TREATING RELAPSED / REFRACTORY MYELOMA AT THE LEADING EDGE

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1 TREATING RELAPSED / REFRACTORY MYELOMA AT THE LEADING EDGE PRESENTED BY: Pooja Chaukiyal MD Hematologist/Oncologist New York Oncology Hematology Albany, NY April 16, 2016

2 Background The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade The goal is to prolong the first remission for as long as possible MM is characterized by relapses and remissions, with each remission typically of shorter duration than the previous one Kumar SK, et al. Mayo Clin Proc. 2004;79 In the past few years treatment options for MM have increased and becoming more effective MM therapy is getting more individualized

3 Variable Components of the initial therapy Degree and duration of response to primary therapy Previous toxicities Type of relapse Age and performance status Considerations Novel agents? ASCT? PR, VGPR, CR? 6 mo, 1 y? Myelosuppression Peripheral neuropathy Aggressive Indolent Elderly Frail Blade, J et al, How I treat relapsed myeloma, BloodVolume 125(10): March 5, 2015

4 Questions 1. To treat or not to treat asymptomatic relapses 2. How to use available drugs 3. For how long should a rescue treatment be continued 4. When to consider a rescue second ASCT? 5. Is there a role for allogeneic transplantation? Considerations When treatment can be safely delayed? When early treatment should be administered? Sequential approach? Multidrug combination approach? Limited number of cycles? Indefinite? What should be the minimal response duration from the first ASCT? When should it be considered? Blade, J et al, How I treat relapsed myeloma, BloodVolume 125(10): March 5, 2015

5 Risk Stratification at the Time of Relapse Time to relapse: relapse < 12 months after SCT have a shorter median survival than those who have a longer duration of response Palumbo A, et al. Cancer. 2007;110(4):824. High-risk disease: FISH for high risk disease (t(4;14), del(17/17p), t(14;16), t(14;20)) High LDH Plasma cell leukemia

6 Relapse After Autologous Stem Cell Transplant Alegre et al retrospectively analyzed 280 patients and categorized them into 4 patterns: Clinically symptomatic disease (66%) Asymptomatic disease characterized by increase in monoclonal protein (18%) Extramedullary disease (14%) Plasma cell leukemia (2%) Alegre et al. Different patterns of relapse after autologous PBST. Hematologica

7 Management of Relapse/Progressive Disease After First ASCT The 3 general approaches to management of symptomatic relapse after initial ASCT Re-induction followed by salvage ASCT Re-induction followed by allogeneic SCT (allosct) Re-induction with continuation of conventional dose chemotherapy using rational combinations of novel therapies for relapsed/refractory disease Multiple studies have shown that patients who relapse early after a stem cell transplant derive less benefit from a second ASCT Holstein et al. Management of Relapsed Multiple Myeloma after Autologous Stem Cell Transplant. Biology of Blood and Bone Marrow Transplant. 2015;21.

8 Time from first ASCT to relapse < 18 months months > 36 months Re-induction R/R regimen or clinical trial Re- induction R/R regimen or clinical trial AlloSCT ASCT Management of Relapsed Multiple Myeloma after Autologous Stem Cell Transplant, Holstein et al, Biology of Blood and Bone Marrow Transplant, 21 ( 2015)

9 Salvage AlloSCT Reduced-intensity conditioning allosct in the salvage setting is sometimes considered for younger patients with good performance status and highrisk features, including del 17p, t(4;14), t(14;16), or high-risk gene expression profile, High LDH, or plasma cell leukemia Prospective randomized studies comparing salvage allosct with salvage ASCT have not been performed Retrospective studies in aggregate, demonstrate a higher nonrelapse mortality rate with AlloSCT, and PFS/OS rates favor salvage ASCT Wirk et al; Outcomes of salvage autologous vs allogenic trans in MM patient; J clinic medicine Res Qazilbath et al Second autologous vs. allo transp in patients of MM. Cancer 2006; 106 As the number of effective regimens for relapsed/refractory disease continues to increase, the role of salvage allosct continues to be defined and evolve

10 RELAPSED / REFRACTORY REGIMENS

11 Single Agents Doublets Triplets Multi Agent CT Bortezomib Bortezemib/dexamethasone Bortezomib/cyclophosphamide/dexamethasone DT-PACE Ixazomib Panobinostat/carfilzomib Bortezomib/lenalidomide/dexamethasone DCEP Bendamustine Lenalidomide/dexamethasone Panobinostat/bortezemib/dexamethasone VDT-PACE High-dose cyclophosphamide Pomalidomide/dexamethasone Ixazomib/lenalidomide/dexamethasone Daratumumab Ixazomib/dexamethasone Elotuzumab/lenalidomide/dexamethasone Lenalidomide Thalidomide/dexamethasone Cyclophosphomide/lenalidomide/dexamethasone Carfilzomib Bortezomib/vorinostat Carfilzomib/lenalidomide/dexamethasone Carfilizomib/cexamethasone Bortezomib/thalidomide/dexamethasone Carfilzomib/cyclophosphamide/dexamethasone NCCN Guidelines 2016

12 Multimodality targeting of MM in the context of the BM microenvironment Giada Bianchi et al. Blood 2015;126: by American Society of Hematology

13 Monoclonal Antibodies Elotuzumab : Anti CS 1 antibody (present in myeloma cells as well as NK cells) Daratumumab : Anti CD 38 antibody Pembrolizumab : Anti PD 1 antibody

14 Monoclonal antibody therapeutic targeting of MM Kenneth C. Anderson JCO 2012;30: by American Society of Clinical Oncology

15 Daratumumab SIRIUS Trial, An open-label, international, phase II trial in relapsed MM (median of 5 prior therapies) were treated with daratumumab (16 mg/kg, weekly for 8 weeks and then every 2 weeks for 16 weeks) The ORR was 29 percent with a median time to first response of 1 month and responses lasting an average of 7.4 months The quality of the observed responses (11% VGPR or better, 2 CRs, and 3 scrs) was noteworthy in this highly refractory population Lonial et al; Phase II study of daratumumab monotherapy in patient with > 3 lines of therapy, ASCO abstract 2015,; 33 ( Suppl18)

16 Combination of Daratumumab With Backbone Agents Daratumumab in combination with lenalidomide and dexamethasone among heavily pretreated patients (> 4 lines of therapy) response rates approaching 100% were noted, 75% of which were VGPR Addition to backbone agents did not lead to increased toxicities; the most common toxicities were infusion reactions, pneumonia, and thrombocytopenia Multiple combination trials are ongoing for its approval Plesner et al, Safety and efficacy of Daratumumab with Lenalidomide and dexamethasone in R/R MM; Blood 2014; 124:24

17 Daratumumab Safety Considerations Daratumumab is a human IgG kappa monoclonal antibody that can be detected on SPEP and IFE assays As such, it may obfuscate the response assessment in patients with IgG kappa myeloma protein Daratumumab can interfere with cross-matching and red blood cell antibody screening Patients should have a type and screen performed prior to receiving daratumumab Antiviral prophylaxis to prevent herpes zoster reactivation is initiated within 1 week of starting daratumumab and continued for 3 months following the last dose

18 Elotuzumab ELOQUENT-2 trial is a phase 3 study, with elotuzumab plus lenalidomide and dexamethasone vs lenalidomide and dexamethasone alone Lonial et al; Elotuzumab therapy for R/R myeloma. NEJM 2015; 373

19 Lonial S et al. N Engl J Med 2015;373: Progression-free Survival.

20 Adverse Events The addition of elotuzumab to lenalidomide led to an effective and durable benefit with minimal incremental toxicities associated with the addition of elotuzumab Lonial S et al. N Engl J Med 2015;373:

21 Proteasome inhibitors Bortezomib Carfilzomib Ixazomib

22 ASPIRE Trial 792 patients were randomized to receive lenalidomide and dexamethasone with or without carfilzomib for 18 cycles. Stewart AK et al. N Engl J Med 2015;372:

23 Stewart AK et al. N Engl J Med 2015;372: Overall Survival.

24 Stewart AK et al. N Engl J Med 2015;372: Adverse Events in the Safety Population.

25 Ixazomib is an oral proteasome inhibitor (once weekly pill) indicated in combination with lenalidomide and dexamethasone for relapsed MM Ixazomib The approval was based on TOURMALINE-MM1 trial a multicenter, randomized, double-blind, placebo-controlled trial enrolling 722 patients The median PFS on the combination arm of ixazomib, lenalidomide and dexamethasone was 20.6 months vs months on the combination arm of placebo, lenalidomide and dexamethasone Benefit with IRd was also noted in pts with high-risk cytogenetics, including those with del(17), in whom median PFS was similar to all IRd-treated pts - indicating that ixazomib may have a favorable impact on the adverse prognosis associated with genetic mutations Adverse reactions associated with an increased rate on the ixazomib arm were diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, and back pain Moreau P et al; Ixazomib, an Investigational Oral Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone, Significantly Extends PFS for Patients with RRMM: The Phase 3 Tourmaline-MM1 Study (NCT ) (abstract 727) Blood. 2015;

26 Hi DAC Inhibitors Panobinostat combinations Vorinostat combinations

27 PANORAMA trial Panobinostat is a potent pan-deacetylase inhibitor that affects the growth and survival of multiple myeloma cells through alteration of epigenetic mechanisms and protein metabolism Panobinostat plus bortezomib and dexamethasone led to a significant increase in PFS vs placebo plus bortezomib and dexamethasone in patients with R/R MM Common grade 3/4 adverse events included thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/fatigue This analysis demonstrated a clear PFS benefit of 7.8 months with PAN- BTZ-Dex among patients who received 2 prior regimens including bortezomib and an IMiD

28 Paul G. Richardson et al. Blood 2016;127: by American Society of Hematology

29 Immunomodulatory Drugs Thalidomide Lenalidomide Pomalidomide

30 Pomalidomide FDA granted approval to pomalidomide for R/R MM who have received at least 2 prior therapies, including lenalidomide and bortezomib based on a multicenter, randomized, open-label study in 221 patients Overall response rate of 13% in patients treated with pomalidomide alone vs. 33% in those treated with pomalidomide plus low-dose dexamethasone Richardson PG, et al. Blood. Mar Pomalidomide with dexamethasone showed promising results in R/R MM with del(17p) Response rate are accentuated when combined with dexamethasone and further synergistic effect is seen with proteasome inhibitors such as bortezomib and carfilzomib In relapse setting, pomalidomide in combination with bortezomib and dexamethasone showed a PR rate 70%, VGPR of 43% Richardson PG, et al. Blood. 2013;122(21). Pomalidomide combinations with carfilzomib, HDAC inhibitors, daratumumab are being studied

31 Mechanism of action Drugs Proteasome inhibitors Immunomodulatory drug Carfilzomib Ixazomib Pomalidomide Temsirolimus PI3K/AKT/mTOR inhibitors Everolimus Perifosine Histone deacetylase inhibitor Alkylating plus purine analog p38/jnk activators Hypoxia-activated alkylator DNA-damaging agents Kinesin spindle protein inhibitor Panobinostat Vorinostat Bendamustine Plitidepsin TH-302 Zalypsis Arry-520 Elotuzumab Monoclonal antibodies Daratumumab SAR Blade, J et al, How I treat relapsed myeloma, BloodVolume 125(10): March 5, 2015

32 Take Home points Multiple choices available for treatment of R/R MM Treatment of R/R MM should be individualized after considering patient- and disease-related factors Combination treatment even in relapsed setting has shown better response rate Treatment can be safely delayed in a subset of patients with asymptomatic relapse, whereas those with symptomatic relapse, advanced disease at diagnosis, or significant paraproteinemic increase require prompt rescue therapy

33 QUESTIONS?