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Should we treat 
smoldering myeloma? 
Is the data convincing? 
Prof. Prantar Chakrabarti 
Head 
Department of Haematology ...
•What is smoldering myeloma ? 
• Why do we call it “smoldering” ? 
• Is it a homogenous group ? 
•Why do we want to start ...
ACTIVE MULTIPLE MYELOMA AND ITS PRECURSOR 
N Engl J Med 2007;356:2582-90.
Diagnostic Criteria of Smoldering Myeloma in Different 
Reported Series
IMWG CONSENSUS CRITERIA-2010 
Leukemia (2010) 24, 1121–1127
Why do we call it “smoldering” ?
• 10% average annual risk of progression to MM for the 
first 5 years after diagnosis, 
• Decreasing to 3% annually for th...
IS IT UNIFORM? 
J Clin Oncol 28:690-697; 2009
RISK FACTOR FOR PROGRESSION FROM SMM TO 
MYELOMA 
A. BMPC >10%; M band > 30gm/L 
B. BMPC >10%; M protein > 30gm /L and inv...
“It is critical to recognize that in a disease such 
as multiple myeloma, in which defining 
criteria rely on the presence...
Trying to define multiple myeloma 
• Based on the presence of end-organ damage, including bone lytic 
lesions 
• Radiologi...
• Hillengass et al reported recently that 30% of patients with SMM have BM 
infiltration patterns similar to multiple myel...
• In SMM, MRI of the spine and pelvis can detect occult lesions 
• Between 30% and 50% of patients with SMM have an abnorm...
Is CRAB enough ? 
• Renal impairment is a defining criterion of MM. 
• Aside from a serum creatinine 2.0 mg/dL attributabl...
Time to modify CRAB ? 
• In one recent study, among patients with symptomatic 
MM, 74% presented with CRAB symptoms, 20% 
...
All that glitters is not gold ! 
“The definition of myeloma-related symptomatology should 
also be refined to consider the...
Clinical Lymphoma, Myeloma & Leukemia August 2010
Progression of MGUS to MM 
• The linear model of progression is now 
challenged. 
• The branching model is now accepted, 
...
Different cytokines concentrations show that SMM falls within the 
continuum of progression of disease biology from MGUS t...
Who would benefit most ? 
• The patient at other end of the spectra are 
candidates for early treatment 
• The presence of...
• Numerous studies have been 
done to identify the SMM 
patients with higher risk of 
progression.
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 ...
“ Identification and validation of other biomarkers 
will be needed before clinicians can determine 
whether initiation of...
Newer markers of Risk 
stratification 
• Flow cytometry of abberant plasma 
cells 
• The serum FLC monomer-dimer 
patterns...
Relative risk of progression 
Rajkumar, S. V. & Kyle, 
R. A. Nat. Rev. Clin. 
Oncol. 10, 554–555 
(2013);
Ultra high risk SMM 
• Bone marrow plasmacytosis of >60% affects 2% to 8% of 
all SMM patients 
• The involved FLC/ uninvo...
What happens when 
we treat SMM early ?
• 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 zolendron...
What we learnt ? 
• Paradoxically, patients who initially displayed at least a 
PR to thalidomide had a shorter median tim...
• The rate of adverse events, particularly 
infection, was much higher in the treatment 
group than in the observation gro...
Drawbacks 
• Only patients of high risk SMM taken. 
• Bone status of the SMM patients were not included 
• No MRI was perf...
Drawbacks contd.. 
• Although these therapeutic strategies have 
facilitated improved survival, cure remains elusive. 
• 4...
Drawbacks contd.. 
• This strategy may result in overtreatment of 
approximately 40% of patients at 3 years, 30% of patien...
Drawbacks contd.. 
• Addition of DEX was allowed at the time of asymptomatic 
biologic progression in treatment group but ...
Drawbacks contd.. 
• Patients in the observation arm were not only differently 
managed compared with patients in the trea...
• In highly active disease, i.e. ultra high risk, may simulate the 
scenario 1, and can benefit from early treatment. 
• B...
TRIALS IN PATIENTS WITH SMOLDERING 
MYELOMA
Swedish Myeloma Registry 
NEJM 2013 
From January 1, 2008, through December 31, 2011, a total of 2494 patients (median age...
HOWEVER, THIS CONCEPT NEEDS TO BE ENDORSED BY IMWG FOR A CONSENSUS 
Rate of progression - 
>80% at 2-3 years 
LEN –DEX bas...
BLOOD, 19 DECEMBER 2013 x VOLUME 122, NUMBER 26
TREATMENT YES / NO
smoldering myeloma
smoldering myeloma
smoldering myeloma
smoldering myeloma
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smoldering myeloma

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

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smoldering myeloma

  1. 1. Should we treat smoldering myeloma? Is the data convincing? Prof. Prantar Chakrabarti Head Department of Haematology NRS Medical College, Kolkata, India
  2. 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. 3. ACTIVE MULTIPLE MYELOMA AND ITS PRECURSOR N Engl J Med 2007;356:2582-90.
  4. 4. Diagnostic Criteria of Smoldering Myeloma in Different Reported Series
  5. 5. IMWG CONSENSUS CRITERIA-2010 Leukemia (2010) 24, 1121–1127
  6. 6. Why do we call it “smoldering” ?
  7. 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. 8. IS IT UNIFORM? J Clin Oncol 28:690-697; 2009
  9. 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. 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. 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. 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. 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. 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. 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. 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
  17. 17. Clinical Lymphoma, Myeloma & Leukemia August 2010
  18. 18. 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
  19. 19. 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
  20. 20. 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
  21. 21. • Numerous studies have been done to identify the SMM patients with higher risk of progression.
  22. 22. Risk stratification schemes for MGUS and Smoldering Myeloma
  23. 23. 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.
  24. 24. “ 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
  25. 25. 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
  26. 26. Relative risk of progression Rajkumar, S. V. & Kyle, R. A. Nat. Rev. Clin. Oncol. 10, 554–555 (2013);
  27. 27. 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
  28. 28. What happens when we treat SMM early ?
  29. 29. • Pre 1990 era. Melphalan based therapy • Post 1990 era. Thalidomide based therapy
  30. 30. • 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
  31. 31. 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
  32. 32. • 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.
  33. 33. 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.
  34. 34. 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
  35. 35. 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.
  36. 36. 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)
  37. 37. 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
  38. 38. • 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.
  39. 39. TRIALS IN PATIENTS WITH SMOLDERING MYELOMA
  40. 40. 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.
  41. 41. 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
  42. 42. BLOOD, 19 DECEMBER 2013 x VOLUME 122, NUMBER 26
  43. 43. TREATMENT YES / NO

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