1. Multiple Myeloma Plasma cell disorder: CRAB Estimated 24,050 cases and 11,090 deaths in 2014 [1] Median age at diagnosis: 69 yrs [2] 5-yr survival has improved substantially (45% in 2004-2010 vs 28% in 1987-1989 [2] ) due to novel agents R/O amyloidosis Revised ISS—LDH, cytogenetics The future: risk-adapted therapy, individualized treatment 1. American Cancer Society. Cancer facts & figures. 2014. 2. SEER stat fact sheet: myeloma. 2013.

2. Updated IMWG Criteria for Diagnosis of Multiple Myeloma *C: Calcium elevation (> 11 mg/dL or > 1 mg/dL higher than ULN) R: Renal insufficiency (creatinine clearance 2 mg/dL) A: Anemia (Hb < 10 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. 2014;15:e538-e548. MGUS  M protein < 3 g/dL  Clonal plasma cells in BM < 10%  No myeloma defining events Smoldering Myeloma  M protein ≥ 3 g/dL (serum) or ≥ 500 mg/24 hrs (urine)  Clonal plasma cells in BM ≥ 10% to 60%  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 ≥ 60%  Serum free light chain ratio ≥ 100  > 1 MRI focal lesion

3. MM Risk Categories Risk FactorsStandard Risk (Expected OS: 6-7 Yrs) High Risk (Expected OS: 2-3 Yrs) FISHt(11;14) t(6;14) Del(17p) Del(1p) Gain(1q) t(4;14)* t(14;16) CytogeneticsHyperdiploidyHypodiploidy Del(13) β 2 -microglobulin*Low (< 3.5 mg/L)High (≥ 5.5 mg/L) Isotype--IgA Gene expression profileGood riskHigh risk *Patients with t(4;14), β 2 -microglobulin < 4 mg/L, and Hb ≥ 10 g/dL may have intermediate- risk disease. Fonseca R, et al. Leukemia. 2009;23:2210-2221. Munshi N, et al. Blood. 2011;117:4696-4700.

4. Clinical Challenges in Treatment Selection Renal failure, plasmapheresis Aged 70 yrs or older Extramedullary MM High-risk MM Advanced bone disease Marrow failure

5. Factors Affecting Transplantation Eligibility Age – Older than 65 yrs of age may not be eligible – Older patients more sensitive to toxicity; less physical reserve Performance score Comorbidities – Increased risk of infection – Decreased tolerability for high-dose therapy

6. Current Considerations for Initial Treatment of MM Induction for younger patients – 3-drug induction followed by auto-transplant and consolidation in first response [1] – Maintenance therapy post auto-transplant [2] – Maximize depth, duration of first response [3,4] – Assessing depth of response and understanding implications for patient outcome [5] 1. Cavo M, et al. Lancet. 2010;376:2075-2085. 2. McCarthy PL, et al. Expert Rev Hematol. 2014;7:55-66. 3. Palumbo A, et al. N Engl J Med. 2011;364:1046-1060. 4. Lenhers N, et al. ASH 2013. Abstract 3183. 5. Paiva B, et al. Blood. 2012;119:687-691.

7. Transplantation in the Novel Therapy Era Transplantation improves CR/VGPR rate – CR/VGPR correlates with improved PFS and OS – CR/VGPR pre- and posttransplantation improves PFS and OS Tandem transplantation benefits a subgroup of patients Novel agents improve induction CR/VGPR rate Posttransplantation maintenance may improve CR/VGPR and thereby PFS and OS Bensinger W. J Clin Oncol. 2008;26:480-492. Mehta J, et al. Bone Marrow Transplant. 2008;42(suppl 1):S28-S34.

8. Role of MRD Assessment Remains a research tool, but indications are that lower levels of MRD predict for better outcomes – Can contribute to better definition of response – Potential to monitor efficacy of therapy Best, easily exportable method and optimal time point is still under investigation Even pts who achieve MRD- state can relapse, so all may not be able to stop therapy Unsure if changing therapy based on depth of response alters survival outcomes, unsure of next steps for MRD-

9. Post-ASCT Maintenance in Newly Diagnosed MM Does maintenance therapy prolong survival (PFS, OS) and does the choice of maintenance therapy make a difference? – If so, who should get treatment, for how long, and at what dose schedule? NCCN recommended maintenance therapies – Category 1: thalidomide, lenalidomide – Category 2A: bortezomib NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2013.

10. Why Approach Older Patients Differently? More sensitive to toxicity Less physical reserve Effective therapy should: – Induce high response rates – Not have severe toxicity – Improve survival compared with standard comparator

11. FIRST Trial: Efficacy Analysis of Len/Dex vs MPT in SCT-Ineligible Patients With MM Facon T, et al. ASH 2013. Abstract 2. PFS (Mos) Patients (%) 100 80 60 40 20 0 06121824303642485460 72 wks Median PFS, Mos Rd (n = 535)25.5 Rd18 (n = 541)20.7 MPT (n = 547)21.2 HR (P value): Rd vs MPT: 0.72 (.00006) Rd vs Rd18: 0.70 (.00001) Rd18 vs MPT: 1.03 (.70349) 4-Yr OS, % Rd (n = 535)59.4 Rd18 (n = 541)55.7 MPT (n = 547)51.4 HR (P value): Rd vs MPT: 0.78 (.0168) Rd vs Rd18: 0.90 (.307) Rd18 vs MPT: 0.88 (.184) Overall response (continuous Rd vs MTP): 75% vs 62% (P <.00001) Similar, tolerable safety profiles between treatment groups; incidence of secondary primary malignancies 0.4% in Rd arm vs. 2.2% in MPT OS (Mos) Patients (%) 100 80 60 40 20 0 06121824303642485460

12. Summary of Recent Therapies What is the optimal therapy for newly diagnosed MM? – Transplantation ineligible (NCCN recommendations) Category 1 combinations of lenalidomide/low-dose dexamethasone, MPV, MPR, or MPT Category 2A combinations of VD or MP Does choice of initial therapy matter? Yes – Age, high-risk patients, renal impairment – SWOG trial NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2013.

13. Salvage Therapy for Relapsed/Refractory MM NCCN Category 1 – Bortezomib – Bortezomib/liposomal doxorubicin – Lenalidomide/dexamethasone (Rd)  Large number of other choices if initiaI iMiD and proteasome inhibitor resistant – Carfilzomib—Endeavor, Aspire trials – Pomalidomide combinations – Panobinostat NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2013.

14. Salvage Auto Transplant in the Relapsed Setting: Reasonable Option ? Recent data from Mayo Clinic Transplant Center suggests that auto SCT2 appears safe and effective treatment for relapsed MM (N = 98) – ORR: 86%; median PFS: 10.3 mos; median OS: 33 mos – Rate of TRM: 4%, suggesting a favorable benefit- to-risk ratio Shorter TTP after auto SCT1 predicts shorter OS post auto SCT2 Gonsalves WI, et al. Bone Marrow Transplant. 2013;48:568-573.

15. New agents Daratumumab, antiCD38, combos Oral prot inhibitors—Ixazomib, combos Elotuzumab and SLAMF7, combos Exciting agents in trial Checkpoint inhibitors CAR T—BCMA, CD19 filanesib

16. Phase II SIRIUS: Daratumumab Shows Activity in Heavily Pretreated MM Median PFS: 3.7 mos (95% CI: 2.8-4.6); 1-yr OS: 65% (95% CI: 51.2-75.%) Most common grade 3/4 AEs: thrombocytopenia (25%), anemia (24%), neutropenia (14%); infusion-related reactions occurred in 43% (most grade 1/2) sCR 3% VGPR 9% PR 17% Overall Pt Population 0 15 20 25 30 35 Pts achieving objective response (%) 29 Age ≥ 75 yr 10 5 Lonial S, et al. ASCO 2015. Abstract LBA8512. CrCl ≥ 60 mL/min > 3 Lines of Tx Extramedullary High-risk Cytogenetics PIs and IMiD Carfilzomib Pomalidomide Carfilzomib, Pomalidomide Bortezomib, Lenolidomide Bortezomib, Lenolidomide, Carfilzomib, Pomalidomide 33 30 21 20 30 29 28 26 21 ORR by Subgroup ORR by Refractory Status

17. Phase III TOURMALINE-MM1: Statistically Significant Improvement in PFS Most common AEs: thrombocytopenia (78%), diarrhea (42%), constipation (34%), PN (28%), nausea (26%), peripheral edema (25%), vomiting (22%), and back pain (21%) Ixazomib Package Insert. Nov 2015. Moreau P, et al. ASH 2015. Abstract 727. 024681012141618202224 Time (mos) from Randomization Ixazomib/len/dex Placebo/len/dex Median PFS, Mos (95% CI) Events, n/N 129/360 157/362 20.6 (17.0-NE) 14.7 (12.9-17.6) HR (95% CI) 0.74 (0.59-0.94) P value.012 0 20 40 60 80 100 Probability of PFS

18. 80 ELOQUENT-2: Significant Increase in PFS with Elotuzumab in Relapsed MM Significant PFS improvement and higher response rates with elotuzumab + RD vs RD alone in relapsed MM –ORR: 79% vs 66% (P =.0002), respectively Similar PFS benefit across subgroups, including older pts and pts with high-risk cytogenetics del(17p), t(4;14) 100 60 40 20 04812162024283236 PFS (mos) 0 PFS, % Elo/RD RD Median PFS, Mos (95% CI) 19.4 (16.6-22.2) 14.9 (12.1-17.2) HR (95% CI) 0.70 (0.57-0.85) P- value.0004 Lonial S, et al. N Engl J Med. 2015;373:621-631.

19. Relapsed/Refractory Disease All MM patients relapse Factors affecting choice of treatment for relapsed patients – Patient comorbidities Presence of significant neuropathy may preclude bortezomib History of DVT may prevent lenalidomide use – Time from previous therapy Same regimen may be considered if a sizable amount of time has passed – Response to previous therapy Consider clinical trial (if available)

20. Risk Factors for Thrombosis Age Obesity Cardiovascular disease Chronic renal disease Acute infection Immobilization General surgery Central venous catheter use Trauma Anesthesia Erythropoietin Hypercoagulable disorder Palumbo A, et al. Leukemia. 2008;22:414-423.

21. Current Treatment of Myeloma Bone Disease Bisphosphonates [1] – Pamidronate – Zoledronic acid Surgical procedures [1] – Vertebroplasty – Balloon kyphoplasty Radiotherapy [1] RANKL inhibitor denosumab (investigational in this setting) [2] 1. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014. 2. ClinicalTrials.gov. NCT01345019.

22. Management of Multiple Myeloma: Conclusions Doublet or triplet combination approaches should be used in both transplantation-eligible and -ineligible patients – Maintenance therapy can prolong response – MRD is achievable with current combination therapies Optimal management approaches should emphasize improving QoL by identifying potential complications of therapy and minimizing long-term toxicity New classes of agents and second-generation agents have activity and are of considerable interest