Current management of multiple myeloma. Jorge J. Castillo, MD Assistant Professor of Medicine Harvard Medical School

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1 Current management of multiple myeloma Jorge J. Castillo, MD Assistant Professor of Medicine Harvard Medical School

2 Multiple myeloma MM is a plasma cell neoplasm characterized by the accumulation of malignant plasma cells in the bone marrow producing a monoclonal paraprotein. MM accounts for 10% of all hematologic malignancies. Risk factors MGUS (1% per year) Age: median 66 years Sex: Male > female Race: blacks > whites > Asians/Hispanics Obesity

3 Castillo. CPPOP 2016 Myeloma subtypes

4 Diagnosis of myeloma Clonal bone marrow plasma cells greater than or equal to 10% OR Biopsy-proven bone or soft tissue plasmacytoma Hypercalcemia: serum calcium >11 mg/dl Renal insufficiency: creatinine clearance <40 ml/min or serum creatinine >2 mg/dl Anemia: hemoglobin <10 g/dl Bone lesions: osteolytic lesions on radiographs, CT, PET/CT, or MRI Rajkumar et al. Lancet Oncol 2014

5 Diagnosis of myeloma

6 Diagnostic update The following represent an 80% risk of developing active MM within 2 years and should be considered active MM: Clonal bone marrow plasma cell involvement greater than or equal to 60% Serum FLC ratio greater than or equal to 100; kappa:lambda in kappa-restricted myeloma or lambda:kappa in lambdarestricted myeloma Greater than 1 focal lesion on MRI Rajkumar et al. Lancet Oncol 2014

7 Improved survival in patients with myeloma Kumar et al. Blood 2008 Kumar et al. Leukemia 2014

8 Greipp et al. J Clin Oncol 2005

9 Palumbo et al. J Clin Oncol 2015

10 Timeline of Advances in Multiple Myeloma Through

11 Mechanism of action of proteasome inhibitors

12 Mechanism of action of immunomodulators Van de Donk et al. Cancer Managem Res 2012

13 Mechanism of action of monoclonal antibodies Van de Donk et al. Blood 2016

14 Treatment for myeloma - frontline

15 Treatment for myeloma - frontline

16 Attal et al. N Engl J Med 2017

17 Moreau et al. Blood 2016

18 Lenalidomide (n=306) Placebo (n=302) Hematologic cancers 13 (4%) 5 (2%) Solid tumors 10 (3%) 4 (1%) Nonmelanoma skin cancers 5 (2%) 3 (1%) Total 32 (9%) 12 (4%) Attal et al. N Engl J Med 2012

19 McCarthy et al. N Engl J Med 2012 Lenalidomide (n=231) Placebo (n=229) Hematologic cancers 8 (3%) 1 (0.4%) Solid tumors 10 (4%) 5 (2%) Nonmelanoma skin cancers 4 (2%) 3 (1.3%) Total 22 (9%) 12 (5%)

20 Treatment for myeloma - relapsed

21 Dimopoulos et al. Lancet Oncol 2016

22 Stewart et al. N Engl J Med 2015

23 Moreau et al. N Engl J Med 2016

24 ORR, % P < ORR = 93% b 22.6 CR: 46% c CR: 21% 23.5 VGPR: 76% c ORR = 77% b scr CR VGPR PR VGPR: 46% DRd 31.5 Rd Dimopoulos et al. N Engl J Med 2016

25 Palumbo et al. N Engl J Med 2016

26 Lonial et al. N Engl J Med 2016

27 Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial San Miguel et al. Lancet Oncol 2013

28 Selected Phase III Trials in Relapsed Disease Name of trial No. prior lines Arm N PFS (months) ORR VGPR CR ENDEAVOR 1-3 Kd % 54% 13% Vd % 29% 6% TOURMALINE-MM1 1-3 IRd % 48% 12% Rd % 39% 7% ELOQUENT Elo-Rd % 33% 4% Rd % 28% 7% ASPIRE 1-3 KRd % 70% 32% Rd % 40% 9% PANORAMA Pano-Vd % 11% Vd % 6% NIMBUS (MM-003) 2 Pd % 6% 1% D % 1% 0% CASTOR 1 Vd-dara 251 NE 83% 59% 19% Vd % 29% 9% POLLUX 1 Rd-dara 286 NE 93% 76% 43% Rd % 44% 19% 28

29 Management issues Proteasome inhibitors Zoster prophylaxis Subcutaneous bortezomib is preferred Carfilzomib can cause cardiac and pulmonary toxicity in elderly patients Elotuzumab SPEP interference Immunomodulators Full-dose aspirin for thrombosis prophylaxis Risk of secondary cancers Daratumumab Zoster prophylaxis False positive Coombs SPEP interference Flow interference

30 La Huerta et al. J Clin Oncol 2017

31 Patients progression free and alive (%) Patients progression free and alive (%) PFS According to MRD Status at 10 5 POLLUX CASTOR 100 Rd MRD 100 Vd MRD DVd MRD DRd MRD DRd MRD DVd MRD + 40 Rd MRD Patients at risk Rd MRD negative DRd MRD negative Rd MRD positive DRd MRD positive Months Patients at risk Vd MRD negative DVd MRD negative Vd MRD positive DVd MRD positive Vd MRD Months Usmani, et al. ASH 2016; 653:1151 Mateos, et al. ASH 2016; 653:1150

32 Barlogie et al. Blood 2014

33 Venetoclax Mechanism of Action Anti-apoptotic proteins BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival Venetoclax is a selective, orally available small molecule BCL-2 inhibitor 1 and bortezomib can indirectly inhibit MCL-1 Venetoclax enhanced bortezomib activity in vitro and in vivo 2 Roberts et al. N Engl J Med 2015 Punnoose et al. Mol Cancer Ther 2016

34 Venetoclax + Bortezomib + Dexamethasone N = 66 Median age: 64 y Median of 3 prior lines of therapy ORR, % All patients Not refractory to bortezomib Bortezomib-refractory to 3 prior therapies to 6 prior therapies Bcl-2 high Bcl-2 low Venetoclax/bortezomib/dexamethasone was well tolerated, no MTD Clinical benefit was higher in patients with fewer lines of therapy, patients who were not bortezomib-refractory, and patients who had high Bcl-2 expression n Moreau et al. ASH 2016

35 Selinexor: A new class of drug

36 Selinexor STORM Trial Quad and Penta Refractory STORM Trial N=78 Response VGPR 5 % PR 15 % MR 13 % Patient Characteristics Vogl et al. ASH 2016 Sel Dex Quad Refr Sel Dex Penta Refr Sel VD Sel KD Sel PomD Patients Enrolled Median Priors (range) 7 (3 16) 7 (5 17) 4 (1 11) 4 (2 10) 5 (2 9) ORR 21% 20% 77% 63% 60% CBR 29% 40% 91% 84% 73%

37 CTLA-4 CD80 CD86 CD28 CD70 CD27 Checkpoint inhibitors PDL1 PDL2 T cell Predictors of Clinical Activity (based on solid tumor experience) TCR Nivolumab* Pembrolizumab* Pidilizumab Tumor antigen specific T cells Neoantigens Shared antigens Ipilimumab* Tremelimumab MHC Antigen Presenting Cell Durvalumab Atezolizumab* MSB C BMS *US Food and Drug Administration (FDA) Approved Antigen presentation Evidence of immune recognition Adaptive resistance Target expression Leshokin et al. IMW New Delhi 2017

38 Pembrolizumab + RD for Relapsed/ Refractory MM Best Overall Response n (%) Efficacy Population (n = 40) Lenalidomide Refractory (n = 29) ORR 20 (50) 11 (38) Stringent CR (scr) 1 (3) 1 (3) Very good PR (VGPR) 5 (13) 3 (10) PR 14 (35) 7 (24) SD 19 (48) 17 (59) Disease control rate (CR + PR + SD) 39 (98) 28 (97) Progressive disease (PD) 1 (3) 1 (3) 11 patients NE by central review 3 discontinued within cycle 1 for reasons other than PD (2 no treatment assessments and 1 SD by investigator) 8 inadequate myeloma data for response assessment (5 PD and 3 SD by investigator) Mateos et al. J Clin Oncol 2016

39 Future: CAR T-cells Autologous T-cells engineered to express a T-cell receptor that specifically targets an antigen (BCMA, CD38) on the myeloma cells

40 Future: CAR-T Cell for Refractory MM Lin et al. EORTC-NCI-AACR 2016

41 Conclusions The survival of patients with myeloma is improving. Primary treatment should include RVD followed by ASCT, if appropriate, and maintenance. Multiple treatment options for relapsed and/or refractory myeloma patients. Venetoclax, selinexor, checkpoint inhibitors are undergoing clinical trials.

42 Current management of multiple myeloma Jorge J. Castillo, MD Assistant Professor of Medicine Harvard Medical School