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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”
Diagnostic Test
MM
Monoclonal protein in serum > 3 g/dL
and/or
and/or
Monoclonal protein in urine > 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 Practice
Incidence: 36 of 262 MM patients (14%)
Median follow-up- 63.5 months
Berenson et al. ASH (in press)
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 death
Complications
Disease-related
Side effects
Tolerability
vs
Improve QOL
Prolong survival
Treatment-related
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
Risks in Treating Smoldering Myeloma
►Toxicity
►Prevent use of potentially curative approaches
that may become available in the future
►Negative impact on quality of lifee.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 observationno differences in PFS or OS
• Cytokine inhibitors- IL-1RAsmall 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
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 osteoporosisMonthly zoledronic acid