Phase III MAIA: Daratumumab + Len/Dex vs Len/Dex in Transplantation-Ineligible Newly Diagnosed Multiple Myeloma Integrating New Malignant Hematology Findings Into Practice: Independent Conference Coverage of ASH 2018* December 1-4, 2018; San Diego, California *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. Dex, dexamethasone; Len, lenalidomide. Supported by educational grants from AbbVie, AstraZeneca, Celgene Corporation, Dova Pharmaceuticals, Incyte, Jazz Pharmaceuticals, Novartis Pharmaceuticals, Pharmacyclics, Seattle Genetics, and Takeda Oncology.

About These Slides Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients When using our slides, please retain the source attribution: These slides may not be published, posted online, or used in commercial presentations without permission. Please contact permissions@clinicaloptions.com for details Slide credit: clinicaloptions.com Disclaimer: The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

Daratumumab, Lenalidomide, and Dexamethasone in Myeloma: Background Continuous Rd or triplet VRd followed by maintenance is considered standard of care for ASCT-ineligible newly diagnosed MM Phase III FIRST trial showed significant improvement in PFS with Rd vs MPT[1] Phase III SWOG S0777 showed improvement in OS with VRd vs Rd, even in patients ≥ 65 yrs of age[2] Daratumumab: CD38-targeted monoclonal antibody approved as single agent and in combination with standard regimens in heavily pretreated MM as well as in combination with VMP in ASCT-ineligible newly diagnosed MM In POLLUX trial, addition of daratumumab to Rd in relapsed/refractory MM reduced risk of progression or death by 63%[3] Current analysis: interim results from phase III trial of addition of daratumumab to Rd in transplantation-ineligible patients with newly diagnosed MM[4] ASCT, autologous stem cell transplantation; MM, multiple myeloma; MPT, melphalan/prednisolone/thalidomide; Rd, lenalidomide/dexamethasone; VMP, bortezomib/melphalan/prednisone; VRd, bortezomib/lenalidomide/dexamethasone. Slide credit: clinicaloptions.com 1. Benboubker. NEJM. 2014;371:906. 2. Durie. ASH 2018. Abstr 1992. 3. Dimopoulos. NEJM. 2016;375:1319. 4. Facon. ASH 2018. Abstr LBA-2.

28-day cycles until progression MAIA: Study Design Randomized phase III trial Stratified by ISS (I vs II vs III), region (N America vs other), age (< 75 vs ≥ 75 yrs) Daratumumab 16 mg/kg IV (QW cycles 1-2, Q2W cycles 3-6, Q4W cycle 7+) + Lenalidomide 25 mg/day PO on Days 1-21 + Dexamethasone 40 mg/wk* PO or IV (n = 368) Patients with ASCT-ineligible NDMM, ECOG PS 0-2, CrCl ≥ 30 mL/min (N = 737) 28-day cycles until progression Lenalidomide 25 mg/day PO on Days 1-21 + Dexamethasone 40 mg/wk* PO or IV (n = 369) ASCT, autologous stem cell transplantation; BMI, body mass index; CrCl, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; MRD, measurable residual disease; NDMM, newly diagnosed multiple myeloma; PS, performance status. *Reduced to 20 mg/wk if > 75 yrs of age or BMI < 18.5. Primary endpoint: PFS Secondary endpoints : ≥ CR rate, ≥ VGPR rate, MRD negativity, ORR, OS, safety Slide credit: clinicaloptions.com Facon. ASH 2018. Abstr LBA-2.

MAIA: Patient Characteristics Baseline characteristics well balanced between treatment arms Characteristic All Patients (N = 737) Median age, yrs (range) 73 (45-90) Male, % 52 White, % 92 ECOG PS 0/1/≥ 2, % 34/50/17 ISS stage, % I II III 27 43 29 Disease type, % IgG IgA 62 18 High-risk cytogenetic profile,* n/N (%) 92/642 (14) ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; PS, performance status. *Defined as t(4;14), t(14;16), or del(17p). Slide credit: clinicaloptions.com Facon. ASH 2018. Abstr LBA-2.

MAIA: Patient Disposition Outcome Daratumumab + Rd (N = 368) Rd (n = 369) Patients who discontinued treatment, n (%) 118 (32) 207 (57) Reason for discontinuation, n (%) PD AE Death Patient decision Clinician decision Other Lost to follow-up 53 (15) 27 (7) 21 (6) 13 (4) 2 (< 1) 87 (24) 59 (16) 16 (4) 17 (5) 1 (< 1) Median duration of treatment, mos (range) 25.3 (0.1-40.4) 21.30 (0.03-40.60) Median cycles of therapy, n, (range) 27 (1-44) 22 (1-43) Median relative dose intensity, % (range) Daratumumab Lenalidomide Dexamethasone 98.4 (3.2-107.0) 76.2 (7.9-240.9) 84.2 (11.0-110.7) -- 91.4 (4.8-234.2) 90.7 (18.9-154.5) AE, adverse event; PD, progressive disease; Rd, lenalidomide/dexamethasone. Slide credit: clinicaloptions.com Facon. ASH 2018. Abstr LBA-2.

MAIA: Efficacy Median follow-up for PFS and OS: 28 mos Outcome Daratumumab + Rd (n = 368) Rd (n = 369) HR (95% CI) P Value PFS Median, mos 30 mos, % NR 71 31.9 56 0.56 (0.43-0.73) < .0001 OS Events, n (%) 62 (17) 76 (21) 0.78 (0.56-1.1) ORR, % Stringent CR CR VGPR PR 93 30 17 32 14 81 12 28 MRD negativity, % 24 7 ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; MRD, measurable residual disease; NR, not reached; PS, performance status; Rd, lenalidomide/dexamethasone. Median follow-up for PFS and OS: 28 mos Daratumumab treatment favored in most subgroups analyzed, including age, race, ISS stages, ECOG PS scores Reduced risk of progression or death with MRD negativity in both study arms Slide credit: clinicaloptions.com Facon. ASH 2018. Abstr LBA-2.

MAIA: Safety Hematologic Nonhematologic TEAE, % Daratumumab + Rd (n = 364) Rd (n = 365) Any Grade Grade 3/4 Neutropenia Anemia Thrombocytopenia Lymphopenia 57 35 19 18 50 12 7 15 42 38 19 12 35 20 9 11 Diarrhea Constipation Fatigue Peripheral edema Back pain Asthenia Nausea Pneumonia DVT and/or pulmonary embolism 57 41 40 38 34 32 23 2 8 3 4 1 14 6 46 36 28 29 26 25 13 < 1 <1 Infusion-related reaction -- Invasive SPM TEAE resulting in death Hematologic Nonhematologic DVT, deep vein thrombosis; Rd, lenalidomide/dexamethasone; SPM, second primary malignancy; TEAE, treatment-emergent adverse event. Slide credit: clinicaloptions.com Facon. ASH 2018. Abstr LBA-2.

MAIA: Conclusions Addition of daratumumab to Rd reduced risk of progression or death by 44% in patients with ASCT-ineligible newly diagnosed MM Improved depth of response with daratumumab, including 2-fold higher stringent CR/CR rate and 3-fold improvement in MRD negativity Safety profile of daratumumab/lenalidomide/dexamethasone in newly diagnosed MM similar to previously reported in R/R MM Investigators suggest that these results support use of daratumumab/ lenalidomide/dexamethasone as a new standard of care in patients with newly diagnosed MM who are not eligible for ASCT ASCT, autologous stem cell transplantation; MM, multiple myeloma; MRD, measurable residual disease; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Facon. ASH 2018. Abstr LBA-2.

Go Online for More CCO Coverage of ASH 2018! Short slideset summaries and additional CME-certified analyses with expert faculty commentary on key studies in: Leukemias Lymphomas/CLL Multiple Myeloma Other Hematologic Diseases clinicaloptions.com/oncology