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Scottsdale, Arizona

Scottsdale, Arizona. Rochester, Minnesota. Jacksonville, Florida. Should Alkylators be used Upfront in Transplant-Ineligible Patients? NO!! Lymphoma-Myeloma October 2013. Joseph Mikhael, MD, MEd, FRCPC, FACP Staff Hematologist, Mayo Clinic Arizona. Objectives.

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Scottsdale, Arizona

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  1. Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Should Alkylators be used Upfront in Transplant-Ineligible Patients?NO!!Lymphoma-MyelomaOctober 2013 Joseph Mikhael, MD, MEd, FRCPC, FACP Staff Hematologist, Mayo Clinic Arizona

  2. Objectives • Review the emerging data regarding replacing “MP” as backbone in upfront therapy • Provide practical advice as to initiating therapy in older patients with myeloma • Unequivocally defeat my friend Antonio in this debate  • Concede that cyclophosphamide may be an exception to this general rule

  3. Summary Points – Why Melphalan is no longer standard of initial care in elderly patients • Novel agents are equivalent if not superior to MP+novel agent • MP+ results in greater short term toxicity • As survival is extended in myeloma, using melphalan upfront is not desirable due to marrow toxicity • Melphalan can lead to increased second primary malignancies

  4. mSMART 2.0: Classification of Active MM FISH Del 17p t(14;16) t(14;20) GEP High risk signature All others including: Hyperdiploid t(11;14) t(6;14) Standard-Risk 60% High-Risk 20% Intermediate-Risk 20% • FISH • t(4;14)* • Cytogenetic Deletion 13 or hypodiploidy • PCLI >3% 3 years 4-5 years 8-10 years Mikhael et al Mayo Clinic Proceedings April 2013

  5. mSMART – Off-Study Transplant Ineligible High Risk Intermediate Risk Standard Risk* VRd MP + weekly Bortezomib or weekly CyBorD Rd Bortezomib maintenance Observation Mikhael et al Mayo Clinic Proceedings April 2013

  6. Argument #1 Novel agents are equivalent if not superior to MP+novel agent

  7. Newly Diagnosed, Patients SCT Ineligible MPT: melphalan, prednisone, thalidomide; VMP: bortezomib, melphalan, prednisone; MPR: melphalan, prednisone, lenalidomide; MPR-R: MPR with maintenance lenalidomide; VTP: bortezomib, thalidomide, prednisone. 1Palumbo A, et al. Blood. 2008;112:3107-3114; 2Mateos MV, et al. Blood. 2009;114(22). Abstract 3859; 3,4Palumbo A, et al. Blood. 2010;116(21). Abstract 622 and Abstract 566; 5Mateos MV, et al. Blood. 2009;114(22). Abstract 3.

  8. Primary Study Schema lenalidomide plus RD versus lenalidomide plus Rd in newly diagnosed MM R A N D O M I Z A T I O N 445 patients RD x 4 cycles Patients can go off and proceed to SCT CR/PR Rd x 4 cycles Thal + Dex x 4 cycles Less than PR CR/PR/stable Rajkumar et al

  9. BEST RESPONSE: > PR* *Same observations with VGPR except age > 70 42.3% vs 47.7%

  10. Results Second Interim Analysis RD vs. Rd RD did not result in superior TTP, PFS, or OS compared to Rd OS at 1-year was significantly better with Rd than RD, resulting in early closure of the trial Rajkumar et al, 2010.

  11. Overall Survival-ITT Age < 65 Age > 70 Age > 65 Age > 75 Age > 65 yrs

  12. Survival Rate by Age

  13. Larocca A, et al. Gr. Emat. Milano 2012

  14. Conclusion #1 • MP is not necessary • Lenalidomide-dexamethasone and bortezomib-dexamethasone are effective and viable options

  15. Argument #2 MP+ results in greater short term toxicity

  16. Conclusion #2 • 3 drug regimens that include melphalan are more toxic (and not necessarily more effective) • Dose reduction is critical in the elderly

  17. Argument #3 As survival is extended in myeloma, using melphalan upfront is not desirable due to marrow toxicity

  18. Multiple Myeloma 1971-2006n=2,981 P<0.001 Survival, med 44.8 mo Proportion surviving Survival, med 29.9 mo Diagnosis after 1996 Diagnosis during/before 1996 Time from diagnosis (months) Kumar et al: Blood 111:2516, 2008 CP1315995-1

  19. Multiple MyelomaMayo Patients 2006-2010 66% P < 0.0001 47% 2001-2005 S. Kumar, 2012

  20. Argument #4 Melphalan can lead to increased second primary malignancies

  21. The “NEW” CyBorD All three drugs given weekly Cyclophosphamide 300mg/m2 PO Bortezomib 1.5 mg/m2 IV or SQ Dexamethasone 40mg PO We consider one cycle a 4 week course No “week off” Less neuropathy, more convenience, equal efficacy Always give viral prophylaxis Comment – I see CyBorD as a slight modification to VMP

  22. Summary Points – Why Melphalan is no longer standard of initial care in elderly patients • Novel agents are equivalent if not superior to MP+novel agent • MP+ results in greater short term toxicity • As survival is extended in myeloma, using melphalan upfront is not desirable due to marrow toxicity • Melphalan can lead to increased second primary malignancies

  23. Quote – ASCO 2013 – Dr. Antonio Palumbo “Gli Americani avevano ragione: non dobbiamo usare melphalan come terapia iniziale nei pazienti anziani” “The Americans were right – we should not use melphalan upfront in elderly patients”

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