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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  • Reeder: Thirty-three newly diagnosed, symptomatic patients with MM
    received bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8
    and 11, cyclophosphamide 300 mg/m2 orally on days 1, 8, 15
    and 22 and dexamethasone 40 mg orally on days 1–4, 9–12 and
    17–20 on a 28-day cycle for four cycles.
    All patients undergoing stem cell harvest

    Richardson:
    Abstract
    This phase 1/2 study is the first prospective evaluation of lenalidomide-bortezomib-dexamethasone in front-line myeloma. Patients (N = 66) received 3-week cycles (n = 8) of bortezomib 1.0 or 1.3 mg/m2 (days 1, 4, 8, 11), lenalidomide 15 to 25 mg (days 1-14), and dexamethasone 40 or 20 mg (days 1, 2, 4, 5, 8, 9, 11, 12). Responding patients proceeded to maintenance or transplantation. Phase 2 dosing was determined to be bortezomib 1.3 mg/m2, lenalidomide 25 mg, and dexamethasone 20 mg. Most common toxicities included sensory neuropathy (80%) and fatigue (64%), with only 27%/2% and 32%/3% grade 2/3, respectively. In addition, 32% reported neuropathic pain (11%/3%, grade 2/3). Grade 3/4 hematologic toxicities included lymphopenia (14%), neutropenia (9%), and thrombocytopenia (6%). Thrombosis was rare (6% overall), and no treatment-related mortality was observed. Rate of partial response was 100% in both the phase 2 population and overall, with 74% and 67% each achieving very good partial response or better. Twenty-eight patients (42%) proceeded to undergo transplantation. With median follow-up of 21 months, estimated 18-month progression-free and overall survival for the combination treatment with/without transplantation were 75% and 97%, respectively. Lenalidomide-bortezomib-dexamethasone demonstrates favorable tolerability and is highly effective in the treatment of newly diagnosed myeloma. This study is registered at http://clinicaltrials.gov as NCT00378105.

    had a successful collection. Twenty-three patients underwent
    stem cell transplantation (SCT) and are evaluable through day
    100 with CR/nCR documented in 70% and XVGPR in 74%.

    VRD:
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  • Footnote: As we develop therapies that have lower toxicities and have increasingly higher efficacy for the disease in which they are intended, including the possibility of cure, the number of patients willing to undergo such treatments will also increase. In SMM, clinicians need to discuss the risks and benefits with patients and stay updated as more data becomes available. Until we have access to better knowledge, in circumstances where the benefit of early treatment in terms of overall survival is not well established, the risks versus benefits should be taken more cautiously.
  • smoldering myeloma

    1. 1. Should we treat smoldering myeloma? Is the data convincing? Elisabet Manasanch M.D., M.H.Sc. Assistant Professor, Department of Lymphoma/Myeloma Division of Cancer Medicine
    2. 2. Disclosures Nothing to disclose
    3. 3. Monoclonal Gammopathies MGUS SMM MM M protein < 3 g/dL Bone marrow plasma cells <10% No end organ damage. No other LPD. M protein ≥ 3 g/dL Bone marrow plasma cells ≥ 10% No end organ damage M protein in the serum or urine Bone marrow clonal plasma cells Presence of end organ damage Tumor Burden Durie et al. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003.
    4. 4. SMM Risk Stratification High risk SMM median time to progression is < 2 years PETHEMA Group Criteria (n=89) No. of risk factors No. of patients, n (%) Progression at 5 years 0 28 (31) 4% 1 22 (25) 46% 2 39 (44) 72% Risk factors: • ≥95% abnormal plasma cells • Immunoparesis Pérez-Persona et al. New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood 2007
    5. 5. SMM Risk Stratification Mayo Clinic Criteria (n=273) risk factors No. of patients, n (%) 1 76(28) 25% 2 115 (42) 51% 3 82 (30) 76% Risk factors: • BMPCs >10% • M-protein >3 g/dL • FLC-ratio <0.125 or >8 No. of Progression at 5 years Dispenzieri et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood 2008
    6. 6. SMM Risk Stratification SWOG Criteria (n=117) Risk factors: • GEP70 score > -0.26 • M-protein >3 g/dL • Involved sFLC > 25 mg/dL No. of risk factors No. of patients, n (%) Progression at 2 years 0 76(28) 3% 1 115 (42) 22% ≥ 2 82 (30) 68% Dhodapkar et al. Clinical, genomic and imaging predictors of malignancy: analysis of the first prospective clinical trial in Asymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014.
    7. 7. 100% 80% 60% 40% 20% 0% SWOG Criteria 0 12 24 36 48 60 Months from Registration 2+ RF 1 RF No RF Events / N 12 / 18 9 / 39 2 / 60 24-Month Estimate 66.7% 21.9% 3.4% Variable % (n=117) HR (95% CI) GEP 70-gene risk > -0.26 27 6.81 (2.90, 15.97) Serum M-protein ≥ 3 g/dL 15 6.49 (2.78, 15.18) Involved serum FLC > 25 23 3.15 (1.40, 7.08) mg/dL Dhodapkar et al. Clinical, genomic and imaging predictors of malignancy: analysis of the first prospective clinical trial in Asymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014.
    8. 8. Risk of Clinical MM Requiring Therapy Based on Molecular Subtypes in Asymptomatic Monoclonal Gammopathy 100% 80% 60% 40% 20% 0% 0 12 24 36 48 60 Months from Registration PR MS HY CD-2 MF LB CD-1 Events / N 3 / 5 4 / 11 8 / 31 4 / 28 2 / 17 3 / 28 0 / 6 24-Month Estimate 60.0% 40.0% 22.6% 15.7% 11.8% 10.7% .% Dhodapkar et al. Clinical, genomic and imaging predictors of malignancy: analysis of the first prospective clinical trial in Asymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014.
    9. 9. Ultra high risk SMM 1) ≥ 60% bone marrow plasma cell infiltration 2) iFLC/uFLC ratio >100 3) More than 1 lesion on whole body MRI (may be substituted by PETCT) n=634 n=21 iFLC/uFLC>100 iFLC/uFLC<100 MRI Risk of progression to MM of about 80% at 2 years Larsen JT et al. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia. 2013. Rajkumar SV et al. Diagnosis of smoldering multiple myeloma. N Engl J Med. 2011;365(5):474-475 Kastritis E et al. Extensive bone marrow infiltration and abnormal free light chain ratio identifies patients with asymptomatic myeloma at high risk for progression to symptomatic disease. Leukemia. 2013. Hillengas et al. Prognostic significance of focal Lesions in whole-body magnestic resonance imaging in patients with asymptomatic multiple myeloma. JCO. 2010
    10. 10. Lenalidomide and Dexamethasone in SMM Randomized phase III clinical trial 117 patients Treatment (n=57)  Maintenance (n=50) Observation (n=62) Mateos et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. NEJM.2013.
    11. 11. Treatment of high risk SMM: first randomized trial showing benefit in treatment arm LenDex LenDex 119 high risk SMM patients randomized to: - Lenalidomide plus dexamethasone for 9 cycles (28 days each) followed by Len Maintenance for 2 years - Observation only (currently recommended by guidelines) Mateos et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. NEJM.2013.
    12. 12. Carfilzomib, Lenalidomide and Dexamethasone in SMM Landgren et al. Pilot study: Carfilzomib, lenalidomide and dexamethasone in high-risk smoldering multiple myeloma. ASH.2013.
    13. 13. Carfilzomib, Lenalidomide and Dexamethasone in high-risk SMM Deep level of remission 4/5 patients achieving sCR/CR/nCR were MRD negative Using mutiparameter flow cytometry Analyzing 3-4 x 106 million cells Landgren et al. Pilot study: Carfilzomib, lenalidomide and dexamethasone in high-risk smoldering multiple myeloma. ASH.2013.
    14. 14. Monoclonal Gammopathies MGUS SMM MM M protein < 3 g/dL Bone marrow plasma cells <10% No end organ damage. No other LPD. M protein ≥ 3 g/dL Bone marrow plasma cells ≥ 10% No end organ damage HIGH-RISK HIGH-RISK HIGH-RISK ULTRA HR ULTRA HR ULTRA HR M protein in the serum or urine Bone marrow clonal plasma cells Presence of end organ damage Tumor Burden Durie et al. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003.
    15. 15. YES Summary BENEFITS RISKS Delay of symptomatic disease Relief of psychological burden Possibility of cure Clonal evolution Toxicity Cost Overtreatment Manasanch et al. Smoldering multiple myeloma: special considerations surrounding treatment on versus off clinical trials. Haematologica. 2014. In press.
    16. 16. MDACC Myeloma Center Dr. Robert Orlowski Dr. Jatin Shah Dr. Donna Weber Dr. Sheeba Thomas Dr. Michael Wang Dr. Parmar Dr. Qazilbash Dr. Shah Dr. Bashir Stem Cell Transplant Department Support staff, nurses, coordinators Patients

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