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Smoldering Multiple Myeloma

Smoldering Multiple Myeloma. To treat or not to treat, that is the question James R. Berenson, MD Institute for Myeloma and Bone Cancer Research West Hollywood, CA. Diagnostic criteria for diagnosis of smoldering MM- i.e. “Asymptomatic”. Smoldering or “Asymptomatic” MM.

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Smoldering Multiple Myeloma

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  1. Smoldering Multiple Myeloma To treat or not to treat, that is the question James R. Berenson, MD Institute for Myeloma and Bone Cancer Research West Hollywood, CA

  2. Diagnostic criteria for diagnosis of smoldering MM- i.e. “Asymptomatic”

  3. Smoldering or “Asymptomatic” MM • Approximately 15% of cases of MM • Risk of progression to “symptomatic” MM • Mayo Clinic • 10%/y during the first 5 y • 3%/y during years 5-10 • 1.5%/y after first 10 y • Italian group • 45% during first 10 y • 55% by 15 y • 75% by 20 y • Heidelberg group – 46% by 5 y • SWOG study • 23.2% at 2 y • However, only another 12% during years 3-5 Kyle et al. NEJM 2007, Hose et al. JCO 2014, Rago et al. Cancer 2012, Dhodapkar et al. Blood 2014

  4. Smoldering MM in Our Practice Incidence: 36 of 262 MM patients (14%) Median follow-up- 63.5 months Berenson et al. ASH (in press)

  5. Progression from “Asymptomatic” to “Symptomatic” MM • Poorly defined • CRAB are not symptoms • Progression based on CRAB may NOT be related to myeloma • Calcium- vitamin D intoxication, PTH • Renal failure- diabetes, hypertension, drugs • Anemia- iron or B12 deficiency • Bone disease • lytic bone disease • Changes on X-ray readings that are not real • Osteopenia/osteoporosis from other causes • Vertebral compression fractures are traumatic or related to osteopenia/osteoporosis

  6. Berenson et al. ASH (in press)

  7. Establish the Goals of Therapy for the Smoldering Myeloma Patient • The longest life possible with therapy and a disease that has the least impact on their quality of life! • Does not necessarily mean they want treatment • A reduction in paraprotein (i.e. responses) may be w/o meaningful clinical benefit • Need to show • Prolonged overall survival whereas • Responses are of ??? benefit • Time to treatment endpoints are of ??? benefit • Improved quality of life • Prevention of complications

  8. Treating Smoldering Myeloma: Weighing the Options Side effects Tolerability vs Improve QOL Prolong survival Risk of death Complications Treatment-related Disease-related

  9. Smoldering MM: Goals of Therapy ? Control 1. Long survival 2. Thus, use less toxic drugs & maintain QOL Cure 1. Lower tumor burden 2. ? more drug sensitive i.e. may be easier to eliminate the clone

  10. Risks in Treating Smoldering Myeloma Toxicity Prevent use of potentially curative approaches that may become available in the future Negative impact on quality of life- e.g. neuropathy, somnolence, etc. Produce side effects Secondary malignancies- e.g. Lenalidomide- hematologic malignancies Bortezomib- skin cancers Carfilzomib- cardiac complications Effects of treatment on the myeloma Induce or allow clones to take over that are more aggressive resistant to new therapies in the future

  11. Smoldering Myeloma: Treatment Approaches BUT Not Risk Adapted • Exercise- single case report • Celecoxib- single-arm study • Curcumin- small changes in SFLC • Chemotherapy- MP vs observation- no differences in PFS or OS • Cytokine inhibitors- IL-1RA- small trial w/ limited activity • Bisphosphonates alone- • Reports of responses w/ long PFS • Larger randomized trials: prolong time to bony complications but no impact on TTP or OS Boullosa et al. Med & Science in Sports & Exercise 2013, Berenson et al. 2014, Golombick et al. AM J Hematol 2012, D’Arena et al. Leuk Lymphoma 2011, Musto et al. Leuk Lymphoma 2003, Musto et al. Cancer 2008, Hjorth et al. Eur J Haematol 1993, Riccardi et al. Cancer 1994, Riccardi et al. Br J Cancer 2000, Lust et al. Mayo Clin Proc 2009

  12. Smoldering Myeloma: Treatment Approaches • Thalidomide • alone- several trials show responses but poor tolerability BUT • in one trial responses actually associated w/ shortened survival • w/ bisphosphonates- show higher RR & TTP than bisphosphonates alone but drug is too toxic Barlogie et al. Blood 2008, Rajkumar et al. Leukemia 2001, Detweller-Short et al. Am J Hematol 2010, Witzig et al. Leukemia 2013

  13. Smoldering Multiple Myeloma: Risk Factors for Requiring Treatment Sooner • Bone marrow plasma cells • Total:> 10% or > 60%* • Abnormal vs normal: > 95% vs < 5% • M-protein levels • Higher IgG (> 3 g/dL), IgA (> 2 g/dL) or 24 h urine M-protein (> 1g) • Rapid rise in M-protein • SFLC > 100* or ratio I/U > 8 • Genetics – 17p-, 4;14, 1q21 gain, or hyperdiploid; high-risk GEP • MRI findings- # of lesions > 1* • Reduction in uninvolved Ig levels *Highest risk factors predicting progression Reviewed in Dispenzieri et al. Blood 2013

  14. Smoldering Multiple Myeloma: Prevalence of High-Risk Disease • Uncommon- Overall, SMM makes up 15% of MM cases & only 20% have high-risk! • High-risk depends on risk factors used • PETHEMA- 29% (> 95% aBMPCs & “evolving”) • Mayo Clinic- 15% (SFLC > 100) • GIMEMA- 2.5% ( > 60% BMPCs) • Nordic- 28.8% (> 10% BPMCs & M-protein > 3 g/dL • NIH • Using Mayo Clinic classification- only 5% • Using PETHEMA classification- 50% • Only 28.6% concordance between the two models! Thus, high-risk smoldering MM only in 3% of MM cases Cherry et al. Leuk Lymphoma 2013, Rago et al. Cancer 2012, Kristinsson et al. NEJM 2013, Larsen et al. Leukemia 2013, Perez-Persona et al. Brit j Haematol 2009 -

  15. High-Risk Smoldering MM: A Phase 3, Randomized Trial • High-risk- > 95% aberrant BMPCs &/or decreased uninvolved Ig levels • N=119 • Randomized to • Nine 4-week cycles of LEN 25 mg qd d1-21 & DEX 20 mg qd d1-4, 12-15 followed by LEN 10 qd d1-21, 7 d off • Observation • Primary endpoint- time to symptomatic (TTSxic) disease Mateos et al. NEJM 2013

  16. Time to Progression to Symptomatic Disease Mateos et al. NEJM, 2013

  17. Overall Survival from Time of Study Entry Mateos et al. NEJM, 2013

  18. High-Risk Smoldering MM: A Phase 3, Randomized Trial • However, • Dex given only to active treatment arm when progressing biochemically on single-agent LEN maintenance • Waited until met CRAB criteria to treat observation arm- higher rate of death than would expect • Not a crossover design- ? LEN+DEX use for patients in the observation arm Mateos et al. NEJM 2013

  19. Smoldering Myeloma: Treatment Approaches in Early Phases • Proteasome inhibitors • Bortezomib- alone • Carfilzomib w/ LEN & DEX- small NIH trial w/ 100% response rate BUT small #’s & short f/u • Monoclonal antibodies • Anti-CS-1- Elotuzumab • Anti-IL-6- Siltuximab • Anti-DKK-1- BHQ880 • Anti-KIR- IPH2101

  20. Smoldering Myeloma: Take It Slow • Smoldering MM is uncommon (15% of MM) • Most patients are at low risk to progress • Only a small minority (about 1/5th) of these patients have high-risk disease • Treatment must have specific goals • Improve overall survival • No studies have demonstrated this effect except the PETHEMA study in high-risk disease w/ significant design problems • Quality of life • Prevent complications

  21. Treating Patients w/ Smoldering MM • Highest-risk groups • BMPC > 60%, SFLC > 100 or > 1 focal lesion on MRI • 80% risk of progression w/i 2 y • Therefore, treat as active MM • But still don’t know if this impacts OS or QOL • All other patients should be monitored or placed on clinical trials • Those w/ osteopenia or osteoporosis- Monthly zoledronic acid

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