutoRec><AutoRecTimeIntrvl></AutoRecTimeIntrvl></Settings> <?xml version="1.0"?><AllAnswers /> Newly Diagnosed, SCT Eligible Response to induction D1 N = 235 TD1 VAD2 N = 242 VD2 N = 223 RD3 Rd3 N = 222 CR 3% 8% 6% 15% 5% 4% > VGPR 16% 44% 38% 50% 40% ORR 46% 63% 79% 68% D: dexamethasone TD: thalidomide, dexamethasone VAD: vincristine, adriamycin, dexamethasone VD: bortezomib, dexamethasone; RD: lenalidomide, dexamethasone; Rd: lenalidomide, low-dose dexamethasone; After 4 cycles 1; 2Harousseau JL, et al. J Clin Oncol. 2010 Oct 20;28(30):4621-9; 3Rajkumar SV, et al. Lancet Oncol. 2010;11(11):29-37.

Improved Efficacy with Decreased PN RVD: 28 vs. 21 Day Regimen – Improved Efficacy with Decreased PN 21 Day RVD (n=66 all/35 phase 2) 1 28 Day RVD (n=38) 2 Response rate after 4 cycles of RVD   sCR/CR/ nCR > VGPR > PR > MR > SD All PN Dose ↓ For PN 21d RVD 6 11 75 95 100% 80 44 28d RVD 5 63 97 100 37 7.8 . 1 Richardson et al. Blood . 2010 Aug 5;116(5):679-86. 2 Chari et al, Abstract #. 2949. ASH 2011.

Evolution Randomized Phase 2 Study Induction x 8 3-wk cycles V 1.3 mg/m2 days 1, 4, 8, 11 D 40 mg days 1, 8, 15 C 500 mg/m2 days 1, 8 R days 1–14 VDCR   (15 mg) VDR  (25 mg) VDC VDC-mod  (+ day 15) Maintenance x 4 6-wk cycles V 1.3 mg/m2 (days 1, 8, 15, 22) Response, n (%) VDCR (n = 48) VDR (n = 42) VDC (n = 33) VDC-mod (n = 17) CR 10 (25) 10 (24) 7 (22) 8 (47) ≥ VGPR 23 (58) 21 (51) 13 (41) 9 (53) ORR (≥ PR) 35 (88) 35 (85) 24 (75) 17 (100) Neutropenia 21 (44) 4 (10) 10 (30) 4 (24) Kumar et al; Blood 2012 May 10;119(19):4375-82. 7

When Cyclophosphamide Might Be Used Preferentially As Proteasome Inhibition Partner Renal Failure Poor performance status (e.g. wheelchair bound, paraplegic) due to VTE risk especially if bleeding risk as well Inpatient Need to initiate outpatient therapy rapidly (e.g. impending cord compression) Intolerance of Imids (angioedema) Washout of lenalidomide pre-stem cell harvest Oral therapy not dependable (poor compliance, malabsorption) Inadequate RN/admin support for IMIDs

Car + Len + Dex Induction: Efficacy Independent of ISS and cyto/FISH Jakubowiak et al; Blood. 2012 Aug 30;120(9):1801-9.

Car + Len + Dex Induction: Toxicity During dose escalation, DLTs: 20 mg/m2 (n=4): none 27 mg/m2 (n=13): Gr 3 neutropenia 36 mg/m2 (n=18): Gr 4 pulm edema, Gr 3 dyspnea Probability: 5.9 vs. 8.1 vs. 12% Dyspnea due to hydration, methhemoglobinemia (dapsone) Note: CHF 2/20 in nDMM, 1/8 in sMM with 20/36 mg/m2 CR25D30 Jakubowiak et al; Blood. 2012 Aug 30;120(9):1801-9. Korde et al. Abstract #732 ASH 2012. Landgren Abstract 06: IMWG 2013.

Summary: Efficacy of MM Induction Regimens after 4 cycles   N (I/II) sCR/CR/ nCR (%) > VGPR (%) > PR > MR > SD ISS 3 Adverse cyto/FISH 28d RD vs Rd 422 16 46 76 85 91 26% NA BiRD (after 6 mos) 60 18 57 95 20% 21d RVD 66/35 6 11 75 100 9% 15% 21d RVD (E) 42 7 32 73 19 17 28d RVD 38 5 63 97 11% 8% (18%1q) 28d CRD 49/18 67 88 33% 28d CCTD 35 83 21 d VDCR(E) 48 33 80 21 15 21d VDC (E ) 13 23 21d VDC+ (E) 12 41 82 Rajkumar et al. Lancet Oncol. 2010 Jan;11(1):29-37. Epub 2009 Oct 21. Guy et al. Am J Hematol. 2010 Sep;85(9):664-9. Richardson et al. Blood 2010 Aug 5;116(5):679-86. Chari et al, Blood 2011. Abstract #. 2949 Mikhael, J et al. J Clin Oncol 30, 2012 (suppl; abstr 8010) Jakubowiak et al; Blood. 2012 Aug 30;120(9):1801-9. Kumar et al; Blood. 2012 May 10;119(19):4375-82.

Bortezomib-Thalidomide-Dexamethasone VTD (n=236) vs. TD (n=238) 3 cycles of induction tandem auto SCT 2 cycles of consolidation Maintenance dex 10 20 30 40 50 60 70 80 % Induction First ASCT Second ASCT Consolidation VTD TD 31% 11% 52% 55% 41% 62% 45% P<0.0001 P=0.0024 P=0.0002 33% 14% 57% 63% 73% 61% P<0.004 P=0.123 P=0.020 INDUCTION (21-d cycles) Vel 1.3mg/m2 twice weekly, Thal 100200mg/day, Dex 320mg/cycle CONSOLIDATION (two 35-d cycles): Vel 1.3mg/m2 once weekly, Thal 100mg/day, Dex 320mg/cycle 3 yr PFS: 60 vs 48 % (p 0.043) 3 yr OS: 90 vs 88% (p 0.390) CR + nCR rates Cavo et al. Blood. 2012 Jul 5;120(1):9-19.

Summary: Dose Reductions/Toxicity of MM Induction Regimens   N (I/II) Dose Reductions All PN Dose ↓ For PN 28d RD vs Rd 422 N/A BIRD 60 21d RVD 66/35 44% (R) 35% (V) 48% (D) 80% 44% 21d RVD (E) 42 55% 17%* 28d RVD 38 8% (R) 8% (V) 37% 7.8% 28d CRD 49/18 33% 23% ? 28d CCTD 17 20% 21 d VDCR(E) 48 56% 13%* 21d VDC (E ) 32 66% 21%* 21d VDC+ (E) 47% 8%* Cost? Quality of Life?

Does Quality of Response Matter After HDM-ASCT? van de Velde HJ, et al. Haematologica 2007;92(10):1399-1406.

> VGPR After 1st Auto SCT Does Not Benefit From Tandem Does Quality of Response to Induction Therapy Matter? > VGPR After 1st Auto SCT Does Not Benefit From Tandem Cavo et al. J Clin Oncol. 2007. 25:2434-2441. Attal et al. NEJM. 2003 Dec 25;349(26):2495-502.

Does Induction Response Quality Matter in Era of Novel Therapies? B1 B2 VAD x 4 Vel -Dex x 4 Induction DCEP x 2 Consolidation Transplant 1: melphalan 200 mg/m2 Transplant 2: second ASCT or RIC allo if < VGPR PFS post induction > or < VGPR PFS post ASCT PFS post ASCT > or < VGPR and VAD or VD induction Moreau P. et al. Blood 2011;117(11):3041-3044.

Combination Therapy: The Future Steroids ImIDs Proteasome Inhibitors Conventional Chemo Prednisone Thalidomide Bortezomib Melphalan Dexamethasone Lenalidomide Carfilzomib Cyclophosphamide Pomalidomide MLN9708/Ixazomib Doxil Oprozomib DCEP/D-PACE Marizomib BCNU Bendamustine off label/ investgational ― Epigenetics/ Chaperoning Signal Transduction Inhibitors Cell Cycle/ Apoptosis Monoclonal Antibodies Vorinostat mTOR KSP Inhibitor Anti-CD138 Panobinostat AKT CDK inhibitor Anti-CD38 Romidepsin BTK Aurora Kinase Inhibitor Anti-CS1 HSP90 inhib PIM Bcl2 Inhibitor IGF-R CRM1 inhibitor TRAIL agonist Bone Targeted Agents Bisphosphonates RANKL inhibitors DKK1 antibody Activin A receptor

Combination Therapy Preferable: Conclusions Symptomatic MM patients benefit from rapid & deep resolution of symptoms Multidrug regimens are associated with higher response rates If no overlapping toxicity of individual drugs, combination regimens are very well tolerated Since induction therapy is not continued until PD, resistance is unlikely and retreatment is feasible MM is very hetereogeneous - to date, so called “risk-stratified treatment algorithms” are not based on prospective phase 3 studies with the precision of differential therapies for NHL subtypes: FL vs DLBCL vs. BL. Rather, Risk definitions keep evolving: 13q -> t(4;14) -> ch 1q -> ? Risk is dependent on therapy eg. t(4;14) Improved depth of response pre SCT: 1) improves likelihood of adequate SCH 2) decreases likelihood of second SCT with attendant hospitalization/morbidity/cost and 3) may increase PFS