1. Should Complete Remission be the goal for everyone? NO! Lymphoma Myeloma 2014 Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Joseph Mikhael, MD, MEd, FRCPC, FACP Staff Hematologist, Mayo Clinic Arizona

2. Background Therapy for myeloma has rapidly evolved: More intense regimens Prolonged therapies This has resulted in deeper and more durable responses Translates into doubling (if not tripling) of median overall survival BUT, is it really all about depth of response? It is much more than CR deep…

3. Patient Mrs. Nora Constance Reynolds Diagnosed at 62 with IgG kappa MM 48% plasma cells, hyperdiploid Anemia, lytic disease, compression # Treated with CyBorD achieving PR ASCT 2009 achieving VGPR (M spike 0.5) No Maintenance M spike stable until January 2014 – climbing since then to 1.9… Do you have patients like this?

4. My Thesis Of course CR is good, and should be the goal for most patients However, there remains a subset of patients with more “indolent” myeloma who do not require CR for long term survival Identifying those patients is critical: Modify expectations Not to over-treat Estimate prognosis

5. Choose the right weapon?

6. Recall the Heterogeneity of Myeloma Biological and Clinical differences Myeloma, based on definition, may indeed be the most common malignancy worldwide! We surely cannot treat them all in the same way - individualize Emphasizes the importance of risk stratification

7. Acute Leukemia 3 decades Myeloma M0 M1M2M3M4M5M6M7 SC PreProEarlyMidSHMICSPC Hyperdiploidy t(6:14) t(14;16) t(4:14) t(11;14)

8. Classification of MM PloidyPrognosisH  MorphCD20ras-13 Bone DKK1 CCND t(11;14) (CCND3) NHGoodG  LPL+++++-/+++ D1 D3 t(14;16) (other MAF) NHPoorA PB--+++/-D2 t(4;14) NH/hPoorA PB--++++/-D2 Other IgH H/NHPoor?  ?--/+?+? Hyper HGoodG  Mature-+++/-++D1>D2

9. Mayo Stratification for Myeloma And Risk-adapted Therapy Newly Diagnosed Myeloma Website: www.msmart.org mSMART

10. 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)  FISH  t(4;14)*  Cytogenetic Deletion 13 or hypodiploidy  PCLI >3% High-Risk 20%Intermediate-Risk 20% Standard-Risk 60% 3 years 4-5 years 8-10 years Mikhael et al Mayo Clinic Proceedings April 2013

12. 2006-2010 73% 56% 2001-2005 63% 31% IMPACT OF NOVEL THERAPY 2012/2013 Median 7.3 years 5 YEAR SURVIVAL BY AGE AGE ≤ 65 YRS AGE > 65 YRS 2012 ASH Abstract #3972 Kumar et al

13. Who are these patients that don’t need CR?? Group 1: Patients with MGUS like Myeloma (genotypically) Hyperdiploid MM Possibly some t(11:14) GEP defined MGUS-like MM Group 2: Patients with Indolent Clinical Myeloma (phenotypically) Group 3: Elderly Patients Achievement of CR may be more toxic

14. Group 1 – Genotypically Indolent Gene-Expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis Zhan et al Blood 2007 27% of patients identified as MGUS-Like MM 1. Less likely in CR 2. Improved survival over non MGUS-Like MM 3. Majority of long term survivors were MGUS-Like

15. Group 1 – Genotypically Indolent Complete response in myeloma extends survival without, but not with history of prior monoclonal gammopathy of undetermined significance or smouldering disease Pineda-Roman et BJH 2006 Long-term survival possible in patients post transplant Patients with “evolved” MM (prior MGUS or SMM) had lower CR in Total Therapy 2 (22% vs 48%) 4 year EFS same 54% vs 56% Overall survival similar 65% vs 70% Note that CR was critical in non evolved group

16. Group 2 – Phenotypically Indolent Long-term prognostic significance of response in multiple myeloma after stem cell transplantation Martinez-Lopez et al Blood 2011 Spanish study of 350 pts transplanted 1989-98 No differences in outcomes in pts in nCR, VGPR and PR Plateau at 11 years Those alive at 17 years included 35% of CR group and 11% of nCR+VGPR+PR group

17. Prognostic effect of CR patients versus those in nCR or VGPR or PR versus patients with SD or PD after HDT/ASCT. Martinez-Lopez J et al. Blood 2011;118:529-534 ©2011 by American Society of Hematology

18. Group 3 – Elderly Patients The goal of achieving CR can often lead to more intense therapies Dose reduction in elderly patients remains critical Depth of response may take longer and may not be as deep CR does not always predict for PFS or OS

19. Efficacy Comparisons FIRST (Continuous Rd) (Facon) FIRST (Rd for 72 wks) (Facon) MM-015 (MPR-R) (Palumbo) VISTA (VMP arm for 54 wks) (San Miguel) VMP lite (for 45 wks) (Palumbo) VMPT-VT (Palumbo) VMP-VT (Mateos) CR 15.1%14.2%9.9%30%24%38%46% PFS 25.5 mo20.7 mo31 mo21.7 mo24.8 mo35.3 mo39 mo OS 4-yr OS; 59.4% 4-yr OS: 55.7% 3-yr OS: 70% 5-yr OS: 46% Med OS: 56.4 mo 5-yr OS: 51% Med OS: 60.6 mo 5-yr OS: 61% 5-yr OS: 69% Facon et al. ASH 2013 (Abstract 2), plenary presentation Palumbo et al. N Engl J Med 2012;366(19):1759-69 San Miguel et al. N Engl J Med 2008; 359: 906-917 San Miguel et al. J Clin Oncol 2013;31(4):448-55 Palumbo et al. ASH 2012 (Abstract 200), oral presentation Mateos et al. Blood 2012; 120: 2581-2588

20. What does this mean for my clinic next week? CR is a noble goal and is generally sought after, especially in high risk disease… However, it is NOT the goal in all, especially in 3 groups: 1. Genotypically indolent (hyperdiploid, low risk GEP) 2. Phenotypically indolent (prolonged MGUS/SMM) 3. Elderly patients

21. So, if your patient meets these criteria Be careful not to over-treat (primum non nocere) Anticipate prolonged survival in groups 1 and 2 Remember that CR ≠ CR in standard vs high risk patients Response is always depth PLUS duration

22. Back to my patient NO CR She had 4 years of excellent quality of life on no therapy Repeat marrow confirms hyperdiploid and no high risk features Has now undergone a second ASCT She may never see CR But she will likely live a very long time…

23. Don’t let the smile fool you….

24. Ola is Looking for a CR!