Though SMM is defined as a separate entity, though different disease parameters overlap with the extreme of disease spectrum.
Fig. 1. Comparison of cytokine and chemokine levels in peripheral blood (PB) and bone marrow (BM) supernatant of SMM and MM patients. The IL-6 and TNF-a conc similar in MGUS and SMM. Also other cytokines like IL-8, and IL-10, which are similar to MMM are associated with resistance to therapy, than to disease progression.
both of these studies were performed when the best available treatment for MM was melphalan/prednisone, a regimen with a poor therapeutic index for treatment of an asymptomatic condition This study was further complicated by poor tolerance to thalidomide, as a result of peripheral neuropathy and dizziness resulting in discontinuation in greater than half of patients
PETHEMA STUDY: Panel A shows the Kaplan–Meier estimates of time to progression to symptomatic disease. Panel B shows overall survival from the date of inclusion in the study. Panel C shows overall survival from the date of diagnosis of smoldering multiple myeloma.
Should we treat
Is the data convincing?
Prof. Prantar Chakrabarti
Department of Haematology
NRS Medical College, Kolkata, India
•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 ?
ACTIVE MULTIPLE MYELOMA AND ITS PRECURSOR
N Engl J Med 2007;356:2582-90.
Diagnostic Criteria of Smoldering Myeloma in Different
• 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
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
RISK FACTOR FOR PROGRESSION FROM SMM TO
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
“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
-- Ola Landgren
How good are our tools ?
Trying to define multiple myeloma
• Based on the presence of end-organ damage, including bone lytic
• 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
• 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
• 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
Seminars in Hematology, Vol 48, No 1, January 2011
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
Monoclonal immunoglobulin deposition disease
Light chain proximal tubulopathy
• So organ damage apart from CRAB may indicate symptomatic MM
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)
All that glitters is not gold !
“The definition of myeloma-related symptomatology should
also be refined to consider the novel imaging assessments
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
Clinical Lymphoma, Myeloma & Leukemia August 2010
Progression of MGUS to MM
• The linear model of progression is now
• 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
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
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
• Numerous studies have been
done to identify the SMM
patients with higher risk of
Risk stratification schemes
for MGUS and Smoldering Myeloma
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
• There was significant discordance in overall patient risk classification (28.6%
• 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.
“ 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
Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma:
biological insights and early treatment strategies; Hematology 2013
Newer markers of Risk
• Flow cytometry of abberant plasma
• The serum FLC monomer-dimer
• Estimated doubling time of less than 3
American Journal of Hematology, Vol. 89, No. 9, September
Clinical Lymphoma, Myeloma & Leukemia February 2014
Relative risk of progression
Rajkumar, S. V. & Kyle,
R. A. Nat. Rev. Clin.
Oncol. 10, 554–555
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
•More than 1 focal lesion on whole-body MRI, which
affects 15% of SMM patients
• Pre 1990 era. Melphalan based therapy
• Post 1990 era. Thalidomide based therapy
• In the Hjorth study, the response rate was similar (52 % vs. 55 %)
• Thalidomide plus zolendronic acid versus zolendronic acid in SMM
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
• One should be careful to analyze key end points such as time to
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
• 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.
• 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.
• 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
• On a cautionary note, there is potential for the
development of long-term toxicities with prolonged
novel agent therapy
• 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.
• 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
• Trial results only applicable to a subset with SMM (40%
diagnosed with a flow based definition – A methodology
not available in many institutions)
• 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”
checking the monoclonal immunoglobulin
and other disease markers including MRI for initiating
treatment before the occurrence of symptomatic disease
• 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
Swedish Myeloma Registry
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
29% will be considered for early treatment according to criteria.
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
BLOOD, 19 DECEMBER 2013 x VOLUME 122, NUMBER 26