1. Case 2: Transplant-eligible patient with newly diagnosed myeloma – would you recommend transplant, and if so, what induction regimen? 1 Tomer M. Mark Department of Medicine, Division of Hematology / Oncology Weill-Cornell Medical College / New York Presbyterian Hospital, New York, NY, USA Lymphoma & Myeloma 2013

2. Disclosures Research Funding: Celgene Inc.; Onyx Inc. Speakers Bureau: Celgene Corp; Millennium Inc.; Onyx Inc. Membership on an entity's advisory committees: Celgene Corp., Millennium Inc. Off-label usage of bortezomib, lenalidomide, and carfilzomib are discussed

3. Case History A 45 year-old male with a history of obesity and type-2 diabetes, “diet-controlled”, develops back pain after moving furniture When the back pain doesn’t relent after 3 weeks, he sees his PMD who advises NSAID use There is minimal relief after taking 800mg ibuprofen TID. He sees his PMD again the following week and a plain film of the spine is ordered

4. History Multiple lytic lesions of the lumbar spine are noted The PMD refers to an oncologist who orders bloodwork, a 24 hour urine, skeletal survey, and performs a bone marrow biopsy.

5. Medical History PMHx: Diet-controlled diabetes Episode of Legionella pneumonia Med: Ibuprofen 800mg prn SHx: Works as a hospital administrator Former tobacco use: 10 pack years, quit 15 years ago Social EtOH, no illicit drug use FHx: Mother: Crohn’s disease Sister: breast cancer Uncle: colon cancer ROS: +back pain PE GEN: middle-aged male, NAD HEENT: PERRL, EOMI, anicteric sclerae NECK: no masses, nl carotid upstroke CV: nl S1/S2, RRR, no m/r/g PULM: CTAB ABD: soft, NT/ND, +bowel sounds EXT: no c/c/e MSK: no spinal tenderness on palpation, he lies down on the exam table with great difficulty.

6. Diagnostic Tests Skeletal survey: multiple lytic lesions in the T, L-spine, cranium, pelvis, and R prox femur Bone Marrow Aspirate: 86% plasma cells with atypical features, kappa-light chain restricted Karyotype: 46 XY FISH: 2/20 cells + del13q

7. Diagnostic Tests Laboratory Results: 8.3 9.8 29.4 236 140 3.7 113 19 22 1.4 131 Albumin: 3.6 Calcium 8.9 T. Bili: 0.8 Alk Phos: 57 AST: 38 ALT: 35 LDH: 190  2M: 3.8 CRP: 0.54 Serum Protein Electrophoresis: Decreased amounts of gamma globulins with a monoclonal spike- 3.2 g/dL Immunofixation / Quantitative Immunoglobulins: IgM: <4 mg/dL; IgA: 12 mg/dL; IgG: 4300 mg/dL 24 hr Urine Electropheresis and Immunofixation: Total Protein: 2.08g/day 10% albumin 90% kappa free light chain Serum Free Light Chain Assay: Kappa FLC: 1540 mg/dL Lambda 0.67: mg/dL Kappa/Lambda: 2300

8. Summary 45 year-old male with history of hyperglycemia and newly diagnosed SD Stage 3a, ISS Stage 2, IgG-kappa MM, with extensive skeletal involvement and mild renal insufficiency.

9. Is a Stem Cell Transplant Recommended? Stem cell transplant has a OS benefit –Caveat: data is old Stem cell transplant deepens treatment response –Does a deeper response post-transplant lead to longer OS? –What if pt is in CR prior to transplant?

10. ASCT vs. Conventional Chemotherapy Study TxN CR (%) Median OS (mo) Attal el al (IFM 90) 1 VMCP/BVAP 100544 § VMCP/BVAP->MEL-140/TBI-81002257 § Fermand et al 2 VMCP91--50 VAMP->Bu/MEL-140 or MEL-20094--55 Bladé et al 3 VMCP/VBAD831164 VBMVP/VBAD->MEL-200813072 Child et al 4 ABCM200842 § VAMPC->MEL-200 or MEL-140/TBI2014454 § 1.Attal M et al. N Engl J Med. 1996;335:91. 2.Fermand J et al. Blood. 1998;92:3131. 3.Bladé et al. Hematol J. 2001;2:272 4.Child JA et al. N Engl J Med. 2003;348:1875. § Significant P value

11. Does Transplant Timing Matter? Fermand J et al. Blood 1998;92:3131-3136

12. Does Consolidation With ASCT Improve Outcomes?

13. Impact of Response To Induction Therapy Lahuerta, J. J. et al. J Clin Oncol 26:5775-5782 2008

14. Significance of Depth of Response Lahuerta, J. J. et al. J Clin Oncol 26:5775-5782 2008

15. Significance of Continued Response to HDT “ Upgraders ” do better Lahuerta, J. J. et al. J Clin Oncol 26:5775-5782 2008 Improvement for PR to nCR or CR post transplant increases OS

16. Initial Response to Induction Conventional Chemotherapy does not Impact Transplant Benefit Singhal et al, 2002. Survival post C-VAMP induction ASCT had no correlation with C-VAMP response. Kumar et al, 2004. 50 patients with primary refractory MM (mostly VAD) compared to 100 with chemosensitive disease pre-ASCT. 20% vs. 35% CR post transplant (P = 0.06). 1-year PFS 70% vs. 83% (P=0.65). Alexanian et al, 1995. MM resistant to VAD or high-dose dex quadrupled OS compared to matched controls.

17. Initial Response to Induction Chemotherapy does not Impact Transplant Benefit Important factors on MV analysis: PCLI >1, CR, abnormal cytogenetics, serum M-protein, circulating PC at harvest. Kumar et al. Bone Marrow Transplantation. 2004. 34: 161-167.

18. Initial Response to Induction Chemotherapy does not Impact Transplant Benefit Is this still true in the era of novel agents?

19. Impact of Response Failure To Induction with Immunomodulators N = 286 PFS from Day 0 of transplantation Plateau (232), Refractory (29), Relapse (25) Thal/Dex (189), Len/Dex (97) Medians: 22.1 m (plateau), 15.1 (refractory), 12.0 (relapse) on induction therapy Gertz, M. A. et al. Blood 2010;115:2348-2353

20. Impact of Response Failure To Induction with Immunomodulators Overall survival from Day 0 of transplant Med OS 73.5 (plateau), 32.7 (refractory), 23.8m (relapse on tx) Gertz, M. A. et al. Blood 2010;115:2348-2353

21. Factors That Impact Transplant Success with Immunomodulator Induction VariableUnivariable PMultivariable P Plateau vs. relapse- refractory < 0.0010.04 Albumin0.58 Sex0.78 B2 Microglobulin0.0160.30 Bone marrow plasma cells<0.0010.33 Age0.92 Abnormal Cytogenetics<0.0010.02 CTX mobilization0.0360.30 Labeling Index<0.001 Gertz, M. A. et al. Blood 2010;115:2348-2353

22. Multiple Studies Comparing Novel Agents to CC followed by ASCT Study(N)Post Induction (%)Post-Transplant(%)PFS/OS (months) ORRCR/VGPRORRCR/VGPR Macro et al TD VAD 100 104 NR 25 > VGPR 7 > VGPR NR 44 > VGPR 42 > VGPR NR HOVON-50 TAD VAD 268 71 57 37 > VGPR 18 > VGPR 88 79 66>VGPR 54 > VGPR PFS 34; OS 73 PFS 25; OS 60 IFM 2005-01* Bort/Dex VAD 240 242 79 63 38 > VGPR 15 > VGPR 84 79 54 > VGPR 37 > VGPR PFS 36; 3-yr OS: 81 PFS 30; 3-yr OS: 77 GIMEMA - 3006 VTD** TD 236 238 94 79 62 > VGPR 31 > VGPR NR 87 > VGPR 69 > VGPR 2yr: PFS 85, OS 96 2yr: PFS 75, OS 91 IFM 2007-02 Bort/Dex VTD 99 100 81 90 35 > VGPR 51 > VGPR 84 90 60 > VGPR 73 > VGPR NR

23. Do You Need a Transplant if You Achieve CR With Induction Therapy? Chemo-alone ASCT within 1 yr Wang et al., 2010, Bone Marrow Transplant, 45, 498-504

24. No transplant: 42 patients, 15 events. Median EFS not reached. 3-year EFS = 65% (95% CI = 47.6%, 77.9%) Transplant: 29 patients, 14 events. Median EFS = 37.3 months. 3-year EFS 50.3% (95% CI = 27.2%, 69.5% P=0.64 Do You Need ASCT if You Continue Induction Instead?

25. Conclusions Combinations of novel agents lead to deeper responses pre-transplant Deeper responses pre-transplant translate to better responses post transplant –ASCT is supplementary to induction, not a substitute. –ASCT is a tool to achieve high CR and prolonged PFS Lack of difference in OS is a reflection on efficacy of salvage tx. Achievement of CR prior to transplant gives an equal outcome to CR post-transplant –MRD detection may change this conclusion

26. What Induction Therapy Should be Used? What is More Important? a) Choice of Agent for Induction b) Response attained in Induction

27. Can’t See The Forest for The Trees

28. CyBORD 3 N=35 BCD + BDT 4 N=65 BiRD 1 N=72 VRD 2 N=65 CR 392838.926 nCR NA1813.918 VGPR 223020.830 PR 27NA16.725 MR 1NA5.6NA Refractory 1NA00 Overall 8810090.3100 1.Niesvizky et al Blood, 111, 1101-1109; 2008. 2.Richardson et al. ASH 2008, Abstract 92 6176 73 74 3. Reeder et al, Leukemia 2009, 23:1337-41 4. Bensinger et al. ASH 2008, Abstract 94

29. Thank You