3/19/2018. Clinical Trials in Smoldering MM. Clinical Trials in SMM: The Dilemma. Not All SMM Patients are Created EQUAL

Transcription

1 M-Protein 3/19/2018 Clinical Trials in Smoldering MM Tom Martin, MD Clinical Professor of Medicine Co-Director Multiple Myeloma Program University of California, San Francisco Clinical Trials in SMM: The Dilemma There are no drugs approved for use in SMM The appropriate endpoints have not been established Survival should be the endpoint Long-term survival may occur without treatment Needs well designed randomized trial Can other/surrogate endpoints be used? Is PFS (delaying progression to active MM) good enough? Can MRD (minimal residual disease) be used to estimate OS THE DILEMMA: Not all smoldering MM are created equal Not All SMM Patients are Created EQUAL BIOLOGY IS VARIABLE TIME 1

2 Smoldering Multiple Myeloma 27% will convert in 15 years Roughly 2% per year 50% will convert in 5 years Roughly 10% per year Kyle R et al. N Engl J Med 2007;356: Updated IMWG Criteria for Diagnosis of Multiple Myeloma MGUS M-protein <3 g/dl Clonal plasma cells in BM <10% No myeloma defining events Smoldering Myeloma M-protein 3 g/dl (serum) or 500 mg/24 hours (urine) Clonal plasma cells in BM 10% - 60% No myeloma defining events Multiple Myeloma Underlying plasma cell proliferative disorder AND 1 or more myeloma defining events including either: 1 CRAB feature(s) OR 1 Biomarker driven C: Calcium elevation (>11 mg/dl or >1 mg/dl higher than ULN) R: Renal insufficiency (creatinine clearance <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) Biomarker driven (1) Sixty-percent ( 60%) clonal PCs by BM; (2) Serum-free Light chain ratio involved:uninvolved 100; (3) >1 focal lesion detected by MRI BM, bome marrow; IMWG, International Myeloma Working Group; MGUS, with monoclonal gammopathy of undetermined significance; MRI, magnetic resonance imaging; PC, plasma cell; PET-CT, positive emission tomography-computed tomography; ULN, upper limit of normal Rajkumar SV, et al. Lancet Oncol. 2014;15(12):e538-e548. High Risk SMM: Median TTP ~2 years 10% PCs plus: SMM with M protein 3 gm/dl Absence (<5%) of normal PCs by immunophenotyping plus Immunoparesis Abnormal FLC ratio Del(17p), t4;14, gain(1q21) M protein 4 gm/dl IgA SMM Evolving pattern Increased circulating plasma cells Rajkumar SV, Landgren O, Mateos MV. Blood

3 % surviving without biochemical/diagnostic progression 3/19/2018 QuiRedex Phase 3 trial: Len-dex vs no treatment in high risk SMM (n = 119) Median follow-up: 75 m TTP OS Early treatment with Rd significantly delayed the TTP to Myeloma with a benefit in OS, BUT. Mateos MV, et al. NEJM 2013 Mateos MV, et al. Lancet Oncology 2016 CLINICAL TRIALS IN SMOLDERING MM Phase II Novel agents (minimizing toxicity) Induction with Autologous Transplant (can we cure SMM) Vaccines (can we delay progression/cure SMM) Phase III Mono/Combination therapy vs. no therapy (can we delay progression) NOVEL AGENT 1. Elotuzumab 2. SQ Dara 3. Anti-KIR 4. Situximab 5. IL-1Ra 6. PD-1/PD-L1 Induction 1. ECOG: Len only Transplantation 1. Ascent 2. Cesar Vaccines 1. PVX L-BLP25 3. BB-MPI-03 \ Arm A: Long - Qwk x 8, Q2wk x8, Q4wk x4, Q8wk x 13 Arm B: intermed - Qwk x 8 then Q8wk (total 20 cycles) % 75% 56% Arm A: Long Arm B: Intermediate Arm C: Short Arm C: Short - Qwk x 8 doses Hofmeister et al, ASH Months 3

4 E3A06: Phase III High-Risk Smoldering Myeloma* Lenalidomide vs. observation PI: Sagar Lonial R A N D O M I Z A T I O N Lenalidomide Observation CR/PR/ Stable Prog. anytime Continue therapy till prog. or toxicity Off Rx * Completed Enrollment Aggressive Smoldering Curative Approach Evaluating Novel Therapies (ASCENT): A phase 2 trial of induction, consolidation and maintenance in subjects with high risk smoldering multiple myeloma (SMM) Inclusion: High risk smoldering myeloma, which is untreated, as defined by: Serum M spike > 3 gm/dl AND an involved to uninvolved FLC ratio > 8 AND bone marrow PC% 10% Primary Objective: To determine the confirmed stringent complete response rate of intense induction, consolidation and maintenance treatment in subjects with high risk smoldering multiple myeloma. Secondary Objectives: 1. To determine the toxicities 2. To determine the progression free survival and overall survival rate 3. To determine the persistent MRD negativity rate at 1 year after completion of planned treatment consisting of induction, consolidation and maintenance. GEM-CESAR (n=90) Safety profile Related- Serious Adverse Events (n=8 pts) Pneumoniae (1) Respiratory Infection (1) Infections (2) Enterocolitis (1) Cutaneous exantema (1) Decapited meningitis (1) Massive ischemic stroke (1) All of thembutoneresolved Dose modifications Carfilzomib no pts required reduction Lenalidomide pts required reduction* Dexamethasone pts required reduction* Melphalan no pts required reduction *Neutropenia, infections and skin rash were the causes for reduction 4

5 GEM-CESAR: Study Design Multicenter, open-label, phase II trial Induction 6 x 28-day cycles Consolidation 2 x 28-day cycles Maintenance 24 x 28-day cycles High-risk* Smouldering MM patients N=90 Carfilzomib i.v. 20/36 mg/m 2 Days 1, 2, 8, 9, 15, 16 Lenalidomide 25 mg Days 1 21 Dexamethasone 40 mg Days 1, 8, 15 & 22 High-dose Melphalan [200 mg/m 2 ] Followed by ASCT Carfilzomib i.v. 20/36 mg/m 2 Days 1, 2, 8, 9, 15, 16 Lenalidomide 25 mg Days 1 21 Dexamethasone 40 mg Days 1, 8, 15 & 22 Lenalidomide 10 mg Days 1 21 Dexamethasone 20 mg Days 1, 8, 15 & 22 *High-risk was defined according to the Mayo and/or Spanish models - Patients with any one or more of the biomarkers predicting imminent risk of progression to MM were allowed to be included but - New imaging assessments were mandatory at screening and if bone disease was detected by CT or PET-CT, patients were excluded GEM-CESAR: Consolidation & Maintenance: Efficacy (35/29 pts) Response category Induction (n=71) HDT-ASCT (n=42) Consolidation (n=35) Maintenance (n=29) ORR 69 (98%) 42 (100%) 35 (100%) 29 (100%) scr 21 (30%) 22 (52%) 24 (69%) 24 (83%) CR 9 (13%) 2 (5%) 2 (6%) 2 (7%) VGPR 27 (38%) 12 (29%) 7 (20%) 2 (7%) PR 12 (17%) 6 (14%) 2 (6%) 1 (3%) SD MRD ve, 31% 50% 60% N/A Relapse from CR 2 (3%) Clinical progression * No patients discontinued consolidation or maintenance Conclusions The definition of Smoldering MM will continue to evolve Ideal goal is to eliminate this category, and either patients are in MM or in MGUS like definition Many clinical trials are actively investigating their use in SMM Improving OS from diagnosis of SMM Delaying progression to active MM Immunotherapy may be the most effective and least toxic 5

6 Current Concepts in the Diagnosis of Smoldering Multiple Myeloma and New Active Myeloma Defining Criteria Ajai Chari, MD Associate Professor of Medicine Director of Clinical Research Icahn of School Medicine at Mount Sinai Disclosures Nature of Relevant Financial Relationship Grant or research support Paid consultant Commercial Interest Amgen, Array Biopharma, Celgene, Millenium/Takeda, Novartis Pharmaceuticals, Janssen, Pharmacyclics Celgene, Millenium/Takeda, Novartis Pharmaceuticals, Janssen 2 Plasma Cell Disorders Multiple Myeloma Solitary Plasmacytoma (Bone vs. Extramedullary) Primary Amyloidosis (AL) POEMS syndrome / osteosclerotic myeloma Monoclonal gammopathy of renal significance Light chain deposition disease Heavy chain deposition disease Acquired Fanconi s syndrome TEMPI syndrome Schnitzler s syndrome *Smoldering Multiple Myeloma and *Monoclonal gammopathy of undetermined significance (MGUS) *Diagnoses of exclusion Mount Sinai / Presentation Slide / December 5,

7 Other D/o w/monoclonal Gammopathy B cell lymphoproliferative d/o NHL, CLL, WM, PTLD Cold hemagglutinin - IgM Autoimmune/Connective Tissue d/o Scleromyxedema IgG lambda Cryoglobulinemia type 1 monoclonal (vs 2 mixed and 3 polyclonal ) Other heme d/o MDS, CNL Likely epi-phenomenon due to median age of onset Mount Sinai / Presentation Slide / December 5, Any type of Multiple Myeloma can express free light chains Intact Immunoglobulin 80% Light chain only 15-20% Nonsecretory 1-2% 89% 100% 68-82% Abnormal / sflc ratio Katzmann et al Mayo Clin Proc. 2006; 81(12): Dispenzieri A et al. Leukemia 2009; 23,

8 Percent /19/2018 Risk Stratification Model for MGUS All 3 factors abnormal High Risk Any 2 factors abnormal High-Intermediate-Risk Any 1 factor abnormal Low-Intermediate-Risk Serum M-spike <1.5 gm/dl, IgG Subtype and normal FLC ratio Rajkumar SV et al. Blood 2005;106: Years Mayo and Pethema Risk Stratification of Smoldering Multiple Myeloma Risk factor Mayo Risk Factors (> 10% PC, m > 3/gl, FLCR < or > 8) Pethema Risk Factors (>95% abn PC, immunoparesis) Progression at 5 years 25% 51% 76% 4% 46% 72% Kyle RA, et al. N Engl J Med. 2007;356: ; Kyle RA, et. al. Perez-Persona Curr Hematol Malig E, et al. Rep. Blood ;110: Apr;5(2):62- Risk Factors for Non-CRAB SMM Progression at 2 Years Rajkumar, S. V. & Kyle, R. A. (2013) Nat. Rev. Clin. Oncol. doi: /nrclinonc

9 Current Definitions of MGUS, SMM and MM MGUS SMM MM (1) Serum M-protein < 3 g/dl 3 g/dl or BJP > 500 mg/d Any paraprotein (2) Bone marrow plasma cell % < 10% 10-60% 10% or biopsy-proven plasmacytoma (3) CRAB* None None At least one (4) Myeloma Defining Events** None None Possible For diagnosis All 4 criteria must be met Either (1) OR (2), WITHOUT (3) OR (4) Either (2) + (3), OR (2) + (4) *CRAB criteria: (1) Serum calcium > 11 mg/dl or > 1 mg/dl above ULN, (2) renal insufficiency (serum Cr > 2 mg/dl or Cr Cl < 40 ml/min), (3) anemia (hemoglobin > 2 g/dl below the LLN, or < 10 g/dl), and (4) bone lesions (one or more osteolytic lesions revealed by skeletal radiography, CT, or PET) ** Myeloma defining events: (1) clonal bone marrow plasma cell % 60 (2) involved to uninvolved serum free light chain ratio 100 (3) > 1 focal lesions (each 5 mm in size) on MRI 10 Monitoring Response: using difference in FLC (versus FLCR) sflc (mg/l) sflc (mg/l) / sflc ratio Normal range dflc (mg/l) Baseline Post Treatment iflc / sflc ratio or dflc The same pre- and post-therapy Therapy failure? 90% reduction Therapy successful Smoldering Multiple Myeloma (SMM): Predictive Value of Free Light Chains and Group Based Trajectory Modeling (GBTM) Vernon Wu, Erin Moshier, Ajai Chari ASCO 2017 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 4

10 Comparison of high risk SMM at various institutions MM GIMEMA- University of University of Mayo Clinic Denmark Latium Working Mount Sinai Athens Pennsylvania Group (FLCR), Years of investigation (BMPC) Number of Centers single - single multi multi single Inclusion Criteria yes - - yes yes yes FLCR n FLCR 100 (n/%) 90(15%) - 11(9%) 23(11%) - 27(15%) median TTP (mo) 15mo 13mo 20mo -* - 40mo 2 year progression (%) 72% 98%** 64% 30% - 44% Overall progression (%) 98% 100% % BMPC n BMPC 60 (n/%) 21(3.2%) 8(8%) 6(5%) - 10(2.5%)*** 22(8%) median TTP (mo) 7mo 15mo mo 2 year progression (%) 95% 95.5%**** 100% - 100% 41% Overall Progression (%) - 100% 100% - 100% 73% 1. Larsen JT et al. Leukemia 2013;27: Kastritis E et al. Leukemia 2013;27: Wu et al. ASCO Waxman AJ et al. Leukemia 2015;29: Sorrig R et al. Eur J of Haematology Baseline FLCr > 100 versus Evolving FLCr Mount Sinai / Presentation Slide / December 5, Predictive Value of Group-Based Trajectory Modeling Factors ehb emp eflcr edflc median TTP (mo) Log-Rank 2y PD % overall PD % Specificity % Sensitivity % Diagnostic n (%) P-value Accuracy GBTM Factors No ehb 180 (66%) % 35% < ehb ehb 35 (13%) % 66% 89% 37% 79% Not No Evaluable ehb (69%) 58 (21%) 16% 43% % 72% 79% ehb 27 (10%) % 59% Not Evaluable No emp 58 (21%) 112 (41%) % 38% emp 33 (12%) % 58% 82% 43% 74% emp Not Evaluable 128 (47%) No emp 87 (32%) % 34% % 63% 66% No emp eflcr 58 (21%) 108 (40%) 39.8 Not Reached 35% 14% 66% 31% Evaluable eflcr (47%) 19 (7%) % 63% 88% 29% 78% Not 128 Not Evaluable 146 (53%) eflcr No eflcr 108 (40%) Not Reached 16% 37% No edflc 104 (38%) % 33% % 28% 76% 85% 33% 76% eflcr edflc 19 (7%) 23 (9%) % 30% 68% 48% 45.3 Evaluable 146 (53%) (53%) Not Not 146 edflc No edflc 104 (38%) % 38% % 32% 75% edflc 23 (9%) % 57% Evaluable 146 (53%) Not Over 1 year - ehb patients decrease of 1.57 g/dl (95% CI: 1.29, 1.84) - emp patients experienced either a 64% [95% CI: 44%, 83%] increase in M-protein - eflcr patients on average experienced either a 188% [95% CI: 183%, 193%] increase in FLCr - edflc patients on average experienced a 169% [95%CI: 143%, 195%] increase in dflc 5

11 Multivariable Modeling to predict 2y PD Univariable Multivariable n=90 HR [95% CI] P-value HR [95% CI] P-value [ ] Age Male Sex 0.88 [ ] BMPC 20% 3.29 [ ] BMPC 60% 0.98 [ ] M-Protein 3g/dl 3.59 [ ] IgA SMM 0.72 [ ] Immunoparesis 2.90 [ ] [ ] FLCr 100 and dflc [ ] dflc [ ] emp 3.64 [ ] [ ] < ehb 4.54 [ ] < [ ] < eflcr 2.09 [ ] edflc 3.02 [ ] [ ] Time to progression to symptomatic myeloma stratified based on risk factors (immunoparesis, ehb GBTM, emp GBTM, edflc GBTM). The median times to progression for 0, 1, 2, or >3 risk factors are not reached, 77, 26, and 13mo respectively (p <0.0001). 17 More than 1 Focal MRI Lesion Increases Risk of SMM PD (13 months vs. Not Reached) Hilenglass et al JCO :

12 However, If 2 nd MRI-Stable Disease at 2nd MRI No Higher Risk of Progression Even with Focal/diffuse Lesions on 1st MRI Merz et al. Leukemia 2014;28: Ramifications of New Diagnostic Criteria and Pros/Cons of Early Treatment vs Symptomatic Treatment Clinical Early treatment Symptoms - Deep responses in SMM possible now - Insufficient data re improved OS and PFS - Prevention/reduction of end-organ - Treatment toxicity- Grade 3 /4 or chronic damage and infections Grade 1/2; QOL impairment/pros - Potential for increased OS and? cure - # needed to treat vs harm Pathophysiologic - Potential for increased curability due - Unclear impact on PFS2 to presence of less genomic complexity - Driver mutations have yet to be identified - Ability to target significant mutations - Disease heterogeneity Risk stratification - Truly high-risk SMM very high probability of early progression - Kinetic risk stratification may mitigate some biases - Lack of global concordance, consensus regarding high-risk status - Need to incorporate additional phenotypic and genomics features Trial design - Randomized early vs late treatment - Inability to specifically target using same regimen ethical & feasible significant/driver mutations - Stratify by time from diagnosis - Lead & length time biases can make benefits - Standardized sensitive osseous difficult to discern screening (WBLDCT, PET-CT, or MRI) and to date no treatment data for SLIM - Fix duration of treatment Economic - Less end-organ damage costs - Potential for increased OS -? Cure - Likely prolonged therapy if not fixed duration - Need for stem cell harvest if IMIDs used 20 7

13 Current Treatment for Smoldering Myeloma Jonathan L. Kaufman, MD Associate Professor Winship Cancer Institute of Emory University March 19 th, 2018 Should Patients With High-Risk Smoldering Myeloma Be Treated? Previously, no benefit shown with alkylating agents, bisphosphonates, interleukin-1β antagonists, and thalidomide [1] Current Standard of care is observation or clinical trial Lenalidomide vs observation: phase III randomized trials PETHEMA (N = 119): Lenalidomide/dexamethasone delayed time to progression (median: not reached vs 21 mos, respectively; HR: 0.18; 95% CI: ; P <.001) and improved OS vs observation [2] ECOG-E3A06: Ongoing phase II/III trial of lenalidomide vs observation in smoldering MM (planned N = 380) Initial phase II data: 33% ORR; grade 3 neutropenia and fatigue [4] 1. Landgren O, et al. Clin Cancer Res. 2011;17: Mateos MV, et al. N Engl J Med. 2013;369: ClinicalTrials.gov. NCT Lonial S, et al. ASH Abstract Len Dex vs Observation: PETHEMA/GEM Induction phase 28d cycles x 9 cycles Lenalidomide 25 mg/d D1-21 Dexamethasone 20 mg/d D1-4, Maintenance Lenalidomide 10 mg/d D1-21 every 2 mos High risk SMM* Observation *High risk SMM Both BMPC 10% AND M-protein 3 gm/dl OR one of the above plus apc >95% and immunoparesis Mateos MV, et al. N Engl J Med. 2013;369:

14 Overall Survival since Study Inclusion (%) 3/19/2018 Len Dex vs Observation: PETHEMA/GEM SMM within the past 5 years Stratified Combined Mayo/PETHEMA high risk But no serum FLC Asymptomatic Skeletal survey at screening Repeated only with symptoms No MRI Mateos MV, et al. N Engl J Med. 2013;369: PETHEMA Phase III Trial: Len/Dex vs Observation in High-Risk SM Study limitation in assessing OS: patients received Treatment group Observation group 20 Hazard ratio for death, 0.31 P = Mos No. at Risk Treatment group Observation group treatment off-protocol at the time of disease progression to symptomatic myeloma 53% treated with either bortezomib-based regimens 28% treated with induction therapy followed by autologous stem-cell transplantation 19% treatment not reported Mateos MV, et al. N Engl J Med. 2013;369:

15 Screening % surviving without biochemical/diagnostic progression 1:1:1 RANDOMIZATION % surviving without progression 3/19/2018 CENTAURUS: Study Design Arm A (16 mg/kg IV; 8-week cycles); Long n = 41 Cycle 1: Cycles 2 & 3: Cycles 4-7: QW Q2W Q4W Arm B (16 mg/kg IV; 8-week cycles); Intermediate Cycles 8-20: Q8W Following until PD or end of study (4 years from LPFD) n = 41 Cycle 1: Cycles 2-20: QW Q8W Arm C (16 mg/kg IV; one 8-week cycle); Short Primary endpoints: CR % patients with PD a or death per patient-year n = 41 Cycle 1: QW a As defined by 2014 IMWG CR: proportion of subjects who achieve CR in each arm criteria for SMM. First assessed 6 months after last patient randomized PD/death rate: ratio of subjects with an event (PD or death) to the total follow-up for all patients Assessed 12 months after last patient randomized Disease progression to MM assessed according to IMWG guidelines 1 Pre-infusion medication: methylprednisolone mg, diphenhydramine mg, acetaminophen 650-1,000 mg, montelukast 10 mg (optional) IV, intravenous; QW, once weekly; Q2W, every 2 weeks; Q4W, every 4 weeks; Q8W, every 8 weeks; PD, progressive disease; LPFD, last patient, first dose; CR, complete response. 1. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e CENTAURUS: PFS (Based on SLiM-CRAB) Arm A: Long Arm B: Intermediate Study arm 12-month PFS rate Arm A: Long 95% Arm B: Intermediate 88% Arm C: Short 81% Arm C: Short Post-hoc analysis comparing Arm A + Arm B versus Arm C: P value = Months No. at risk Long Intermediate Short Fewer patients progressed on long and intermediate arms 8 CENTAURUS: PFS (Biochemical or Diagnostic) % Arm A: Long 80 75% Arm B: Intermediate 56% 60 Arm C: Short Biochemical/diagnostic PFS is defined as the earlier of time to biochemical or diagnostic progression or death Biochemical progression: measurable disease increase from nadir by 25% in 2 subsequent assessments per IMWG 1 Diagnostic progression: SLiM- CRAB criteria Post-hoc analysis comparing Arm A + Arm B versus Arm C: P value = No. at risk Long 41 Intermediate 41 Short Months Supports the long dosing schedule for the phase 3 study 1. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e

16 CENTAURUS: Safety Arm A Arm B Arm C Long Intermediate Short (n = 41) (n = 41) (n = 40) Median (range) duration of treatment, 14.9 ( ( (0-1.9) months 22.1) 22.1) Grade 3/4 TEAE, n (%) 15 (37) 4 (10) 6 (15) Most common (>25%) any-grade TEAE, n (%) 16 (39) 25 (61) 9 (23) Fatigue 14 (34) 13 (32) 11 (28) Cough 11 (27) 11 (27) 4 (10) Upper respiratory tract infection 11 (27) 13 (32) 5 (13) Insomnia 11 (27) 8 (20) 13 (33) Headache Most common (>1 pt) grade 3/4 TEAE, n (%) Hypertension 2 (5) 1 (2) 1 (3) Hyperglycemia 1 (2) 2 (5) 0 (0) Hematologic TEAE rate was <10% across all arms Rates of grade 3/4 infection were 5% across all arms 1 death due to disease progression in Arm C 3 SPMs (Arm A: breast cancer, melanoma; Arm B: melanoma) Serious adverse events, n (%) 10 (24) 1 (2) 4 (10) Within the first 8 weeks 5 (12) 0 (0) 4 (10) Discontinued treatment due to TEAE, n (%) 2 (5) 1 (2) 2 (5) Related to daratumumab 1 (2) a 0 (0) 1 (3) b Any-grade IRR rate, n (%) 23 (56) 17 (42) 22 (55) Findings are consistent with other single-agent daratumumab studies IRR, infusion-related reaction; TEAE, treatment-emergent adverse event; SPM, secondary primary malignancy. a Thrombocytopenia; b Unstable angina. 10 Should Patients With High-Risk Smoldering Myeloma Be Treated? Current SOC is observation for all patients, even those at high risk Clinical trials is the other option Two type of trials Delay progression Cure myeloma prior to symptoms 4

17 Defining High Risk Smoldering Multiple Myeloma And How to Manage SMM Patients Cristina Gasparetto, MD Director Multiple Myeloma Program Duke University Medical Center Durham North, Carolina What is Mutliple Myeloma? Normal plasma cell MGUS Smoldering myeloma Intramedullary myeloma Extramedullary myeloma 1 1. Morgan GJ, et al. Nat Rev Canc. 2012;12(5): Nucci M, et al. Clin Infect Dis. 2009;49(8): Kyle RA, et al. N Engl J Med. 2004;351(18): Smoldering Multiple Myeloma 1975: 1976: 1

18 Differential Diagnosis of MGUS, SMM, and MM MGUS Smoldering Myeloma Multiple Myeloma Serum M-spike <3 g/dl Serum M-spike >3 g/dl Serum and/or urine M-spike <10% clonal Plasma Cells >10% clonal Plasma Cells >10% clonal Plasma Cells Absence of end organ damage Absence of end organ damage Evidence of end organ damage Anemia Hgb <10 g/dl Hypercalcemia >11.5 mg/dl Bone lesions or severe osteopenia Renal insufficiency Cr >2 mg/dl Rajikumar et al. Lancet Onc 2014 IMWG 2014: Revised Definition of SMM Rajikumar et al. Lancet Onc 2014 Progression to Symptomatic MM Kyle R, New Eng J Med

19 Ultra-High Risk SMM = Multiple Myeloma Progression rate exceeding 80% at 2 years MDE: Myeloma Defining Events Rajikumar et al. Lancet Onc 2014 Algorithm for reclassifying SMM and active MM Dispenzieri A et al. Blood 2013;122: Risk Models for Progression from SMM to MM Mayo Clinic 1 PETHEMA 2 BMPCs >10% Monoclonal Protein >3 gm/dl Involved:Uninvolved light chain ratio >8 >95% phenotypically aberrant PCs in the Bone Marrow Immunoparesis (reduction below low reference of at least one uninvolved immunoglobulin) In a one-on-one comparison of these models using 77 patients the concordance rate was only 29% 3 1. Dispenzieri et al. Blood 2008, 2. Perez-Persona et al. Blood 2007, 3. Cherry et al. Leukemia Lymphoma

20 Risk Stratification of SMM: Mayo Clinic 80% 70% 60% 50% 40% 30% 20% 10% 0% The probability of progression at 5 years 25% 51% 76% 1 factor 2 factors 3 factors Median TTP 10 yrs 5 yrs 1.9 yrs 1. M-spike >3 gm/dl 2. Abnormal FLC ratio 3. >10% bone marrow involvement Rajkumar et al. Blood 2005 High-Risk and Ultra-High Risk SMM Biomarkers 2-years TTP Reference Clonal bone marrow plasma cell >60% 80% Rajkumar et al Kastritis et al Involved/uninvolved serum FLC ratio >100 80% Larsen et al Kastritis et al whole-body MRI demonstrating >1 focal lesion 80% Hillengass et al Abnormal plasma cell immunophenotype >95% plus 72% Perez-Persona et al, 2007 immunoparesis Cytogenetic subtype: t(4;14) or del17 50% Rajkumar et al Larsen et al. ASCO 2014 #8595 High levels of circulating PCs 80% Witzig et al, 1994 High bone marrow plasma cell proliferative rate by S-phase assessment on multi-parametric flow cytometry Evolving SMM (increase serum M-protein levels by >10% on 2 evaluations within 6-month period 80% Madan et al, % Rosinol et al Dispenzieri A et al. Blood 2013;122: Serial Serum M-spike=Evolving Pattern Ravi et al. Blood Cancer J 2016, 6:e454 4

21 FISH/Cytogenetics Low Risk Intermediate Risk High Risk No abnormalities T(11;14) T (4;14) T(14;16) del17 T(14;20) Hyperdiploidy Gain 1q High Risk FISH abnormalities are associated with <60% TTP at 2 years Rajikumar et al. Leukemia 2013, Neben et al. JCO 2013 Circulating Plasma cells Bianchi et al. Leukemia 2013, Gonsalves et al. Leukemia 2017 Bence-Jones Proteinuria Gonzale-Calle et al. Leukemia

22 Immunoparesis Gonzales-Calle et al. Leukemia 2016, Kastritis et al. Leukemia 2014, Cesana et al. J Clin Onc 2002 Imaging-derived risk factors Hilengass et al. J Clin Onco 2002, Zamagni et al. Leukemia 2016 Evaluation of SMM SMM risk of progression to MM and amyloidosis is greater and based on risk assessment required close monitoring 6

23 Medical Problems Associated with MGUS/SMM Work-up for Newly Diagnosed SMM Muchtar et al. Leukemia and Lymphoma, vol 59, , 2018 Medical history and Physical Exam, FMH, evaluation for systemic symptoms of Amyloidosis Complete Blood Count (circulating plasma cells) Chemistry panel, including Creatinine, Calcium, Beta-2-microglobulin, Albumin, LDH SPEP/IFE, 24 hour urine analysis UPEP/IFE, Immunoglobulin quantification Serum Free Light Chain measurement Bone marrow aspirate and biopsy with FISH and cytogenetics Skeletal survey, CT, or PET/CT MRI of spine and pelvis, or whole body MRI Stratification and Management of SMM Low Risk Intermediate Risk High Risk Absence of high risk factors Risk of progression at 5 year ~8% Yearly follow-up Presence of few high risk factors Risk of progression at 5 years ~42% Every 3-4 months the first year then every 6 months Classified based on Mayo and/or Spanish risk model Risk of progression at 2 years ~50% Every 2-3 months follow-up Treatment as part of clinical trial only Mateos et al. Clinical Lymphoma, Myeloma & Leukemia,

24 Conclusion 8