Should we treat smoldering myeloma? Is the data convincing? Yes: Elisabet Manasanch, MD No: Prantar Chakarbarty, MD

1. Should we treat
smoldering myeloma?
Is the data convincing?
Prof. Prantar Chakrabarti
Head
Department of Haematology
NRS Medical College, Kolkata, India

2. •What is smoldering myeloma ?
• Why do we call it “smoldering” ?
• Is it a homogenous group ?
•Why do we want to start treating it ?
•Who benefits from the treatment ?
• At what cost ?

3. ACTIVE MULTIPLE MYELOMA AND ITS PRECURSOR
N Engl J Med 2007;356:2582-90.

4. Diagnostic Criteria of Smoldering Myeloma in Different
Reported Series

5. IMWG CONSENSUS CRITERIA-2010
Leukemia (2010) 24, 1121–1127

6. Why do we call it “smoldering” ?

7. • 10% average annual risk of progression to MM for the
first 5 years after diagnosis,
• Decreasing to 3% annually for the following 5 years
• Becoming the same 1% annual rate of progression as
MGUS thereafter
Kyle RA, et al. Clinical course and prognosis of smoldering
(asymptomatic) multiple myeloma. N Engl J Med 2007; 356:2582-
• Approximately 15% of all
cases with newly diagnosed
multiple myeloma

8. IS IT UNIFORM?
J Clin Oncol 28:690-697; 2009

9. RISK FACTOR FOR PROGRESSION FROM SMM TO
MYELOMA
A. BMPC >10%; M band > 30gm/L
B. BMPC >10%; M protein > 30gm /L and involved/uninvolved FLC >/= 8
C. Involved / uninvolved FLC >/= 100
D. Abnormal Immunophenotype with immunoparesis
E. > 1 focal bone lesion on whole body MRI
F. Based on FISH report
G. High risk interphase FISH and high tumor burden (M protein > 20 g/L)
H. M protein > 30 g/L; abnormal FLC; heavy chain IgA or IgM
BLOOD 2013

10. “It is critical to recognize that in a disease such
as multiple myeloma, in which defining
criteria rely on the presence or absence of
end-organ damage, diagnosis is only as good
as the tools and technology able to detect end-organ
damage”
-- Ola Landgren
How good are our tools ?

11. Trying to define multiple myeloma
• Based on the presence of end-organ damage, including bone lytic
lesions
• Radiological skeletal survey used for the initial workup
• But, 30% to 50% of the bone mass has to be destroyed before
conventional radiography is able to detect the damage
• New imaging techniques allow detection of myeloma
manifestations earlier than conventional radiography

12. • Hillengass et al reported recently that 30% of patients with SMM have BM
infiltration patterns similar to multiple myeloma when using whole body MRI.
• So these patients should have been classified as Multiple myeloma, and should
get benefit of earlier therapy.
• SMM patients with > 1 focal BM lesion have a significantly (P <0.001) shorter
time (median time to progression: 13 months vs not reached) to develop
multiple myeloma

13. • In SMM, MRI of the spine and pelvis can detect occult lesions
• Between 30% and 50% of patients with SMM have an abnormal MRI
• Diffusion- weighted whole-body MRI (DWI-MRI), dynamic contrast-enhanced
MRI (DCE-MRI), may be able to identify myelomatous bony
involvement at an earlier stage.
• So improved diagnostic technique can enhance our diagnosis of
symptomatic multiple myeloma, earlier than conventional imaging
methods
Seminars in Hematology, Vol 48, No 1, January 2011

14. Is CRAB enough ?
• Renal impairment is a defining criterion of MM.
• Aside from a serum creatinine 2.0 mg/dL attributable to the plasma cell
dyscrasia, the current guidelines do not define the renal disease any further.
 Acute tubular necrosis resulting from hypercalcemia or nonsteroidal anti-inflammatory
drugs,
 Monoclonal immunoglobulin deposition disease
 Light chain proximal tubulopathy
• So organ damage apart from CRAB may indicate symptomatic MM

15. Time to modify CRAB ?
• In one recent study, among patients with symptomatic
MM, 74% presented with CRAB symptoms, 20%
presented with non-CRAB manifestations, and 6% had
both clinical features.
• Should we use only CRAB criteria to determine MM ?
Talamo G, et al: Clin Lymphoma Myeloma Leuk. 2010;10(6)

16. All that glitters is not gold !
“The definition of myeloma-related symptomatology should
also be refined to consider the novel imaging assessments
and
those patients who would currently be considered high- or
ultra-high-risk SMM based on the presence of focal
lesions in MRI or PET/CT and tomorrow be reclassified
as symptomatic MM.”
Curr Hematol Malig Rep (2013) 8:270–276

18. Clinical Lymphoma, Myeloma & Leukemia August 2010

19. Progression of MGUS to MM
• The linear model of progression is now
challenged.
• The branching model is now accepted,
as different clones of myeloma cells
acquire different genetic changes and
may progress differentially to MM
• So, all MGUS/SMM patients do not
behave similarly

20. Different cytokines concentrations show that SMM falls within the
continuum of progression of disease biology from MGUS to MM.
A. Zingone et al. / Cytokine 69 (2014) 294–297

21. Who would benefit most ?
• The patient at other end of the spectra are
candidates for early treatment
• The presence of several prognostic factors
are able to discriminate subgroups of
patients with different degrees of risk of
progression to active disease

22. • Numerous studies have been
done to identify the SMM
patients with higher risk of
progression.

23. Risk stratification schemes
for MGUS and Smoldering Myeloma

24. Discordance in risk score
• Landgren’s team prospectively evaluated this two most widely accepted risk
models, the Mayo and Salamanca criteria, in a series of 77 patients with SMM
• Patients were categorized as low, standard or high risk according to the two
criteria.
• There was significant discordance in overall patient risk classification (28.6%
concordance)
• Significant discordance was also in classifying patients as low versus high (P
.0001), low versus non-low (P .0007), and high versus non-high (P .0001) risk.
Cherry BM, et al. Modeling progression risk for smoldering multiple
myeloma: results from a prospective clinical study. Leuk Lymphoma.

25. “ Identification and validation of other biomarkers
will be needed before clinicians can determine
whether initiation of early treatment is beneficial to
patients with high-risk SMM. ”
-- Ola Landgren
Expertspeak
Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma:
biological insights and early treatment strategies; Hematology 2013

26. Newer markers of Risk
stratification
• Flow cytometry of abberant plasma
cells
• The serum FLC monomer-dimer
patterns.
• Estimated doubling time of less than 3
months
American Journal of Hematology, Vol. 89, No. 9, September
2014
Clinical Lymphoma, Myeloma & Leukemia February 2014

27. Relative risk of progression
Rajkumar, S. V. & Kyle,
R. A. Nat. Rev. Clin.
Oncol. 10, 554–555
(2013);

28. Ultra high risk SMM
• Bone marrow plasmacytosis of >60% affects 2% to 8% of
all SMM patients
• The involved FLC/ uninvolved FLC of >100 or greater
captures approximately 7% to 15% of the SMM
population
•More than 1 focal lesion on whole-body MRI, which
affects 15% of SMM patients

29. What happens when
we treat SMM early ?

30. • Pre 1990 era. Melphalan based therapy
• Post 1990 era. Thalidomide based therapy

31. • In the Hjorth study, the response rate was similar (52 % vs. 55 %)
• Thalidomide plus zolendronic acid versus zolendronic acid in SMM
patients,
 the rate of ≥PR was 37 % in the thalidomide arm versus 0 %,
 but there were no significant differences either in the TTP to
symptomatic MM (4.3 vs. 3.3 years) or in the overall survival.
 most of the patients discontinued treatment due to peripheral
neuropathy.
• One should be careful to analyze key end points such as time to

32. What we learnt ?
• Paradoxically, patients who initially displayed at least a
PR to thalidomide had a shorter median time to
treatment (< 2 years) than patients who showed no
improvement (not reached in 8 years).
• This may be a result of selection of aggressive clones
because of treatment

33. • The rate of adverse events, particularly
infection, was much higher in the treatment
group than in the observation group
• all grade infection: 47% [including a fatal
respiratory infection] vs. 22%.
• Median follow-up of 40 months- not sufficient
to allow assessment of different
consequences of the treatment such as
secondary malignancies and negative effect
on further therapy.
-- N Engl J Med 2013;369:438-47.

35. Drawbacks
• Only patients of high risk SMM taken.
• Bone status of the SMM patients were not included
• No MRI was performed at baseline and a higher
incidence of MRI signal abnormalities in the
observation group could not be excluded.

36. Drawbacks contd..
• Although these therapeutic strategies have
facilitated improved survival, cure remains elusive.
• 4 cycle Lenalidomide/ dexamethasone without
transplant in symptomatic myeloma has 3 year
survival of only 55 %.
• So, Lenalidomide/ dexamethasone is generally
given indefinitely until disease progression ( based
on single-institution studies as well as on the
E4A03 trial.)
• On a cautionary note, there is potential for the
development of long-term toxicities with prolonged
novel agent therapy

37. Drawbacks contd..
• This strategy may result in overtreatment of
approximately 40% of patients at 3 years, 30% of patients
at 4 years, and 20% of patients at 5 years
• With the regimens (ie, lenalidomide plus
dexamethasone), the annual cost of therapy is
approximately $100 000 USD, not including the extra
monitoring required for patients on active therapy and
management of adverse events.

38. Drawbacks contd..
• Addition of DEX was allowed at the time of asymptomatic
biologic progression in treatment group but not in the
observation group. (‘time varying confounding’ effect) –
this might have given a false impression on Overall
survival difference
• Trial results only applicable to a subset with SMM (40%
diagnosed with a flow based definition – A methodology
not available in many institutions)

39. Drawbacks contd..
• Patients in the observation arm were not only differently
managed compared with patients in the treatment arm,
but were also not managed according to current “good”
clinical practices
 checking the monoclonal immunoglobulin
 and other disease markers including MRI for initiating
treatment before the occurrence of symptomatic disease

40. • In highly active disease, i.e. ultra high risk, may simulate the
scenario 1, and can benefit from early treatment.
• But other SMM patients will follow scenario 2 or 3, where
therapy will not change the position, rather may be
detrimental.

41. TRIALS IN PATIENTS WITH SMOLDERING
MYELOMA

42. Swedish Myeloma Registry
NEJM 2013
From January 1, 2008, through December 31, 2011, a total of 2494 patients (median age, 72
years) received a diagnosis of multiple myeloma, of whom 360 (14.4%) had smoldering multiple
myeloma. Of the patients with smoldering multiple myeloma, 104 (28.8%) had high-risk
disease (defined as an M-protein level of ≥3 g per deciliter and plasma-cell infiltration of
≥10%); these patients accounted for 4.2% of all patients with multiple myeloma. After 2 years,
56.6% of the patients with high-risk smoldering multiple myeloma had progression to
symptomatic disease, and after a median follow-up time of 29.8 months, 70.4% had
progression.
29% will be considered for early treatment according to criteria.

44. HOWEVER, THIS CONCEPT NEEDS TO BE ENDORSED BY IMWG FOR A CONSENSUS
Rate of progression -
>80% at 2-3 years
LEN –DEX based on
phase 3 data

45. BLOOD, 19 DECEMBER 2013 x VOLUME 122, NUMBER 26

46. TREATMENT YES / NO