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smoldering myeloma

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Should we treat smoldering myeloma? Is the data convincing? …

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

Published in: Health & Medicine

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  • 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.
  • Transcript

    • 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
    • 17. Clinical Lymphoma, Myeloma & Leukemia August 2010
    • 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. 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. 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. • Numerous studies have been done to identify the SMM patients with higher risk of progression.
    • 22. Risk stratification schemes for MGUS and Smoldering Myeloma
    • 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. “ 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. 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. Relative risk of progression Rajkumar, S. V. & Kyle, R. A. Nat. Rev. Clin. Oncol. 10, 554–555 (2013);
    • 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. What happens when we treat SMM early ?
    • 29. • Pre 1990 era. Melphalan based therapy • Post 1990 era. Thalidomide based therapy
    • 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. 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. • 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. 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. 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. 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. 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. 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. • 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. TRIALS IN PATIENTS WITH SMOLDERING MYELOMA
    • 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. 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. BLOOD, 19 DECEMBER 2013 x VOLUME 122, NUMBER 26
    • 43. TREATMENT YES / NO