Myeloma: What do We Know? 215: An Update Thomas Martin, MD Associate Director, Myeloma Program Clinical Professor of Medicine University of California, San Francisco Plasma Cell Disorders! MGUS! Solitary Plasmacytoma! Multiple Myeloma! Waldenstrom s LL Macroglobulinemia! Amyloidosis! POEMS Syndrome! Lymphoplasmacytic lymphoma SP MM POEMS MGUS Amyloid WM 1
Incidence and death in multiple myeloma Estimates for MM in the United States for 211 1 Accounts for 1% of hematologic cancers in the United States 2 Increased incidence in African Americans 3 Median age of diagnosis is 7 years 2 1. American Cancer Society. Cancer Facts & Figures 211. Atlanta, GA; American Cancer Society; 211. 2. Munshi NC et al. In: DeVita VT Jr et al, eds. Cancer: Principles & Practice of Oncology. Vol 2. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 28:235-2342. 3. Howlader N et al, eds; National Cancer Institute. SEER Cancer Statistics Review, 1975-28. http://seer.cancer.gov. Posted April 15, 211. Accessed August 1, 211. Myeloma Survival by Decade Improved due to new drugs: Auto PSC-T Thalidomide Lenalidomide Bortezomib 2
Multistep pathogenesis of multiple myeloma MGUS: monoclonal gammopathy of undetermined significance Palumbo A et al. N Engl J Med. 211;364(11):146-16. 3
Evaluation for Plasma cell dyscrasia! CBC, Lytes, Cr, Ca 2+, Albumin! Quantitative immunoglobulins, β2 microglobulin! SPEP, SIFE, SFLC! 24 hour urine for TP, UPEP, UIFE! Skeletal survey, MRI spine or PET/CT! BMBx: H+E, Flow, cytogenetics, FISH! Optional: Sequenta! GENE EXPRESION PROFILE 4
Historical Criteria for Diagnosis of Myeloma MGUS! < 3 g/dl M spike! < 1% plasma cells SMM! 3 g/dl M spike! 1% plasma cells Active MM! 1% plasma cells! M spike + in serum and/or urine AND NO CRAB* features or end-organ damage AND CRAB* features *C: Calcium elevation (> 1.5 mg/l or ULN) R: Renal dysfunction (serum creatinine > 2 mg/dl) A: Anemia (Hb < 1 g/dl or 2 g < normal) B: Bone disease (lytic lesions) IMWG. Br J Haematol. 23;121:749-757. Kyle RA, et al. Leukemia. 29;23:3-9. Durie BG, et al. Hematol J. 23;4:379-398. 5
Samples available for 3/9 Median number of samples available 3.5 (1-14) PPCD detected in 27/3 +SPEP and/or IFE 21 + sflc 6 First detected MGUS: Walter Reed Study Weiss et.al. sflc alone 6 IFE alone 1 SPEP + IFE 5 IFE + sflc 1 All three 14 Smoldering Multiple Myeloma Probability of Progression (%) 1 8 6 4 Smoldering MM MGUS 51 27% will convert in 15 years Roughly 2% per year 78 73 66 27% more will convert in remaining 15 yrs ~ 2% per yr 51% will convert in first 5 yrs ~ 1% per yr 2 21 4 16 1 5 1 15 2 25 Yrs Since Diagnosis Kyle RA, et al. N Engl J Med. 27;356:2582-259. Greipp PR, et al. J Clin Oncol. 25;23:3412-342. 6
Biomarkers to Predict Risk of Progression % Progression to MM! FLC ratio 1 predicts risk (P <.1) 1..8.6.4.2 FLC ratio 1 Median TTP: FLC ratio < 1 15 mos Median TTP: 55 mos 6 12 18 24 3 36 42 48 54 6 66 Mos to Progression 72! Clonal plasma cells in BM predicts risk (P <.1) % Progression to Symptomatic Myeloma 1..8.6.4.2 BM plasma cells 6% BM plasma cells < 6% HR: 13.7; P <.1 2 4 6 8 1 12 Mos to Progression Larsen JT, et al. Leukemia. 213;27:941-946. Kastritis E, et al. Leukemia. 213;27:947-953. Updated IMWG Criteria for Diagnosis of Multiple Myeloma MGUS! M protein < 3 g/dl! Clonal plasma cells in BM < 1%! No myeloma defining events Smoldering Myeloma! M protein 3 g/dl (serum) or 5 mg/24 hrs (urine)! Clonal plasma cells in BM 1% to 6%! No myeloma defining events Multiple Myeloma! Underlying plasma cell proliferative disorder! AND 1 or more myeloma defining events! 1 CRAB* feature! Clonal plasma cells in BM 6%! Serum free light chain ratio 1! > 1 MRI focal lesion *C: Calcium elevation (> 11 mg/dl or > 1 mg/dl higher than ULN) R: Renal insufficiency (creatinine clearance < 4 ml/min or serum creatinine > 2 mg/dl) A: Anemia (Hb < 1 g/dl or 2 g/dl < normal) B: Bone disease ( 1 lytic lesions on skeletal radiography, CT, or PET-CT) Rajkumar SV, et al. Lancet Oncol. 214;15:e538-e548. 7
A Multicenter, Randomised, Open-label, Phase III Study of Lenalidomide/Dexamethasone versus Therapeutic Abstention in high-risk Smoldering MM MV Mateos, L López-Corraz, MT Hernández, J de la Rubia, JJ Lahuerta, P Giraldo, J Bargay, L Rosiñol, A Oriol, J García-Laraña, l Palomera, F de Arriba, F Prósper, ML Martino, AI Teruel, J Hernández, G Estevez, M Mariz, A Alegre, JL Guzman, N Quintana, JL García, JF San Miguel. On behalf of Spanish Myeloma Group (PETHEMA/GEM) Smoldering Multiple Myeloma: PCs BM infiltration and Serum M-component level TTP: 2 y TTP: 8 y TTP: 19 y Group 1: PCBM 1% + MC 3g/dl Group 2: PCBM 1% + MC < 3g/dl Group 3: PCBM < 1% + MC 3g/dl Kyle R. N Engl J Med 27; 356:2582-9 8
SMM Trial: High-risk smoldering MM PCs BM 1% plus M-protein 3 g/l or PCs BM 1% or M-protein 3 g/l but BM apc/npc > 95% plus immunoparesis Time elapsed from diagnosis to inclusion not superior to 5 years No CRAB (hypercalcemia, anemia, bone lesions, renal impairment) symptoms Schedule of therapy Treatment arm Control arm Induction: Nine 4-wks cycles Lenalidomide 25 mg/daily during 21d every 28 d Dexamethasone 2 mg D1-D4 and D12-D15 every 28 d Therapeutic Abstention Maintenance Lenalidomide 1 mg/daily during 21 d every 2 months Therapeutic Abstention Randomization according to: diagnosis in the last 6 months diagnosis more than 6 months 9
Objectives Primary objective " Time to progression to symptomatic MM Secondary objectives " Response rates " Duration of response " Progression Free Survival, Overall Survival " Safety and tolerability SMM Trial: Time to Progression (n:94) Median follow-up: 14 m (1-24) 1 pt # IC withdrawal during the 1 st cycle 1 pt # discontinuation after the 8th cycle 1, Lendex,8,6,4,2, No treatment Median TTP: 19.3 m p<,1 Progressions in abstention arm (n=16) 6 pts: lytic lesions 3 pts: lytic lesions plus anemia 1 pt:lytic lesions renal failure & Ca2+ 5 pts: anemia 1pt: PD due to a rapid increase of BJ prot from 4,5g/24h to 9g/24h in 1 month 3 6 9 12 15 18 21 24 1
SMM Conclusions 1. Treat Ultra-high risk SMM as MM 2. Follow HR patients closely 3. Consider HR-SMM for Clinical Trial ECOG: Rev vs. Observation Elotuzumab Daratumumab Natural History of Multiple Myeloma Asymptomatic Symptomatic M Protein (g/l) 1 5 2 MGUS or smoldering myeloma ACTIVE MYELOMA 1. RELAPSE Plateau remission 2. RELAPSE REFRACTORY RELAPSE First-line therapy Second-line therapy Third-line therapy 11
! From Diagnosis Overall Survival From Start of Therapy by Regimen Number Myeloma Survival from Dx Cumulative Probability (%).2.4.6.8 1. Regimen 1 Regimen 2 Regimen 3 Regimen 4 Regimen 5 Regimen 6 2 4 6 8 1 After the Novel Drugs, what s next? Years From Start of Regimen Myeloma Treatment: It s An Art 12
Initial Approach to Treatment of Myeloma Nontransplant Candidate (based on age, performance status, and comorbidities) Induction treatment Transplant Candidate Induction treatment (4-6 cycles) Maintenance? Stem cell harvest Stem cell transplantation Consolidation therapy? Maintenance? 13
MM Risk Categories Risk Factors Standard Risk (8%) (Expected OS: 6-7 Yrs) High Risk (2%) (Expected OS: 2-3 Yrs) FISH t(11;14), t(6;14) del(17p), t(4;14)* t(14;16), +1q21 Cytogenetics Hyperdiploidy Hypodiploidy del(13q) β 2 -microglobulin* Low (< 3.5 mg/l) High ( 5.5 mg/l) PCLI < 3% High ( 3%) Isotype -- IgA Gene expression profile Good risk High risk *Pts with t(4;14), β 2 -microglobulin < 4 mg/l, and Hb 1 g/dl may have intermediate-risk disease. Dispenzieri A, et al. Mayo Clin Proc. 27;82:323-341. Kumar SK, et al. Mayo Clin Proc. 29;84:195-111. Mikhael JR, et al. Mayo Clin Proc. 213;88:36-376. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.215. Chng WJ, et al. Leukemia. 214;28:269-277. Risk-Adapted Therapy for Myeloma:! M-SMART High Risk Intermediate Risk Standard Risk FISH FISH All others including: Del 17p t(4;14) FISH t(14;16) Cytogene@c del 13 t(11;14) t(14;2) Hypodiploidy t(6;14) GEP High risk signature PCLI hyperdiploid 14
Risk-Adapted Therapy for Myeloma: 3 yr 4-5 yr 8-1 yr OS (Mikhael et al. MCP 213) Current OS and High Risk Myeloma A good risk stra9fica9on system should allow iden9fica9on of this ~25% pa9ents 15
Does Response Matter? Cure vs. Control Depth and TTP 1 5 1 PR VGPR CR PR CR scr MRD \1 5 yr PCR, MRI, Flow-cytometry INDUCTION: Blockbuster Agents! Proteasome Inhibitors Bortezomib (Velcade) Carfilzomib (Kyprolis) Ixazomib (MLN 978), (an oral PI)! IMiDs Lenalidomide (Revlimid) Thalidomide (Thalomid) Pomalidomide (Pomalyst) 16
Goals of Induction Therapy! High response rate; rapid response! Depth of response (MRD?)! Improve performance status and quality of life! Not limit PBSC mobilization (for younger pts)! Current issues: Role of transplant Optimal duration of therapy How deep of a response should we aim for? Achieving VGPR or CR Should Be the Goal of Therapy Achieving VGPR [1] Achieving CR [2] 1. 1. Probability of OS.75.5.25 P =.17 CR + VGPR (n = 445) PR (n = 288) 1 2 3 4 5 6 7 8 Yrs Since Transplantation Probability of OS.8.6.4.2 CR or better VGPR 1 2 3 PR SD PD 4 5 6 7 Yrs Since Transplantation 1. Harousseau JL, et al. J Clin Oncol. 29;27:572-5726. 2. Kapoor P, et al. J Clin Oncol. 213;31:4529-4535.! Pts with scr have a significantly better outcome: estimated 5-yr OS 8% with scr vs 53% with CR or 47% with ncr 17
Phase III Trials: Induction Regimens for Transplantation-Eligible Pts Pts Achieving VGPR (%) 1 8 6 4 2 Cavo 62 PETHEMA/ GEM 28 29 6 IFM 25-1 15 38 HOVON-65 GMMG-HD4 14 42 4 E4A3 5 1. Cavo M, et al. Lancet. 21;376:275-285. 2. Rosiñol L, et al. Blood. 212;12:1589-1596. 3. Harousseau JL, et al. J Clin Oncol. 21;28:4621-4629. 4. Sonneveld P, et al. J Clin Oncol. 212;3:2946-2955. 5. Rajkumar SV, et al. Lancet Oncol. 21;11:29-37. Earlier Phase Studies: Induction Regimens for Transplantation-Eligible Pts Regimens Survival Bortezomib/lenalidomide/ 18-mo PFS: 75% dexamethasone (RVD) [1] 18-mo OS: 97% Carfilzomib/lenalidomide/ dexamethasone (KRd) [2,3] 12-mo PFS: 97% [2] 24-mo PFS: 92% [2] 3-yr PFS: 79% [3] 3-yr OS: 96% [3] Carfilzomib/thalidomide/ dexamethasone (KTd) [4] 3-yr PFS: 72% Bortezomib/ cyclophosphamide/ dexamethasone (CyBorD) [5] 5-yr PFS: 42% [6] 5-yr OS: 7% [6] Pts Achieving VGPR (%) 1 8 6 4 2 67 81 68 6 58 Ixazomib/lenalidomide/ 12-mo PFS: 88% dexamethasone [7] 12-mo OS: 94% 1. Richardson, PG et al. Blood. 21;116:679-686. 2. Jakubowiak A, et al. Blood. 212;12:181-189. 3. Jasielec J, et al. ASH 213. Abstract 322. 4. Sonneveld P, et al. Blood. 215;125:449-456. 5. Reeder CB, et al. Blood. 21;115:3416-3417. 6. Reeder CB, et al. ASH 213. Abstract 3192. 7. Kumar SK, et al. Lancet Oncol. 214;15:153-1512. 18
EVOLUTION Trial: Combinations of VD With Cyclophosphamide or Lenalidomide! Randomized phase II trial of VDC vs VDR vs VDCR in previously untreated MM VDCR (n = 48) VDR (n = 42) VDC (n = 33) VCD-mod VDC-mod (n = 17) Proportion of Pts 1..8.6.4.2 PFS, Not Censored for ASCT VDC-mod VDR VDC VCDR 1..8.6.4.2 OS VDR VDC VCDR 6 12 18 24 3 36 42 48 54 6 66 72 78 84 9 Days Kumar S, et al. Blood. 212;119:4375-4382. 6 12 18 24 3 36 42 48 54 6 66 72 78 84 9 Days High-Dose Mel + ASCT vs MPR in NDMM! A randomized, controlled phase III trial exploring utility of transplant in NDMM (N = 273) From time of diagnosis High-dose Mel plus Len maintenance High-dose Mel plus no maintenance MPR plus Len maintenance MPR plus no maintenance Probability of PFS 1 75 5 25 37.4 21.8 54.7 34.2 6 12 18 24 3 36 42 48 54 6 66 Mos Palumbo A, et al. N Engl J Med. 214 ;371:895-95. Probability of OS 1 75 5 25 6 12 18 24 3 36 42 48 54 6 66 Mos 19
IFM/DFCI29: Conventional Dose RVD to High-Dose Treatment With ASCT! Randomized, open-label phase III trial Pts with previously untreated MM; measurable disease; between age 18-65; ECOG PS -2 (planned N = 7) 3-21-day cycles Bortezomib + Lenalidomide + Low-Dose Dex Bortezomib + Lenalidomide + Low-Dose Dex ASCT Two 21-day cycles Bortezomib + Lenalidomide + Low-Dose Dex 3-21-day cycles Five 21-day cycles Bortezomib + Lenalidomide + Low-Dose Dex 12 mos Maintenance Lenalidomide 12 mos Maintenance Lenalidomide Collection of PBSCs using cyclophosphamide and GCSF! Primary endpoint: PFS! Secondary endpoints: RR, TTP, safety ClinicalTrials.gov. NCT11916. Phases of Therapy: Transplant Ineligible! Transplant ineligible Induction chemotherapy 8-12+ cycles Maintenance therapy PR VGPR CR 1+ years Supportive Care Biphosphonates Vitamins relapse Salvage therapy C1 C6! Goals Control disease (PR/CR) Improve PFS/OS Limited toxicity QUALITY of LIFE 2
FIRST: Lenalidomide/Dexamethasone vs MPT in NDMM SCT-Ineligible Pts [1] Randomized 1:1:1 Arm A Continuous Rd Arm B Rd18 Arm C MPT Active treatment + PFS follow-up phase Len + LoDex Continuously Lenalidomide 25 mg Days 1-21/28 LoDex 4 mg Days 1, 8, 15, 22/28 Len + LoDex 18 cycles (72 wks) Lenalidomide 25 mg Days 1-21/28 LoDex 4 mg Days 1, 8, 15, 22/28 Mel + Pred + Thal 12 cycles [2] (72 wks) Melphalan.25 mg/kg Days 1-4/42 Prednisone 2 mg/kg Days 1-4/42 Thalidomide 2 mg Days 1-42/42 Len dose adjusted based on creatinine clearance. Pts aged older than 75 yrs: LoDex 2 mg Days 1, 8, 15, 22/28; Thal [3] 1 mg Days 1-42/42; Mel [3].2 mg/kg Days 1-4. Stratified by age, country, and ISS stage. 1. Facon T, et al. ASH 213. Abstract 2. 2. Facon T, et al. Lancet. 27;37:129-1218. 3. Hulin C, et al. J Clin Oncol. 29;27:3664-367. PD or unacceptable toxicity Phase III (N = 1623) PD, OS, and subsequent anti-mm Tx FIRST Trial: Efficacy Analysis of Len/Dex vs MPT in SCT-Ineligible Pts With MM 1 Median PFS, Mos Rd (n = 535) 25.5 Rd18 (n = 541) 2.7 MPT (n = 547) 21.2 HR (P Value) Rd vs MPT:.72 (.6) Rd vs Rd18:.7 (.1) Rd18 vs MPT: 1.3 (.7349) 1 4-Yr OS, % Rd (n = 535) 59.4 Rd18 (n = 541) 55.7 MPT (n = 547) 51.4 HR (P Value) Rd vs MPT:.78 (.168) Rd vs Rd18:.9 (.37) Rd18 vs MPT:.88 (.184) 8 8 Pts (%) 6 4 Pts (%) 6 4 2 72 wks 6 12 18 24 3 36 42 48 54 6 PFS (Mos) 2 6 12 18 24 3 36 42 48 54 6 OS (Mos)! Overall response (continuous Rd vs MTP): 75% vs 62% (P <.1)! Similar, tolerable safety profiles between treatment groups; incidence of secondary primary malignancies.4% in Rd arm vs. 2.2% in MPT Facon T, et al. ASH 213. Abstract 2. 21
MM-15: Study Design Newly diagnosed, Transplantineligible MM (N = 459)! Primary endpoint: PFS Cycles 1-9 (28-day cycle) MPR-R (n = 152) M:.18 mg/kg Days 1-4 P: 2 mg/kg Days 1-4 R: 1 mg/day PO Days 1-21 MPR (n = 153) M:.18 mg/kg Days 1-4 P: 2 mg/kg Days 1-4 R: 1 mg/day PO Days 1-21 MP (n = 154) M:.18 mg/kg Days 1-4 P: 2 mg/kg Days 1-4 Pbo: Days 1-21 Cycles 1 Maintenance Len 1 mg/day Days 1-21 Maintenance Placebo Days 1-21 Maintenance Placebo Days 1-21 After progression Len 25 mg/ day ± Dex! Secondary endpoint: OS, ORR, TTR, DOR, safety Dimopoulos MA, et al. ASH 213. Abstract 45. MM-15: MPR With Maintenance R Efficacy Analysis PFS Updated OS 1 MPR-R (n = 152) MPR (n = 153) MP (n = 154) Median PFS 31 mos 14 mos 13 mos 1 MPR-R (n = 152) MPR (n = 153) MP (n = 154) Median OS 56 mos 52 mos 54 mos 8 8 Pts (%) 6 4 Pts (%) 6 4 MPR-R vs MPR 2 (HR:.49; P <.1) MPR-R vs. MP (HR:.4; P <.1) 5 1 15 2 25 3 35 4 MPR-R vs MPR 2 (HR:.88; P <.43) MPR-R vs MP (HR:.95; P <.74) 12 24 36 48 6 72 Mos (Median follow-up: 3 mos) Mos (Median follow-up: 62 mos) Dimopoulos MA, et al. ASH 213. Abstract 45. 22
CRd Treatment Schema Carfilzomib, Lenalidomide and low dose Dexamethasone CRd Induc9on CRd Maintenance Lenalidomide (off protocol) Transplant- eligible and - - ineligible pa9ents CRd Cycles 1 4 CRd Cycles 5 8 Transplant-eligible PR ASCT Stem cell collec9on CRd Cycles 9 24 LEN Cycles 25+ Un9l disease progression or unacceptable toxicity Assessments on D1 and 15 of C1 and D1 thereafter using modified IMWG Criteria with ncr Cycles 1 8 CFZ 2-27-36 mg/m 2 Days 1 2, 8 9, 15 16 1 LEN 25 mg Days 1 21 DEX 4 mg weekly Cycles 1-4, 2 mg weekly Cycles 5 8 Cycles 9 24 CFZ on Days 1 2 and 15 16 only CFZ, LEN, DEX at last best tolerated doses Cycles 25+ LEN at last best tolerated dose Jakubowiak AJ, et al. Blood. 212;12(9):181-189. 45 CRd Best Response Median 12 cycles (range 1 25) 65 years Age >65 y/o Overall Patients (%) 1" 8" 6" 4" " PR" " VGPR" " ncr" "scr" 98# 81# 62# 42# 2" N=23 N=25 " N=53 2/22 patients with no MRD* 46 23
Initial Therapy: What is SOC? Transplant Eligible Non-Transplant! RD (<6 cycles)! V(D)! RVD! VCD! 4-Drug VTCD VRCD! RD! V(D)! VCD! RVD! BiRD! MP + T or R or V Suggested Empiric Age-Adjusted Dose Reduction in Pts With Myeloma Agent Younger Than 65 Yrs 65-75 Yrs Older Than 75 Yrs Dexamethasone Melphalan Cyclophosphamide Thalidomide Lenalidomide Bortezomib 4 mg/day Days 1-4, 15-18 q4w or Days 1, 8, 15, 22 q4w.25 mg/kg Days 1-4 q6w 3 mg/day Days 1, 8, 15, 22 q4w 2 mg/day 25 mg/day Days 1-21 q4w 1.3 mg/m 2 bolus Days 1, 4, 8, 11 q3w Palumbo A, et al. N Engl J Med. 211;364:146-16. 4 mg/day Days 1, 8,1 5, 22 q4w.25 mg/kg Days 1-4 q6w or.18 mg/ kg Days 1-4 q4w 3 mg/day Days 1, 8, 15 q4w or 5 mg/day Days 1-21 q4w 1 mg/day or 2 mg/day 15-25 mg/day Days 1-21 q4w 1.3 mg/m 2 bolus Days 1, 4, 8, 11 q3w or Days 1, 8, 15, 22 q5w 2 mg/day Days 1, 8, 15, 22 q4w.18 mg/kg Days 1-4 q6w or.13 mg/ kg Days 1-4 q4w 5 mg/day Days 1-21 q4w or 5 mg/day QOD Days 1-21 q4w 5 mg/day to 1 mg/day 1-25 mg/day Days 1-21 q4w 1.- 1.3 mg/m 2 bolus Days 1, 8, 15, 22 q5w 24
Getting to Minimal Residual Disease: New Definitions for CR S.S. Patient CR Stringent CR Disease burden Newly diagnosed 1 x 1 8 1 x 1 12 Molecular/flow CR Cure? 1 x 1 4 Bortezomib. Lenalidomide Antibodies Methods for Assessing Minimal Residual Disease to Predict Outcome PFS (Proportion) 1..8.6 8-Color Flow [1] Next-Gen Sequencing [2] PET/CT [3,4] PFS.4 MRD-.2 MRD+ Overall 6 12 18 24 3 36 42 Mos TTP (%) 1 8 6 4 2 MRD- MRD+ 5 TTP (CR Pts) P =.1 n = 26 PFS (Proportion) 1..8.6 PFS (CR Pts After First-line Therapy) PET CR median: 9 mos.4 n = 36 NO PET CR.2 median: 5 mos P =.1 1 15 12 24 36 48 6 72 Mos Mos 1. Roussel M, et al. J Clin Oncol. 214;32:2712-2717. 2. Martinez-Lopez J, et al. Blood. 214;123:373-379. 3. Zamagni E, et al. Blood. 211;118:5989-95. 4. Zamagni E, et al. ASH 213. Abstract 1936. 25
Maintenance in Myeloma! PFS advantage [1-3]! OS improvements? [2]! Toxicities of treatment Myelosuppression [3] Second primary malignancies [3,4] Quality of life! Unclear whether all pts benefit from maintenance! Unclear which agent and duration of therapy 1. Attal M, et al. ASH 213. Abstract 46. 2. McCarthy PL, et al. N Engl J Med 212;366:177-1781. 3. Attal M, et al. N Engl J Med. 212;366:1782-1791. 4. Palumbo A, et al. Lancet Oncol. 214;15:333-342. IFM 25-2: Lenalidomide vs Placebo Maintenance After ASCT for Myeloma Pts (%)! Phase III study in pts < 65 yrs after ASCT in first line (N = 459)* 1 75 5 2 Consolidation: Len 25 mg/day PO Days 1-21 every 28 days for 2 mos; maintenance: randomize to Len 1-15 mg/day or placebo until relapse PFS HR Len vs Pbo:.5; P <.1 6 12 18 24 3 36 42 48 54 6 Mos of Follow-Up Len Pbo *Induction with VD or VAD; consolidation with lenalidomide. Attal M, et al. ASH 213. Abstract 46.! 5-yr PFS (primary endpoint) superior with Len: 42% vs 18% with placebo (P <.1) PFS benefit independent of subgroup (eg, β 2 -M, ORR)! Median EFS: 4 mos with Len vs 23 mos for placebo! Median OS: similar (> 8 mos)! Grade 3/4 PN: similar in both groups 26
CALGB 114: Lenalidomide vs Placebo Maintenance Following ASCT for Myeloma! Phase III trial with D-S stage 1-3 pts; < 71 yrs and > 2 cycles of induction with SD or better (N = 46)! PFS: ITT analysis with median follow-up from transplant of 34 mos! OS: 35 deaths with lenalidomide and 53 deaths with placebo Estimated HR:.48 (95% CI:.36-.63); median TTP: 46 vs 27 mos 3-yr OS 88% vs 8%, HR.62 or a 38% reduction in death with the cross over Probability of PFS 1..8.6.4.2 2-sided P <.1 86 of 128 placebo pts crossed over to lenalidomide Lenalidomide Placebo 1 2 3 4 5 6 7 Mos Since Autologous HSCT McCarthy PL, et al. N Engl J Med. 212;366:177-1781. Probability of OS 1..8.6.4 Placebo Lenalidomide 2-sided P =.3.2 Median follow-up of 45 mos 1 2 3 4 5 6 7 Mos Since Autologous HSCT HOVON-65/GMMG-HD4: Bortezomib Induction, Maintenance in NDMM Pts with newly diagnosed MM (N = 827) VAD* (n = 414) PAD (n = 413) Primary endpoint: PFS adjusted for ISS stage Sonneveld P, et al. ASH 213. Abstract 44. HDM ASCT HDM ASCT Thalidomide 5 mg QD for 2 yrs Bortezomib 1.3 mg/m 2 1x/2 wks for 2 yrs Secondary endpoints: response, PFS A, PFS/PFS A from last HDM, OS, safety, toxicity *VAD: 3 cycles of vincristine.4 mg IV QD, Days 1-4; doxorubicin 9 mg/m 2 QD, Days 1-4; dexamethasone 4 mg oral QD, Days 1-4, 9-12, 17-2, every 28 days. PAD: 3 cycles of bortezomib 1.3 mg/m 2 QD, Days 1, 4, 8, 11; doxorubicin 9 mg/m 2 QD, Days 1-4; and dexamethasone 4 mg oral QD, Days 1-4, 9-12, 17-2, every 28 days. HOVON, single cycle; GMMG 2 cycles. 27
HOVON-65: Bortezomib in Induction and Maintenance for Newly Diagnosed MM! CR/nCR superior with PAD induction (3% vs 15% with VAD) and by best response (35% vs 49% with VAD) (P <.1 for both) [1]! PFS and OS superior with bortezomib-based treatment regimen [1] Cumulative Percentage 1 75 5 25 PFS, Censored at Allo SCT HR:.76 (95% CI:.64-.9; P =.1) N F VAD 414 311 PAD 413 284 Cox LR stratified P =.2 12 24 36 48 6 72 84 Mos OS HR:.78 (95% CI:.64-.9; P =.1)! Bortezomib significantly improved OS for pts presenting with renal failure (P <.1) [2] 1. Sonneveld P, et al. ASH 213. Abstract 44. 2. Sonneveld P, et al. J Clin Oncol. 212;24:2946-2955. Cumulative Percentage 1 75 5 N D 25 VAD 414 182 PAD 413 155 Cox LR stratified P =.5 12 24 36 48 6 72 84 Mos Cumulative incidence (%) Cumulative Incidence of Secondary Primary Malignancies by Treatment 1 5 Solid SPMs Len + Mel Len + Cyclo Len + Dex No Len (Mel regimens) 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Cum Incidence, % Solids SMP Hematological SMP 3 Yrs 5 Yrs 3 Yrs 5 Yrs Len + Mel 2.7 4.4 1.8 3.9 Len + Cyclo 3.5 NE.3 NE Len + Dex 2.2 2.6.3 1.3 No Len 2.9 3.4.4 1.4 Palumbo A, et al. Lancet Oncol. 214;15:333-342. Cumulative incidence (%) 1 5 Hematological SPMs Len + Mel Len + Cyclo Len + Dex No Len (Mel regimens) 28
Options for Relapsed/Refractory Disease Initial Therapy >6 months Relapse No Response/Relapse 6 months Repeat initial therapy Clinical trial Revlimid + dex Clinical trial A different initial therapy regimen Velcade ± dex Relapse after Revlimid and Velcade Velcade + Doxil SCT Additional combinations eg,rvd Kyprolis Pomalyst + dex SCT Clinical trial SCT=Stem cell transplant RVD=Revlimid, Velcade, dexamethasone Myeloma Therapeutics Over Time 1992 22 212 29
Novel Salvage Treatments for Multiple Myeloma T N K M Apoptosis Proliferation New Drugs in Multiple Myeloma! Proteasome Inhibitors 2 nd generation/oral! Immunomodulatory drugs 3 rd generation! Monoclonal antibodies! Inhibitors of proliferation and apoptosis AKT inh, mtor inh, Pim kinase inh! Inhibitors of protein homeostasis! Novel pathways Selective inhibitor of nuclear export Kinesin spindle protein inhibitor 3
Monoclonal Antibody Based Therapy Current Agents in Clinical Trials! Antibody Target Elotuzumab SlamF7 Dara, SAR65984, Mor22 CD38 B-B4, nbt62->> CD138 MK-3475, BMS-936559 PD1, PDL1 IPH 211 KIR Lucatuzumab CD4 AVE1642 IGF-1 Antibodies: Multiple Mechanisms to Kill Cancer Cells. T-cell signals 1. Delivery of poison payload (ADC), direct cellular cytotoxicity 2. Antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) NK cell, Macrophage 3. Complementdependent lysis (CDC) 4. Direct cellular signaling (apoptosis) CD38 enzymatic activity inhibition PD-L1 CD13 8 X NAD cadpr ADPR? Cancer Cell membrane 62 Antibody Fc Receptor Complement 31
Monoclonal antibodies: Elotuzumab (anti-slamf7): Elotuzumab + Len + LoDex in relapsed/refractory MM (Len naïve) Elotuzumab 1 mg/kg Elotuzumab 1 mg/kg! Little difference in response, in spite of poor cytogenetics Patients, n 36 37 73 ORR: 8% and 84%, high risk and standard risk, respectively Total OR ( PR), n (%) 33 (92) 28 (76) 61 (84) CR/stringent CR, n (%) 5 (14) 4 (11) 9 (12) VGPR, n (%) 17 (47) 14 (38) 31 (43) PR, n (%) 11 (31) 1 (27) 21 (29) <PR, n (%) 3 (8) 9 (24) 12 (16) $ Little difference in response, regardless of poor cytogenetics - ORR 8% and 84%, high-risk and standard-risk, respectively - PFS in 1 mg/kg cohort ~33 months $ Two Large Phase III Trials Comparing Len/LoDex vs ELO/Len/LoDex Richardson PG, et al. ASH 212. Abstract 22 63 Monoclonal antibodies: Elotuzumab PFS with Elotuzumab + Len + LoDex Proportion of Progression Free Patients (%) 1 9 8 7 6 5 4 3 2 1 Median time to progression/death: 1 mg/kg (n=36): not yet reached 2 mg/kg (n=37): 18.6 mos (95% CI 12.9-29.7) 3 6 9 12 15 18 21 24 27 3 33 Number at risk: Time (months) 36 32 3 29 23 2 18 18 13 9 3 37 29 26 23 21 17 15 13 13 1 3! At a median follow-up of 2.8 months, median PFS has not been reached in the 1 mg/kg arm Richardson PG, et al. ASH 212. Abstract 22 1 mg/kg 2 mg/kg 64 32
Daratumumab: A Novel anti-cd38moab Well tolerated - Infusion reactions (3%) - Minimal count suppression *Preliminary evidence of single agent activity Plesner et al, ASH 212: Abstr 73 Daratumumab: A Novel anti-cd38 MoAB Dose 4-24 mg/kg Qwk ORR~42% Maximal Reduction of Serum M-Component Plesner et al, ASH 212: Abstr 73 33
Daratumumab: Single Agent in Relapse MM Part II: Optimizing dose and infusion times Weekly dosing Infusion time A: Dara 8 mg/kg B: Dara 8 mg/kg C: Dara 8 mg/kg 4 6 6.5 6.5 n 16 8 6 2 D: Dara 16 mg/kg # priors 4 6.5 5 4 ORR 8% Best responses PR s 35% 2CR 1 PR Lockhorst et al, ASCO 214: Abstr 8513 SAR65984: Phase I Studies Single Agent: TED1893 Accelerated escalation 1 patient/cohort.1 mg/kg q2w.1 mg/kg q2w.1 mg/kg q2w.3 mg/kg q2w.1 mg/kg q2w Basic escalation 3 6 patients/cohort.3 mg/kg q2w 1 mg/kg q2w 3 mg/kg q2w 5 mg/kg q2w 1 mg/kg q2w 1 mg/kg q1w 2 mg/kg q2w 2 mg/kg q1w Expansion Cohorts (n=36) At recommended Phase 2 dose in patients with MM Standard Risk High-risk SAR Responses Maximum change in paraprotein 1 q2w 3 q 2w 5 q2w 1q2w 1qw 2q2w *ORR=32% *CBR 37% * % 5% 9% Martin et al. ASCO 214 34
SAR65984 Phase I Studies SAR65984 /Len /LoDex! Adults with RRMM! At least 2 prior therapies Prior IMiD therapy permitted Refractory to IMiD OK Standard dose escalation (3 + 3 design) 3 6 patients per cohort SAR65984 iv, Days 1 and 15 per 28 day cycle Cohort 1 3 mg/kg Cohort 2 5 mg/kg STUDY Population! Median 6 prior regimens! 81% IMiD refractory! 52% Bortezomib refractory! 48% Carfilzomib refractory Cohort 3 1 mg/kg *MTD not reached Lenalidomide 25 mg on days 1 21 per 28-day cycle Dexamethasone 4 mg Qw (Days 1, 8, 15 and 22) Expansion cohort 18 patients 1 mg/kg* Methylprednisolone 1 mg iv, diphenhydramine 5 mg iv, ranitidine 5 mg iv, and acetaminophen 65 1 mg po (or equivalents) Martin et al. ASCO 214 SAR65984 Phase I Studies Phase I: SAR/ Len/LoDex All Number of patients (%) (n=31) Overall response rate 18 (58) Very good partial response 7 (23) Partial response 11 (35) Minimal response 2 (6) Patients, % 1 8 6 4 ORR 25% CBR 5% 25% Minimal response Partial response Very good partial response ORR 67% 67% ORR 63% CBR 67% 4% 38% ORR 58% CBR 65% 6% 35% Clinical benefit (MR or better) 2 (65) Stable disease 3 (1) 2 25% 25% 23% Progressive disease 7 (23) 3 (n=4) 5 (n=3) 1 (n=24) Overall (n=31) Not evaluable 1 (3) SAR65984 dose level, mg/kg q2w Martin et al. ASCO 214 35
SAR65984 Phase I: Clinical Results SAR65984+Len/LoDex: Response according to prior therapy Very good partial response Partial response Minimal response Lenalidomide refractory (n=25) 2 28 8 ORR 48% Lenalidomide non-refractory (n=6) Pomalidomide refractory (n=9) Bortezomib refractory (n=16) Carfilzomib refractory (n=15) 33 67 11 22 11 ORR 33% 25 19 13 7 33 13 ORR 44% ORR 4% ORR 1% Patients, % 2 4 6 8 1 Change in paraprotein, % 1 75 5 25 25 5 75 3 5 dose level, 1 mg/kg q2w SAR65984 + Len/LoDex M-Protein Response 1 ARRY-52: Targeting KSP! ARRY-52 is a targeted Kinesin Spindle Protein (KSP) inhibitor Novel MOA critical to the function of proliferating cells Little cross- resistance to other drugs! Phase II (Lonial et al ASH 213) RRMM : >2 priors With or without Dex! Phase I (Shah et al EHA 213) With Carfilzomib RRMM 72 36
ARRAY-52-212 Phase 2 Study Design Lonial et al. ASH 213 ARRY-52 1.5 mg/m 2 q 2 weeks Cohort 1: ARRY-52 Single Agent 1 2 1 2 G-CSF G-CSF 2-stage, single-arm study Cohort 2: ARRY-52 + Dexamethasone Combination ARRY-52 1.5 mg/m 2 q 2 weeks 1 2 1 2 G-CSF Dexamethasone 4 mg PO weekly G-CSF 2-stage, single-arm study Lonial et al ASH 213 ARRY-52-212 Pre-Dose AAG Levels Correlate with Clinical Outcome 2.8 [AAG] (g/l) 2.4 2 1.6 1.2 High [AAG] Partial Response Minimal Response.8.4 5 1 15 2 25 3 35 Time on Treatment (months) AAG Cutoff 1.1 g/l in Array ELISA was qualitatively assigned Absolute value of cutoff is likely to change in final assay Lonial et al ASH 213 37
% 4/27/15 ARRAY-52-212 Low AAG is Associated with Higher ORR ARRY-52 Single Agent All Pts 1 AAG- High AAG- Low All Pts 2 ARRY-52 + dex AAG- High AAG- Low n 32 6 21 55 15 36 ORR ( PR) 5 (16%) (%) 5 (24%) 8 (15%) (%) 7 (19%) CBR ( MR) 6 (19%) (%) 6 (29%) 11 (2%) (%) 1 (28%) Duration of Response (months) Time to Next Treatment (Months) 8.6-8.6 5.1-5.2 3.7 2.6 5.3 3.4 2. 5.1 OS (months) 19. 4.5 23.3 1.5 2.9 1.8 1 5 patients did not have a baseline AAG measurement 2 4 patients did not have a baseline AAG measurement, including 1 responder 75 Lonial et al ASH 213 Novel Drugs: Nuclear Export Inh.! Cancer cells over express XPO1 $ TSP s assess DNA damage/cell fate Nuclear localization and activation of multiple TSPs $ SINE compounds inhibit XPO1- Reduces Oncoproteins MYC, BCL2/BCL6, CycD1, Inhibits NF- κb Courtesy of KaryoPharm 38
SINE Inhibitor: Phase 1 Trial in Advanced Hematologic Malignancies Focus on Multiple Myeloma (EHA Update Data through June 214) CBR=Clinical Benefit Response (MR+PR+sCR), ORR=Overall Response Rate (scr+pr), scr= Stringent Complete Response, PR=Partial Response, MR=Minor Response, SD=Stable Disease, PD=Progressive Disease, NE=Non Evaluable Novel drugs in clinical trials for MM! Immunotherapy Checkpoint inhibitors CAR-T cells! Protein Metabolism HDAC Inhibitors P97 inhibitor! Other - cell cycle, etc. CDK inhibitors PIM Kinase inhibitors Bromodomain inhibitors! Targeted Therapies B-RAF inh vemurafenib MEK inh. trametinib FRFR3 Inh Dovitinib, su542 Mab s 39
4/27/15 Precision Medicine: The Future of Drug Development Workflows Support: Single Agent Combinations Drug Libraries Transduction GFP/luc fusion 384 well HT Evaluation Co-culture Format CD138- DMSO BM stroma and/or Immune Effectors Differential Agent Potency CD138+ annexin V Mono-culture Format Validation in Primary Myeloma Samples Drug Patient BMSCs In Vivo Integration of: Pearson & 1. Gene Expression Spearman 2. Whole Exome Seq Correlations 3. Copy Number PI Rational Access to Annotated Biosamples Cross-Referencing to Clinical Datasets Expression Mutation Copy Number Correlates for Response Associates Putative Correlates to Clinical Populations Conclusions! Many promising agents Blockbusters: anti-cd38 mab s Potential Blockbusters: ARRY52, other mab s SINE inh, ACY1215, PIM Inh, Bromodomain inh.! Future efforts should focus on: Identifying biomarkers for response Optimizing combinations and dosing strategies Using genomic data to help select targets/therapy! All patients are appropriate for Clinical Trials 4
Current Management of Bone Disease! Treat the myeloma! Novel therapies have benefits Direct effect on inflammatory cytokines Inhibition of bone resorption Osteoclast stimulation! Bisphosphonates Pamidronate Zoledronic acid! Supplement with calcium and vitamin D3 to maintain calcium homeostasis! Radiotherapy (low dose) Impending fracture Cord compression Plasmacytomas! Vertebroplasty/kyphoplasty! Orthopedic consultation Impending or actual long-bone fractures Bony compression of spinal cord Vertebral column instability Niesvizky R, et al. J Natl Compr Canc Netw. 21;8(suppl 1):S13-S2. Christoulas D, et al. Expert Rev Hematol. 29;2:385-398. Drake MT. Oncology (Williston Park). 29;23(14 suppl 5):28-32. Terpos E, et al. J Clin Oncol. 213;31:2347-2357. Webb SL, et al. British J Pharmacol. 214;[Epub ahead of print]. Bisphosphonates and Osteonecrosis! Uncommon complication causing avascular necrosis of maxilla or mandible! Suspect with tooth or jaw pain or exposed bone! May be related to duration of therapy! Incidence between 3% and 4% with zoledronic acid or pamidronate 41