Is Myeloma Curable in 2012?

Is Myeloma Curable in 2012? YES Cure is living long enough to die of another cause April 2012 Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Joseph Mikhael, MD, MEd, FRCPC Staff Hematologist, Mayo Clinic Arizona Disclosures Vincent Rajkumar is my mentor - so for the record, he must be right 1

Objectives 1. Outline the rapidly evolving history of treating myeloma 2. Emphasize the critical importance of risk stratification in myeloma 3. Discuss the step wise process of curing a disease 4. Match that process to the progress made in myeloma 5. Convince you that a subset of myeloma may indeed be curable Kyle, R. A. and Rajkumar S. V. Blood 2008;111:2962-2972 2

Treatment sequence Front line treatment Maintenance Relapsed Induction Consolidation Post consolidation Rescue OLD VAD DEX SCT Nothing Prednisone Thalidomide Few options VAD. Archenemy of M. Myeloma. Born May 24, 1984 Barlogie, TX Died July 1 st 2005 Rajkumar, MN After a distinguished career fighting back MM VAD has finally died. In its latter years its inability to keep up with the new warriors lead to its demise. Furthermore, one of its main ingredients added not much except neuropathy, and the other had questionable efficacy. Thank you for the years, but you will not be missed 3

Treatment sequence NEW Thal/Dex SCT Nothing Cyclo/vel/dex VD/VRD Thalidomide? VD MPT? Bortezomib? RevVel VMP? Lenalidomide? VTD Bortezomib Lenalidomide Thalidomide Carlfilzomib Pomalidamide Elotuzumab HDAC Bendamustine Front line treatment Maintenance Relapsed Induction Consolidation Post consolidation Rescue OLD VAD DEX SCT Nothing Prednisone Thalidomide Few options 4

msmart Mayo Stratification for Myeloma And Risk-adapted Therapy Newly Diagnosed Myeloma Website: www.msmart.org Kumar et al. Mayo Clin Proc 2009: 84:1095-1110 msmart : Classification of Active MM High-Risk Intermediate-Risk Standard-Risk FISH Del 17p t(14;16) t(14;20) Cytogenetic Deletion 13 Cytogenetic hypodiploidy GEP defined highrisk FISH t(4;14)* PCLI >3% All others including: Hyperdiploid t(11;14) t(6;14) 5

Enough Therapy Holy ygrail may well be the sweet spot of not too much and not too little Balance of quantity and quality of life Quality adjusted life years Historical Cure Transplant Allo transplant has most rationale for cure due to marrow eradication and GVM effect Plagued by TRM, GVHD (acute and chronic) and relapse Likely 10-15% have genuine long term benefit with manageable toxicity Likely optimal role now is in pts with very high risk dz with rapid relapse Even with auto-transplant, 3-10% have essential cure with CR in 10 years 6

Actual Cure Needed Steps 1. Completely eradicate tumor clone As with other diseases, the deeper the response the more durable Unprecedented rates of CR BUT - some will be cured who never achieve CR perhaps returned to MGUS state Most likely hyperdiploid IMPLICATION Depth of response is important, but be aware of returning to MGUS state You need good combinations 7

Actual Cure Needed Steps 2. Be able to measure cure MRD measurement with molecular studies, quantitative PCR and multicolor flow Spanish study Blood January 2012 Possible role of PET Others? IMPLICATION treat to deeper response but don t OVERtreat Actual Cure Needed Steps 3. Balance QUANTITY and QUALITY of life Learn from HD and ALL Extended and combined therapy has resulted in cures BUT follow and reduce toxicity Still poor measure of QoL in MM IMPLICATION using more aggressive approaches, but selecting the right patients for the right intensity (stratification) 8

msmart 2.0: Classification of Active MM High-Risk 20% Intermediate-Risk 20% Standard-Risk 60% FISH Del 17p t(14;16) t(14;20) GEP High risk FISH t(4;14)* Cytogenetic Deletion 13 or hypodiploidy High risk signature PCLI >3% All others including: Hyperdiploid t(11;14) t(6;14) 3 years 4-5 years 8-10 years Standard Risk Disease Standard-Risk** All others including: Hyperdiploid t(11;14)*** t(6;14) 80% OS at 5 years in 150 transplant eligible standard risk patients treated with RD, CRD or CBD +/- HDM. 9

Even in elderly 90 80 70 60 50 40 PFS 3 Year OS 30 20 10 0 MP TD CTD MPR MPT Rd MPR-R MPV MPVT-VT MPV-VT High risk disease High-Risk No del(17p) FISH Del 17p t(14;16) t(14;20) GEP High risk signature p<.0001 Del(17p) pos VD induction + HDM median OS is 3 years 10

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Myeloma Survival: All Ages SEER Program, 1980-2007 SUBJECTS: Newly diagnosed (incident) cases of Myeloma diagnosed in 9 core areas of the SEER Program during the time period 1980 2007 NUMBER OF SUBJECTS: Diagnosed 1980 89: 7901 (48.82 % alive after 3 years) Diagnosed 1990 99: 9353 (50.56 % alive after 3 years) Diagnosed 2000 2007: 8300 (57.64% alive after 3 years) Total subjects = 25,554 P Value: <0.0001 Survival outcomes in elderly patients with plasma cell myeloma: The three-decade Eastern Cooperative Oncology Group (ECOG) experience Most of the survival benefit is seen in <65 Analyzed 4 Phase 3 clinical trials (ASCT excluded) Three cohorts: A 1988-1993 B 1994-2000 C 2001-2006 E Campagnaro et al ASCO Abstract 8021 12

Survival outcomes in elderly patients with plasma cell myeloma: The three-decade Eastern Cooperative Oncology Group (ECOG) experience E Campagnaro et al ASCO Abstract 8021 Cure in Low Risk Patients? B d 61% CR t d >90% 5 Based on 61% CR rate and >90% 5-yr continuous CR project in GEP-defined low-risk myeloma a 55% cure rate (Barlogie, ASH 2011) 13

Conclusions 1. Myeloma is a complex disease with dramatically improved survival rates, not over 10 years 2. Most low risk patients, with right therapy, can be considered functionally cured risk stratification remains crucial 3. The future is bright with better therapies more effective, less toxic and more feasible 4. Measuring cure has been enhanced 5. We must balance quantity and quality of life 6. Although our goal is greater than dying of something else, we are nearly there 14