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
Diagnostic criteria for diagnosis of smoldering MM- i.e. “Asymptomatic”
Diagnostic Test MM
Monoclonal protein in serum
and/or
Monoclonal protein in urine
> 3 g/dL
> 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)

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 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
Disease-related
Treatment-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, 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