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Tomer M. Mark Department of Medicine, Division of Hematology / Oncology

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

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Tomer M. Mark Department of Medicine, Division of Hematology / Oncology

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  1. Case 2: Transplant-eligible patient with newly diagnosed myeloma – would you recommend transplant, and if so, what induction regimen? 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: CelgeneInc.; 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. 9.8 8.3 236 29.4 140 113 22 131 3.7 19 1.4 Diagnostic Tests Laboratory Results: 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 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

  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 § Significant P value Attal M et al. N Engl J Med. 1996;335:91. Fermand J et al. Blood. 1998;92:3131. Bladé et al. Hematol J. 2001;2:272 Child JA et al. N Engl J Med. 2003;348:1875.

  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 ClinOncol 26:5775-5782 2008

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

  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 ImmunomodulatorInduction Gertz, M. A. et al. Blood 2010;115:2348-2353

  22. Multiple Studies Comparing Novel Agents to CC followed by ASCT

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

  24. Do You Need ASCT if You Continue Induction Instead? P=0.64 • 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%

  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. 73 74 61 76 • Niesvizky et al Blood, 111, 1101-1109; 2008. • Richardson et al. ASH 2008, Abstract 92 3. Reeder et al, Leukemia2009, 23:1337-41 4. Bensinger et al. ASH 2008, Abstract 94

  29. Thank You

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