1. Should We Treat Smoldering Myeloma? YES! Lymphoma Myeloma 2014 Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Joseph Mikhael, MD, MEd, FRCPC, FACP Staff Hematologist, Mayo Clinic Arizona

2. Additional Disclosures There is no such thing as Mikhael Oncology I am not incorporated I am just the average Joe… James R. Berenson, MD President and CEO - James R. Berenson, MD, Inc. Medical & Scientific Director - Institute for Myeloma & Bone Cancer Research (IMBCR) Chief Executive Officer - Oncotherapeutics

3. Background Remember Myeloma is a unique cancer – defined by the presence of organ damage – not just pathology Traditionally we wait until CRAB But does that really make sense? Do we have to wait until damage is present to intervene??

4. What if your friend is walking towards a cliff? Will you wait until they are falling to rescue them? What if they are running? What if they are enjoying the walk?

5. My Thesis – there are 3 groups within Smoldering Myeloma Group 1: “Ultra” High Risk Plasmacytosis ≥ 60% Involved/Uninvolved Light Chains ≥ 100 1 or more focal lesions on MRI/PET TREAT AS IF TRUE MYELOMA Groups 2: High Risk (Defn to follow) DEBATE: To Treat or Not to Treat Group 3: Low Risk DON’T TREAT

6. Smoldering Multiple Myeloma Low-risk SMM 5%/year Ultra-High Risk >60% BMPC FLCr >100 >1 MRI focal lesions High-Risk SMM 25%/year

7. SMM Paradigm Shift MGUS SMM 10% per year x 5 years ~1% per year after 10 years

8. Ultra High Risk SMM = Active Myeloma Not CRAB but now SLiM CRAB S (60%) Li (Light chains I/U >100) M (MRI 1 or more focal lesion) C (calcium elevation) R (renal insufficiency) A (anemia) B (bone disease)

9. Bone Marrow Plasma Cell ≥60% Rajkumar SV et al. N Engl J Med 2011; N Engl J Med 2011; 365:474-475

10. >100 <100 FLC Ratio >100 and Risk of progression to myeloma Larsen J, et al. Leukemia advance online publication 27 November 2012; doi: 10.1038/leu.2012.296

11. Rajkumar SV, Merlini G, San Miguel JF. Nat Rev Clin Oncol 2012

12. High Risk SMM = Median TTP ~2 years: Mayo: SMM with M protein ≥3 gm/dL and ≥10% PCs Spanish: ≥10% PCs, Absence (<5%) of normal PCs by immunophenotyping and Immunoparesis of ≥1 immunoglobulins Abnormal FLC ratio 8-100 Deletion 17p, t4;14, 1q amp Evolving pattern IgA SMM SMM with M protein ≥4 gm/dL Increased circulating plasma cells Increased plasma cell proliferative rate Rajkumar SV, Merlini G, San Miguel JF. Nat Rev Clin Oncol 2012

13. Management of High Risk SMM: What does the data say? Do we believe the Spanish Trial? Recall – Randomized, Phase 3 Trial of high risk SMM pts Lenalidomide – dexamethasone vs observation

14. Mateos M et al. N Engl J Med 2013;369:438-447. Len/Dex versus Observation in High Risk SMM: TTP

15. Mateos M et al. N Engl J Med 2013;369:438- 447. Len/Dex versus Observation in High Risk SMM: OS

16. 1. Generalizability –Mayo Criteria - BMPC ≥ 10% and M-protein ≥ 30 g/L or –Spanish Criteria BMPC ≥ 10% or M-protein ≥ 30 g/L and –BM aPC/nPC > 95% and – immunoparesis –BUT note that 60% met Mayo Criteria!! Issues with the Spanish Trial

17. Mateos M et al. N Engl J Med 2013;369:438-447. 2. Tolerability

18. Len-dex vs. no treatment: TTP to active disease (n = 119) ITT analysis Median follow-up: 32 months (range 12–49) Lenalidomide + dex Median TTP: NR 9 Progressions (15%) 5 pts:early disc followed by PD 4 pts:symptomatic PD No treatment Median TTP: 23m 37 Progressions (59%) 20 patients: bone disease 7 patients: renal failure HR: 6.0; 95% IC (2.9–12.6); p < 0.0001 Time from inclusion Proportion of patients alive Mateos. ASH 2012 3. Consequences

19. Spanish Trial Conclusions Early intervention in high risk SMM Prolongs TTP Improves OS Does not result in appreciable toxicity Prevents irreversible damage to kidneys and bones that occur … “on our watch!”

20. Conclusions Don’t forget new criteria (SLiM CRAB) for myeloma (Ultra High Risk SMM = Myeloma) Low risk can be watched High risk is complex Recall 50/50 in 2 years Consider therapy these patients in an individualized manner Not limited to len-dex, but all active therapy

21. Don’t let your patients fall…

22. Management Low-risk SMM: Observe High-Risk MM Ultra-High Risk: Treat Debate: Rx or Trials