Multiple Myeloma in Session 2015: An Online Journal Club for Hematology/Oncology Fellows This program is supported by educational grants from Celgene Corporation and Onyx Pharmaceuticals.

An Overview of New Diagnostic Criteria for Multiple Myeloma From the International Myeloma Working Group Slideset on: Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538-e548.

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Background: IMWG Diagnostic Criteria for Multiple Myeloma MM: clonal plasma cell proliferative disease with heterogeneous cytogenetics[1,2] MM usually preceded by asymptomatic MGUS[3,4] Smoldering MM: clinical stage between MGUS and progression to MM New guidelines redefine diagnostic criteria for MM and smoldering MM[5] IMWG, International Myeloma Working Group; MM, multiple myeloma; MGUS, monoclonal gammopathy of undetermined significance. 1. Palumbo A, et al. N Engl J Med. 2011;364:1046-1060. 2. Rajkumar SV. Nat Rev Clin Oncol. 2011;8:479-491. 3. Landgren O, et al. Blood. 2009;113:5412-5417. 4. Weiss BM, et al. Blood. 2009;113:5418-5422. 5. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

Rationale for New Diagnostic Criteria for Multiple Myeloma Previous IMWG criteria developed in 2003 with only minor clarifications in 2009[1,2] Clinicopathologic disease criteria needed for diagnosis (ie, major end- organ damage) prevents early administration of therapy when disease still in its microenvironment Newer regimens safer and more effective with data showing extended survival from early intervention in high-risk asymptomatic pts[3] Criteria for CRAB features need updating due to advances in imaging and laboratory techniques[4] Biomarkers needed to identify pts with smoldering MM at risk for progression Other clarifications needed for M protein and bone marrow plasma cell requirements CRAB, calcium elevation, renal insufficiency, anemia, bone lesions; IMWG, International Myeloma Working Group; MM, multiple myeloma. 1. International Myeloma Working Group. Br J Haematol. 2003;121:749-757. 2. Kyle RA, et al. Leukemia. 2009;23:3-9. 3. Mateos MV, et al. N Engl J Med. 2013;369:438-447. 4. Dispenzieri A, et al. Blood. 2013;122:4172-4181.

Revised IMWG Diagnostic Criteria for Multiple Myeloma* MGUS Smoldering Myeloma Multiple Myeloma M protein < 3 g/dL Clonal plasma cells in BM < 10% No myeloma defining events M protein ≥ 3 g/dL (serum) or ≥ 500 mg/24 hrs (urine) Clonal plasma cells in BM 10% to 60% No myeloma-defining events Clonal BM plasma cells ≥ 10% or ≥ 1 biopsy-proven plasmacytoma AND 1 or more MM-defining events: ≥ 1 CRAB† feature ≥ Biomarker of malignancy: Clonal plasma cells in BM ≥ 60% Serum FLC ratio ≥ 100 > 1 MRI focal lesion ≥ 5 mm on MRI BM, bone marrow; CrCl ,creatinine clearance; CT, computed tomography; FLC, free light chain; Hb, hemoglobin; IMWG, International Myeloma Working Group; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; MRI, magnetic resonance imaging; PET, positron emission tomography; ULN, upper limit of normal. †C: Calcium elevation (> 11 mg/dL or > 1 mg/dL higher than ULN) R: Renal insufficiency (CrCl < 40 mL/min or serum creatinine > 2 mg/dL) A: Anemia (Hb < 10 g/dL or 2 g/dL < normal) B: Bone disease (≥ 1 lytic lesions on skeletal radiography, CT, or PET/CT) *New criteria associated with ≥ 80% risk of progression to MM within 2 yrs. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

Biomarkers of Malignancy: ≥ 60% Clonal Plasma Cells in Bone Marrow[1] Based on conventional bone marrow aspirate or biopsy (use higher of 2 values)[2] Estimation of bone marrow plasma cells should not be based on proportion reported by flow cytometry; studies ongoing to determine feasibility of flow-based enumeration[3] Clonality established via: κ/λ light-chain restriction on immunohistochemistry or immunofluorescence Evidence on flow cytometry of phenotypic clonality Assay demonstrating rearrangement of immunoglobulin-coding genes 1. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548. 2. Rajkumar SV, et al. Am J Hematol. 2001;68:269-275. 3. Johnsen HE, et al. Cytometry B Clin Cytom. 2010;78:338-347.

Biomarkers of Malignancy: Involved-to-Uninvolved Serum FLC Ratio ≥ 100[1-4] Automated nephelometric assay measuring κ and λ circulating serum light chains Abnormal FLC ratio and degree of abnormality predict risk of progression in MGUS, smoldering MM, AL amyloidosis, and solitary plasmacytoma FLC Ratio Adjusted for M Spike and Percent BMPC[2] 20 10 5 Relative Risk of Progression 1 AL, amyloid light-chain; BMPC, bone marrow plasma cells; FLC, free light chain; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma. 0.5 1 10 0.01 0.1 0.26 1.65 100 1000 0.0001 0.001 1. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548. 2. Dispenzieri A, et al. Blood. 2008;111:785-789. 3. Kastritis E, et al. Leukemia. 2013;27:947-953. 4. Waxman AJ, et al. ASCO 2014. Abstract 8607.

Biomarkers of Malignancy: > 1 Focal Lesion ≥ 5 mm on MRI[1,2] Diffuse marrow plasmacytosis associated with risk of progression but insufficient to establish diagnosis of MM Follow-up MRI in 3-6 mos strongly recommended for pts with diffuse marrow infiltration, a solitary focal lesion, or equivocal findings Clinical judgment should be used in management of pts with suspected MM who have < 10% clonal BMPC with lytic lesions or plasmacytomas inaccessible for biopsy BMPC, bone marrow plasma cells; MM, multiple myeloma; MRI, magnetic resonance imaging. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548. Dimopoulos M, et al. Leukemia. 2009;23:1545-1556.

MM Criteria: Additional Considerations CRAB features, whether symptomatic to the pt or revealed by tests, must be attributable to underlying clonal plasma cell disorder Term “multiple myeloma” now preferred over “symptomatic multiple myeloma” Non-CRAB end-organ damage (eg, hyperviscosity), AL amyloidosis, recurrent bacterial infections, and peripheral neuropathy insufficient for diagnosis of MM in absence of above criteria and not recommended for use for initiation of treatment Investigate hypercalcemia without MM bone disease to rule out other etiologies Use clinical judgment in pts with significant anemia with relatively minimal involvement of BMPC AL, amyloid light-chain; BMPC, bone marrow plasma cells; CRAB, calcium elevation, renal insufficiency, anemia, bone lesions; MM, multiple myeloma. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

Future Directions Multiparametric flow cytometry helps differentiate between normal and clonal plasma cells Higher risk for progression in smoldering MM with immunophenotypic pattern of MM (> 95% clonal cells) Ultra-high risk of progression associated with high level of circulating plasma cells and rapidly proliferative BMPC Challenges include: Methods of identification not universally available Cutoff points needed for sensitive and automated multiparametric flow cytometric methods BMPC, bone marrow plasma cells; MM; multiple myeloma. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

Future Directions Cytogenetic abnormalities (eg, t[4;14], 1q amp, del[17p]) associated with high risk of progression from smoldering MM; use with known biomarkers to improve predictive value Data on increasing M protein currently insufficient to qualify as MM-defining criteria Used to subdivide into secretory and nonsecretory MM subtypes Further research promises to identify additional biomarkers Those associated with risk of progression to MM of ≥ 80% within 2 yrs and validated by at least 2 independent studies will be added to future diagnostic criteria by IMWG Promising biomarkers in development with varying predictive specificity for progression to MM IMWG, International Myeloma Working Group; MM, multiple myeloma. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

2-Yr Probability of Progression to MM, % Biomarkers in Development With Predictive Specificity for MM Progression Biomarker 2-Yr Probability of Progression to MM, % High levels of circulating plasma cells 80 High BMPC proliferative rate Evolution of smoldering MM* 65 Abnormal PC immunophenotype ≥ 95% plus immunoparesis Cytogenetic subtypes: t(4:14), 1q amp or del(17p) 50 Unexplained decrease in CrCl ≥ 25% with rise in urinary M protein or serum FLC concentrations Not known BMPC, bone marrow plasma cell; CrCl, creatinine clearance; FLC, free light chain; MM, multiple myeloma; PC, plasma cell. *Increase in serum M protein by ≥ 10% on each of 2 successive evaluations in 6-mo period. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

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