Multiple Myeloma at ASH Kevin Song MD, FRCPC Vancouver General Hospital Leukemia/BMT Program of BC Vancouver, British Columbia

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2 Multiple Myeloma at ASH 2017 Kevin Song MD, FRCPC Vancouver General Hospital Leukemia/BMT Program of BC Vancouver, British Columbia

3 Session: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Genomics of The Pathogenesis and Progression of Multiple Myeloma Sunday, December 10, 2017: 10:30 PM Bldg B, Lvl 3, B304-B305 (Georgia World Congress Center) Abstract # 395 Utility of Clinical-Grade Sequencing of Relapsed Multiple Myeloma Patients; Interim Analysis of the Multiple Myeloma Research Foundation (MMRF) Molecular Profiling Protocol Daniel Auclair, PhD. and P. Leif Bergsagel, MD Many MM cases harbor potentially actionable oncogenic molecular alterations MMRF Molecular Profiling Protocol will enroll 500 relapsed patients that would be molecularly profiled using clinical-grade sequencing performed on the Michigan Oncology Sequencing platform

4 Methods Bone marrow aspirates and matched normal peripheral blood are shipped to the Michigan Center for Translational Pathology (MCTP) Clinical Sequencing Lab DNA and RNA are isolated from MM cells and matched normal Libraries are generated and subjected to the Oncoseq1500 gene exome capture. Deep targeted re-sequencing (>600x) is carried out on HiSeq2500 run in rapid mode. A molecular report highlighting actionable findings is produced, reviewed internally by a genomic Tumor Board and returned within 10 days

5 Results Report on 228 consecutive cases analyzed with 84% of the sequenced samples (192) 76% of cases were found to harbor at least one potentially actionable alteration. Of those cases, 53% had alterations in the MAPK pathway, 14% in the CCND1 and cyclindependent kinase (CDK) pathways, 6% had activating FGFR3 mutations followed by a group of events at 3% or less. 16% of cases presented with TP53 mutations (1/4 could also be detected in blood) Also detected in PB were, SF3B1, TET2, ASLX1, ASLX2 and DNMT3A with such mutations (typically subclonal) often co-occurring in the same specimen. In all, 10% of all cases presented with this mutational signature in both BMAs and PB of genes generally associated with MDS, AML and other myeloid disorders. 10% of cases the treating clinician acted upon the information with the indicated targeted agent. Results will be presented.

6 Conclusions Actionable alterations were identified in over three quarter of cases analyzed. Results suggest that Precision Medicine approaches in MM are possible and should be further studied clinically. Authors will launching MyDRUG, a master protocol aimed at developing new myeloma regimens based on individual patient s genomics.

7 Session: 653. Myeloma: Therapy, excluding Transplantation I Monday, December 11, 2017: 3:15PM Bldg C, Lvl 1, Hall C1 (Georgia World Congress Center) Abstract # 741 Deep and Durable Responses in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (MM) Treated with Monotherapy GSK , an Antibody Drug Conjugate Against B-Cell Maturation Antigen (BCMA): Preliminary Results from Part 2 of Study BMA Suzanne Trudel, MD, FRCP(C) and Adam D. Cohen, MD BCMA is expressed on MM cells. BCMA is a cell surface receptor in the TNF superfamily with expression restricted to B lineage cells at later stages of differentiation GSK is a humanized IgG1 anti-bcma antibody conjugated to monomethyl auristatin-f Upon binding to BCMA, GSK is rapidly internalized and active drug released Similar to brentuximab

8 Methods Dose escalation (Part 1) and expansion (Part 2) in MM pts complete GSK is dosed once every 3 weeks as a 1- hr intravenous infusion, Pts remain on treatment until progression or completing 16 treatment cycles. All pts received steroid eye drops for 4 days with each infusion to mitigate corneal events.

9 Results Part 1 results (N=38); no maximum tolerated dose was identified and the RP2D was determined to be 3.4 mg/kg. Part 2 enrolled 35 MM pts treated at the RP2D: median age is 60 years (range 46-75) and 49% are male. Fifty-seven percent received 5 prior lines of therapy (range 1- >10). All pts received and 97% were refractory to PI, all pts received and 91% were refractory to IMiDs, 40% received and 37% were refractory to daratumumab, and 89% were double-refractory to PI and IMiDs. Median # of infusions 5 (range 1-13) and 54% of pts received 5 infusions. The ORR for Part 2 was 60% (21/35; 95% CI ), including 1 scr, 2 CR, 15 VGPR, and 3 PR. ORR in pts previously treated with daratumumab was 43% Median duration of response was not reached, with a median PFS of 7.9 months (95% CI 3.1- NA).

10 Results All pts had at least 1 adverse event (AE); the most frequent ( 25%) regardless of cause were corneal events (63%), Corneal events (most frequent 20%: vision blurred, dry eye, photophobia) were mostly Grade (Gr) 1/2 and were reversible. thrombocytopenia/platelet count decreased (57%), anemia (29%), AST increased (29%), and cough (26%). Gr 3/4 AEs reported in 10% of pts were thrombocytopenia/platelet count decreased (34%) and anemia (14%). Serious AEs were reported in 40% (14/35) of pts. Infusion reactions not severe. A total of 18 pts discontinued treatment for: disease progression (n=15), AE (n=2; thrombocytopenia, CPK elevation) pts decision (n=1); 17 pts are ongoing

11 Conclusions GSK monotherapy: ORR of 60%, and deep (51% VGPR) and durable responses in heavily pre-treated relapsed/refractory MM pts Results show a manageable safety profile, with thrombocytopenia/platelet count decreased and low grade corneal events being the most frequently reported AEs and most frequent reason for dose modifications.

12 Session: 653. Myeloma: Therapy, excluding Transplantation: Immunotherapy in Myeloma and Amyloid Sunday, December 10, 2017: 4:30 PM Bldg C, Lvl 1, Hall C4 (Georgia World Congress Center) Abstract # 505 Safety and Efficacy of B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells (CART-BCMA) with Cyclophosphamide Conditioning for Refractory Multiple Myeloma Adam D. Cohen, MD..Michael C. Milone, MD, PhD Kochenderfer et al. 2009; J Immunother

13 Methods 3+3 dose-escalation study, relapsed/refractory MM patients (pts) receive CART-BCMA cells Three cohorts are planned: x 10 8 CART cells alone 2. cyclophosphamide (CTX) 1.5 g/m x 10 7 CART cells 3. CTX 1.5 g/m x 10 8 CART cells. Split-dose infusions (10% on day 0, 30% on day 1, and 60% on day 2)

14 Results / Characteristics 33 pts consented. 28 Eligible, 21 Infused. 4 waiting infusion, 3 not infused due to rapid progression / clinical deterioration. Median lines of therapy is 7 (range 3-11); 100% are proteasome inhibitor and IMID-refractory, 67% daratumumab-refractory. 95% had high-risk cytogenetics, 67% del17p or TP53 mutation; 29% extramedullary disease. with 18 pts (86%) receiving full planned dose, and 3 pts receiving 40% of dose (3 rd infusion held due to fevers).

15 Results / Toxicities Cohort 1 (n=9) included cytokine release syndrome (CRS) in 8 pts (3 grade 3/4, with 4 receiving tocilizumab) and neurotoxicity (grade 4 encephalopathy) in 2 pts. Cohorts 2 and 3 (n=12), CRS has occurred in 9 pts (3 grade 3, 0 grade 4, none requiring tocilizumab), and neurotoxicity in 1 pt (grade 2 confusion/aphasia), with no unexpected/dose-limiting toxicities, and no treatment-related deaths.

16 Results / Efficacy Cohort 1: 6/9 pts responded (1 scr, 2 VGPR, 1 PR, 2 MR), with 1 ongoing scr at 21 months, and other responses lasting 1.5 to 5 months. Cohort 2: 2/5 pts responded (1 PR, 1 MR) but progressed at 4 and 2 months Cohort 3: median follow-up is currently 1 month, with 5/6 pts responding (1 CR, 3 PR, 1 MR) and 1 not yet evaluable. Median peak expansion (as measured by copies/µg DNA) is 6160, 14761, and in Cohorts 1, 2, and 3, respectively Suggests a benefit with adding Cy, though this was not statistically significant. PR or better is associated with higher peak CART-BCMA levels and decline in soluble BCMA, but not with baseline soluble BCMA level or intensity of baseline BCMA expression by flow on MM cells. Serial marrow flow cytometry demonstrates that 5/6 pts with PR and detectable residual MM cells have decreased BCMA intensity on MM cells post-infusion compared with baseline.

17 Conclusion CART-BCMA infusions following Cy lymphodepletion are feasible and have significant clinical activity in highly-refractory MM pts with poor-risk genetics and limited treatment options. Efficacy appears lower at the 10 7 dose, compared with 10 8, and remaining pts are now being enrolled in Cohort 3. CRS remains a common but manageable toxicity. Decreased BCMA expression on residual MM cells post-infusion may be an escape mechanism reflecting CART-BCMA-induced immune editing. These data provide further support for exploration of CART-BCMA in relapsed/refractory MM, with updated cohort 3 data to be presented at the meeting.

18 Session: 723. Clinical Allogeneic and Autologous Transplantation: Late Complications and Approaches to Disease Recurrence: Progress in survivorship care of transplant patients Sunday, December 10, 2017: 7:45AM Bldg C, Lvl 2, C211-C213 (Georgia World Congress Center) Abstract # 332 Effect of Autologous Hematopoietic Stem Cell Transplant (ahsct) on the Development of Second Primary Malignancies (SPM) in Multiple Myeloma Patients Aaron Seth Rosenberg, MD,. and Theresa H.M. Keegan, PhD, MS Improved survival and risk of SPM s with modern anti-myeloma therapy Direct comparison of the effect of ahsct on development of SPMs in MM patients is necessary to better advise patients and physicians on the potential risks.

19 Methods Patients diagnosed were identified in the California Cancer Registry linked to the California hospital Patient Discharge Database. Inclusion criteria included a first primary diagnosis of MM and a minimum 1 year of follow up. SPMs were defined as distinct malignancies arising 1 year after MM diagnosis. The cumulative incidence (CI) of developing any SPM, and associated 95% confidence intervals were computed, accounting for the competing risk of death. ahsct recipients and those without ahsct, patients were matched 1:2 on age, year of diagnosis, race/ethnicity, socioeconomic status and comorbidities.

20 Results Among 16,331 patients, 933 (5.7%) developed a SPM 1 year after diagnosis. (12.8%) were hematologic malignancies, primarily leukemia (81, 9%). The most common solid tumors were malignancies of the digestive (184, 19.7%), respiratory (119, 12.8%), and male genital (115, 12.3%) systems. An additional 310 SPMs were diagnosed <1 year after diagnosis and were excluded from further analysis. The 5- and 10-year CI of developing : any SPM was 4% (3.7% - 4.3%) and 6.6% (6.2% - 7.1%) respectively. solid SPM was 3.5% (3.3% 3.9%) and 5.7% (5.3% - 6.2%). hematologic SPM was 0.5% (0.4% - 0.6%) and 0.9% (0.7% - 1.1%).

21 Multivariable models no increased risk of SPMs among ahsct recipients (adjusted hazard ratio (ahr) 1.13, 95% CI ). Risk of heme SPMs was increased in the ahsct recipients (ahr 1.65, ), Risk of solid SPMs not increased (ahr 1.06, ). Era of diagnosis ( , , , ) was not associated with an increased risk of SPMs.

22 Conclusions Cumulative incidence for SPMs increases over time. ahsct as part of treatment and the era of diagnosis were not associated with a change in risk Though no difference in SPM development over time was noted, follow up time during eras when continuous therapy was more common are still short. A small but significant increase in hematologic SPMs was noted among ahsct recipients. As MM patients continue to live longer, efforts to effectively screen and prevent.

23 IXAZOMIB Update on a Phase II Study of Ixazomib with Lenalidomide As Maintenance Therapy Following Autologous Stem Cell Transplant in Patients with Multiple Myeloma Number: 437 Presenter: Krina Patel Session: 653. Myeloma: Therapy, excluding Transplantation: Upfront Therapy for Multiple Myeloma: Induction and Maintenance Time and Location: Sunday, December 10, 2017: 12:00 PM-1:30 PM Bldg C, Lvl 1, Hall C4 (Georgia World Congress) CARFILZOMIB Overall Survival (OS) of Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Versus Lenalidomide and Dexamethasone (Rd): Final Analysis from the Randomized Phase 3 Aspire Trial Number: 743 Presenter: A. Stewart Session: 653. Myeloma: Therapy, excluding Transplantation Time and Location: Monday, December 11, 2017: 2:45 PM-4:15 PM BldgC, Lvl 1, Hall C1 (Georgia World Congress Center)

24 Daratumumab Phase 3 Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE) Number: LBA-4 Presenter: Maria-Victoria Mateos Session: Late-Breaking Abstracts Session Time and Location: Tuesday, December 12, 2017: 7:30 AM-9:00 AM Bldg C, Lvl 1, Hall C2-C3 (Georgia World Congress Center) Daratumumab, Lenalidomide, and Dexamethasone (DRd) Versus Lenalidomide and Dexamethasone (Rd) in Relapsed or Refractory Multiple Myeloma (RRMM): Updated Efficacy and Safety Analysis of Pollux Number: 739 Presenter: Meletios Dimopoulos Session: 653. Myeloma: Therapy, excluding Transplantation I Time and Location: Monday, December 11, 2017: 2:45 PM-4:15 PM Bldg C, Lvl 1, Hall C1 (Georgia World Congress Center)

25 Thank you! Enjoy Atlanta, GA and ASH 2017