Smoldering Multiple Myeloma

To treat or not to treat, that is the question

James R. Berenson, MDInstitute for Myeloma and Bone Cancer Research

West Hollywood, CA

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

Diagnostic Test MM

Monoclonal protein in serumand/or

Monoclonal protein in urine

> 3 g/dL and/or> 200 mg/24 h

Bone marrow clonal plasma cells (and/or documented plasmacytoma)

> 10%

No CRAB criteria The above, and none of the following (CRAB criteria):• Calcium elevation (>11.4 mg/dL)• Renal insufficiency (creatinine >2 mg/dL)• Anemia (Hb <10g/dL or 2 g/dL <normal)• Bone disease (osteolytic lesions or osteopenia or fracture)

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

Smoldering MM in Our PracticeIncidence: 36 of 262 MM patients (14%)

Berenson et al. ASH (in press)Median follow-up- 63.5 months

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

Berenson et al. ASH (in press)

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

Treating Smoldering Myeloma: Weighing the Options

Risk of deathComplications

Disease-related

Side effectsTolerability

vsImprove QOL

Prolong survival

Treatment-related

Smoldering MM: Goals of Therapy

? Cure1. Lower tumor burden2. ? more drug sensitive i.e. may be easier to eliminate the clone

Control1. Long survival2. Thus, use less toxic drugs & maintain QOL

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

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 OSBoullosa 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

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

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

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-

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

Time to Progression to Symptomatic Disease

Mateos et al. NEJM, 2013

Overall Survival from Time of Study Entry

Mateos et al. NEJM, 2013

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

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

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

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