Multiple Myeloma: Update from ASH. Kenneth C. Anderson, M.D. Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute Harvard Medical School

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1 Multiple Myeloma: Update from ASH Kenneth C. Anderson, M.D. Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute Harvard Medical School

2 Integration of Novel Therapy Into Myeloma Management Bortezomib, Lenalidomide, Thalidomide, Doxil, Carfilzomib Target MM in the BM microenvironment to overcome conventional drug resistance in vitro and in vivo Effective in relapsed/refractory, relapsed, induction, consolidation, and maintenance therapy Eight FDA approvals and median survival prolonged from 3-4 to 6-7 years, with additional prolongation from maintenance New approaches needed to treat and ultimately prevent relapse Combinations in the Upfront Treatment of MM Stewart AK, Richardson PG, San Miguel JF Blood 2009

3 Summary of ASH Use of novel agents as initial, maintenance, and relapsed/refractory MM therapy 2. Second generation proteasome inhibitors and immunomodulatory drugs 3. Development of novel combination therapies 4. Monoclonal antibody therapies 5. Treatment of side effects Impact of Novel Agents in the Treatment of Elderly Pts with Newly Diagnosed MM Substantial improvements in PFS and OS Median PFS (mos) Median OS (mos) MP MPT VMP 7,8, % (3-yr OS)* MPR-R 9 31 N/A VMP-VT/VP % (3-yr OS)* VMPT-VT % (3-yr OS)* *Median OS not reached N/A: not available 1 Palumbo et al. Blood 2008; 112: Facon et al. Lancet 2007; 370: Hulin et al. J Clin Oncol 2009; 27: Waage et al. Blood 2010; 116: Wijermans et al. J Clin Oncol 2010; 28: Beksac et al. Eur J Haematol 2011;86: San Miguel et al. N Engl J Med 2008; 359(9): ; Supplementary Appendix 8 Mateos et al. J Clin Oncol 2010; 28(13): Palumbo et al. ASH 2010 (Abstract 622) 10 Mateos et al. Lancet Oncol 2010; 11(10): Palumbo et al. ASH 2010 (Abstract 620)

4 Treatment schedule 511 patients (older than 65 years) randomized from 58 Italian centers Patients: Symptomatic multiple myeloma/end organ damage with measurable disease 65 yrs or <65 yrs and not transplant-eligible; creatinine 2.5 mg/dl R A N D O M I Z E VMP Cycles 1-9 Bortezomib 1.3 mg/m 2 IV: days 1,8,15,22* Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 days x 5-week cycles in both arms VMPT Cycles 1-9 Bortezomib 1.3 mg/m 2 IV: days 1,8,15,22* Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 days 1-4 Thalidomide 50 mg/day continuously NO MAINTENANCE Until relapse MAINTENANCE Bortezomib 1.3 mg/m 2 IV: days 1,15 Thalidomide 50 mg/day continuously * 66 VMP patients and 73 VMPT patients were treated with twice weekly infusions of Bortezomib Conclusion VMPT-VT VMP P value 5-year PFS 29% 13% < year TNT 41% 19% < year OS 61% 51% year OS from relapse 47% 46% 0.63 P a

5 Treatment discontinuation VMPT VT VMP Discontinuation rate a, % years of age > 75 years of age Bortezomib dose intensity, % years of age > 75 years of age a Discontinuation due to AEs Palumbo et al ASH 2013 Abstr 200 Carfilzomib: A Novel Proteasome (Chymotryptic) Inhibitor Novel chemical class with highly selective and irreversible proteasome binding Tetrapeptide Improved antitumor activity with O consecutive day dosing N O H N O N H O H N O N H O O No neurotoxicity in animals Epoxyketone Durable responses in relapsed and relapsed/ refractory MM w/o neuropathy led to accelerated FDA approval in July 2012 Carfilzomib lenalidomide Dex versus lenalidomide Dex phase III trial for full drug approval

6 VTD Consolidation post-asct Study details n=39 in VGPR after ASCT 1 treated with 4 cycles VTD Molecular substudy of GIMEMA trial: VTD vs TD induction and consolidation 2 n=67 with ncr after ASCT, treated with two 35-d cycles VTD or TD Results Median follow up: 42 mos: No relapse in pts with molecular remission Significant increase in molecular remissions and reduction in tumor burden with VTD versus TD n=46 PR after HDM 3 treated with 2 cycles vtd (bortezomib 1mg/m 2 twice/wk, thal 100 mg/d, dex 40 mg/d once/wk) Improvement of response in 39% postconsolidation 1 Ladetto et al. J Clin Oncol 2010; 28(12): Terragna et al. Haematologica 2011; 96 (s1): S96 (Abstract P-224); poster presentation at IMW Roussel et al. ASH 2010 (Abstract 3041), poster presentation Carfilzomib, Thalidomide and Dexamethasone (CTd) for induction and consolidation in transplant for MM Induction Intensification Consolidation Carfilzomib 20/27mg/m 2 days 1,2,8,9,15,16 of a 28 day cycle. HDM Carfilzomib 27mg/m 2 days 1,2,8,9,15,16 of a 28 day cycle. Thalidomide 200 mg days 1-28 of a 28 day cycle Dexamethasone 40 mg days 1,8,15,21 of a 28 day cycle Stem Cell Harvest 200m g/m 2 ASCT Thalidomide 50 mg days 1-28 of a 28 day cycle Dexamethasone 40 mg days 1,8,15,21 of a 28 day cycle 4 cycles. 4 cycles. Sonneveld et al ASH 2013 Abstr 333

7 Cumulative Response (%) response (%) CR VGPR PR 0 Induction HDM/ASCT Consolidation Sonneveld et al ASH 2013 Abstr 333 Conclusions CTd is feasible and tolerable and effective Response is rapid and increases with HDM/ASCT and consolidation High CR (44 %), also in high-risk patients PNP only grade 1+2, mostly Thalidomide related Successful stem cell harvest in all eligible patients Longer follow-up needed for PFS and OS Dose level 20/36 mg/m 2 was completed per 10/2012 Dose level 20/45 mg/m 2 will start 12/2012

8 CYCLONE Initial Therapy in MM Agent Dose Level Route Day Rx Carfilzomib See Phase I and II dosing (15-45 mg/m 2 ) IV 1,2,8,9,15,16 Every 28 days Thalidomide 100mg PO 1-28 Every 28 days Cyclophosphamide 300mg/m 2 PO 1,8,15 Every 28 days Dexamethasone 40mg PO 1,8,15,22 Every 28 days Mikhael et al ASH 2013 Abstr 445 CYCLONE (carfilzomib, cyclophosphamide, thalidomide and dexamethasone) Initial Therapy in MM 1. is highly effective with ORR 96% and VGPR 74% in only 4 cycles 2. CYCLONE is well tolerated, with manageable myelosuppression and no > Grade 1 neuropathy 3. Patients can successfully collect stem cells 4. MTD has been reached at carfilzomib 20/36 mg/m 2 Mikhael et al ASH 2013 Abstr 445

9 Carfilzomib Lenalidomide Dexd in Newly Diagnosed MM *Jakubowiak et al. study Our study Phase I/II, n=53 Phase II, n=45 Combination Therapy CRd (Phase II Cfz 20/36 mg/m 2 ) 8 cycles CRd (Cfz 20/36 mg/m 2 ) 8 cycles Extended dosing CRd (CFZ every other week) 16 cycles Off protocol Rev 25 mg D1-21 after 16 cycles Rev 10 mg D cycles Transplant > PR stem cell collection HDM optional Stem cell collection Correlatives Flow cytometry MRD Flow cytometry MRD (3-4 x 10 6 ) PET-CT Proteasome assays GEP Whole genome sequencing * Jakubowiak A. et al., Blood, 2012; 120(9): Korde et al ASH 2013 Abstr 732 Carfilzomib, Lenalidomide, and Dex in Newly Diagnosed MM Among first 20 patients, no > grade 3 neuropathy Rapid and deep responses; median time to scr: 4.5 cycles (range: 2-7) Best response (median 7 cycles) ncr/scr = 75% ORR (PR or better) = 95% Among 10 ncr/scr patients assessed by flow cytometry, all were MRD negative PET/CT improved Korde et al ASH 2013 Abstr 732

10 MLN2238/9708 Oral Chymotryptic Inhibitor More Potently Blocks MM Cell Growth In Vivo than Bortezomib Clinical Trials Ongoing in Relapsed/Refractory MM and with Lenalidomide Dex as Initial Therapy Chauhan et al., Clin Cancer Res 2011; 17: Phase 1/2 study of MLN9708 lenalidomide and dex in patients with previously untreated MM Induction: up to 12 x 28-day treatment cycles Maintenance MLN9708 MLN9708 MLN9708 MLN9708 Dex 40 mg Dex 40 mg Dex 40 mg Dex 40 mg maintenance Lenalidomide 25 mg, days 1 21 Days 1, 8, day cycles Phase 1: oral MLN9708 dose-escalation Phase 2: oral MLN9708 at the RP2D from phase 1 Stem cell collection allowed after 3 cycles, with autologous stem cell transplantation (ASCT) deferred until after 6 cycles MLN9708 maintenance continued until progression or unacceptable toxicity Mandatory thromboprophylaxis with aspirin or low-molecular-weight heparin Kumar et al ASH 2013 Abstr 332

11 Phase 1/2 study of MLN9708 lenalidomide and dex in patients with previously untreated MM Oral weekly MLN9708, lenalidomide, and dexamethasone is well tolerated incidence of PN has been limited At median drug exposure of 6 months, 92% PR or better, including VGPR 55% and CR 23% Responses increased with number of cycles and deepened over time 88% of patients achieving CR who were evaluable for MRD status were confirmed as MRD-negative A phase 3 trial of MLN9708 plus lenalidomide dexamethasone versus placebo plus lenalidomide dexamethasone in patients with relapsed and/or refractory MM is currently enrolling (NCT ) for new drug approval Kumar et al ASH 2013 Abstr 332 CALGB Schema Registration Restaging Days Randomization D S Stage 1 3, < 70 years > 2 cycles of induction Attained SD or better 1 yr from start of therapy > 2 x 10 6 CD34 cells/kg Mel 200 ASCT McCarthy et al NEJM 2012; 366: 1770 CR PR SD Placebo Lenalidomide* 10 mg/d with (5 15 mg) * provided by Celgene Corp, Summit, NJ

12 CALGB , 10/31/2011 McCarthy et al NEJM 2012; 366: 1770 ITT Analysis with a median follow up from transplant of 34 months. P < Estimated HR=0.48 (95% CI = 0.36 to 0.63), Median TTP: 46 months versus 27 months. CALGB , 10/31/2011 McCarthy et al NEJM 2012; 366 : 1770 Median follow up of 34 months There are 35 deaths in the lenalidomide arm and 53 deaths in the placebo arm. P = 0.028

13 IFM : Risk Factors for Second Malignancies (n= 582) Factors (Multivariate Analysis) P value Treatment arm (Placebo vs Rev) 0.01 Age (<=55 y vs >55 years) 0.01 Sex (M vs F) 0.01 ISS (I +II vs III) 0.01 Induction with DCEP (Yes vs No) 0.02 Atal et al NEJM 2012 Progression-Free and Overall Survival All Patients Median PFS 4-year OS MPR-R 31 months MPR-R 59% MPR 14 months MPR 58% 100 MP 13 months 100 MP 58% 26 Patients (%) HR P <.001 HR P =.135 Patients (%) HR P =.648 HR P = Time (Months) Time (Months) TTP HR advantages were similar: MPR-R vs MP = 0.337; MPR vs MP = HR, hazard ratio; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone, lenalidomide with lenalidomide maintenance; OS, overall survival; PFS, progression-free survival; TTP, time to progression.

14 Second Primary Malignancies All Patients PD/Death Hematologic SPM Solid Tumor MPR-R 100 MPR 100 MP Patients (%) Time (Months) Time (Months) Time (Months) SPM, n (IR per 100 per year) MPR-R MPR MP (n = 150) (n = 152) (n = 153) Total Invasive SPMs 12 (3.04) 10 (2.57) 4 (0.98) Hematologic 7 (1.75) 6 (1.54) 1 (0.24) Solid tumors 5 (1.26) 5 (1.28) 3 (0.74) Non-melanoma skin cancer 2 (0.50) 5 (1.29) 6 (1.50) IR, incidence rate; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone, lenalidomide with lenalidomide maintenance; PD, progressive disease; PY, person-year; SPM, second primary malignancy. GEM05MENOS65 De novo symptomatic MM <65 yrs 1st randomization VBMCP/VBAD x 4 + BORTEZOMIB x 2 THALIDOMIDE/ DEXAMETHASONE x 6 THAL/DEX/ BORTEZOMIB x 6 ASCT (MEL200) 2nd randomization INTERFERON- 2b* (IFN) x 3 yrs THALIDOMIDE** (Thal) x 3 yrs THALIDOMIDE/BORTEZOMIB & (TV) x 3 yrs *3 MU/sc 3 times a week Rosinol ASH 2012 Abstr 3334 **100 mg/day & Thal 100 mg/day. Bortezomib 1.3 mg/m2 days 1,4,8,11 every 3 months

15 Conclusions The addition of bortezomib to thalidomide maintenance resulted in a significantly longer PFS when compared with thalidomide alone or with alfa2 IFN, with no increased toxicity. Discontinuations due to progressive disease were significantly higher with interferon while the single agent thalidomide arm resulted in a higher rate of discontinuations due to toxicity. Finally, the benefit of bortezomib was only observed in patients with good risk cytogenetics. Rosinol ASH 2012 Abstr 3334 Pomalidomide in Myeloma C MM cells IL-6 A B ICAM-1 TNF IL-1 Bone Marrow Stromal Cells D VEGF bfgf Hideshima et al. Blood 96: 2943, 2000 Davies et al. Blood 98: 210, 2001 Gupta et al. Leukemia 15: 1950, 2001 Bone Marrow Vessels Dendritic Cells NFAT PKC PI3K CD8+ T Cells IL-2 CD28 IL-2 IFN E NK Cells NK-T Cells Mitsiades et al. Blood 99: 4525, 2002 Lentzsch et al Cancer Res 62: 2300, 2002 LeBlanc R et al. Blood 103: 1787, 2004 Hayashi T et al. Brit J Hematol 128: 192, 2005

16 Pomalidomide With Low-Dose Dexamethasone Relapsed and Refractory Multiple Myeloma POM was effective in heavily pretreated patients who had already received LEN and bortezomib and who progressed on their last line of therapy The combination of POM with LoDEX improves the ORR due to synergy between immunomodulatory agents and glucocorticoids POM + LoDEX, 34%; POM alone, 15% Response was durable with POM regardless of the addition of LoDEX POM + LoDEX, 8.3 months ; POM alone, 8.8 months POM is generally well tolerated, with low rates of discontinuations due to AEs Age had no impact on ORR, DoR, or safety Jagannath S, et al. Blood. 2012;120:abstract 450. Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Relapsed Myeloma (345 patients) Pom/Dex has high response rates even in heavily pretreated relapsed myeloma Pom/Dex is well tolerated Toxicity and efficacy are similar between the 2mg and 4mg dose levels The strongest predictors of response include the number and type of prior regimens. The strongest predictors of TTP and survival include the number and type of prior regimens, LDH, and B2M. Lacy et al ASH 2013 Abstr 201

17 A Phase III Clinical Trial of Pomalidomide with Low-Dose Dex vs High Dose Dex in Relapsed/Refractory MM POM + LoDEX significantly improved PFS and OS Median PFS: 3.6 vs 1.8 months HR = 0.45; P <.001 Median OS: not reached vs 7.8 months HR = 0.53; P <.001 Equal benefit in pts refractory to both LEN and BORT POM + LoDEX was generally well tolerated POM + LoDEX should be considered as a new treatment option for these pts Dimopoulos et al ASH 2013 LBA6 MM-005: A Phase 1 Trial of Pomalidomide, Bortezomib,, and Low-Dose Dexamethasone in Relapsed or Relapsed/Refractory MM POM + BORT + LoDEX (PVD) well tolerated cohort 5 as the MTD/MPD POM 4 mg; BORT 1.3 mg/m 2 ; DEX 10/20 mg Responses in RR MM across all cohorts ORR: 73%, VGPR: 27%, SD: 27% Responses were rapid; majority are ongoing Efficacy even with adverse cytogenetics Phase III Trial Pom Bort Dex vs Bort Dex for full approval Richardson et al, ASH 2013 Abstr 727

18 Carfilzomib in Relapsed/Refractory MM Study Ph BTZ status n PX 171 II Relapsed and 003 A1 1 refractory Median prior tx lines CFZ dose Mode of admin /27 mg/m min IV infusion ORR 24% PX 171 I/II Relapsed and/or refractory /56 mg/m 2 30 min IV infusion 60% 1. Siegel et al. Blood. 2012;120(14): Papadopoulos KP, et al. Blood. 2011;118(21):Abstract and poster Phase II Study of Infusional Carfilzomib in Patients with Relapsed or Refractory MM CFZ dose of 20/56 mg/m 2 administered as a 30 minute IV infusion resulted in high response rates in our BTZ treated/refractory population. Response rates were comparable to those seen in PX CFZ dose of 20/56 mg/m 2 was associated with more frequent cardiac and pulmonary toxicities, particularly HTN and pulmonary edema/chf. Possible contribution from supportive measures? CFZ dose of 20/56 mg/m 2 continues to be explored in ongoing Phase II/III studies. Lendvai et al, ASH 2013 Abstr

19 Carfilzomib Pomalidomide Dexamethasone (Car-Pom Pom-d) ) in Relapsed/Refractory MM MTD was Carfilzomib 20/27 mg/m 2, Pomalidomide 4 mg, and dexamethasone 40 mg There are limited G 3 and 4 non hematologic toxicities; the regimen was tolerated well with no unexpected toxicity The combination of Car-Pom d is highly active in this heavily pretreated, refractory patient population VGPR 13% ORR 50% CBR 67% PFS (median) 7.4 months OS 1 year The combination has encouraging preserved response rate and survival independent of FISH/cytogenetic risk status Shah et al ASH 2013 Abstr 74 MAb-Based Therapeutic Targeting of Myeloma Antibody-dependent Cellular cytotoxicity (ADCC) Complement-dependent Cytotoxicity (CDC) C1q Apoptosis/growth arrest via targeting signaling pathways Effector cells: CDC C1q ADCC FcR MM MM MM Daratumumab (CD38) Lucatumumab or Dacetuzumab (CD40) Elotuzumab (CS1) Daratumumab (CD38) XmAb 5592 (HM1.24) hun901-dm1 (CD56) nbt062-maytansinoid (CD138) 1339 (IL-6) BHQ880 (DKK1) RAP-011 (activin A) Daratumumab (CD38) Tai & Anderson Bone Marrow Research 2011

20 A Phase 2 Study of Elotuzumab with Lenalidomide and Low-Dose Dex in Relapsed/ Refractory MM Elotuzumab plus lenalidomide and low-dose dexamethasone has a high ORR in relapsed and relapsed/refractory MM* ASH 2012 ORR 84% for the study as a whole, with ORR 92% for pts treated with elotuzumab 10mg/kg ORR 91% in pts who had received only 1 prior therapy Median PFS for elotuzumab 10mg/kg + Len/dex was not yet reached (median follow-up of 20.8 months)* median PFS: 29.7 months for pts treated with 1 prior therapy Elotuzumab + Len/dex was generally well tolerated at both the 10 and 20 mg/kg doses most common Grade 3/4 treatment-emergent AEs : lymphopenia (19%), neutropenia (18%), and thrombocytopenia (16%). Richardson et al ASH 2013 Abstr Daratumumab A human CD38 mab with broad-spectrum killing activity Lokhorst et al EHA

21 PHASE I/II STUDY OF DARATUMUMAB CD38 MONOCLONAL ANTIBODY IN RELAPSED/REFRACTORY MM Favorable safety profile as monotherapy In 15 of 32 (47%) showed benefit 4 patients achieving PR (13%) 6 patients achieving MR (19%) 5 patients achieving SD (16%) At doses 4mg/kg and above, 8 of the 12 patients had at least MR (66%) To be combined with lenalidomide dexamethasone Plesner et al ASH 2013 Abstr Factors impacting QOL Peripheral Neuropathy Cytopenia DVT Fatigue Herpes Zoster (Shingles) Bone Disease

22 Management of Peripheral Neuropathy Prompt Dose Reduction Schedule Change Discontinuation when PN emerges Use of Supplements Symptom Relief Pain medication Anti-depressants Gabapentin, Pregabalin, Duloxitin Prophylaxis and Treatment Multi-B Complex Vitamins Vitamin E Vitamin D Fish Oils Magnesium Potassium Tonic Water Acetyl L-Carnitine Alpha-Lipoic Acid Glutamine Cocoa Butter With B1, B6, B12, folic acid and other B6 should be approximately 50mg daily, not to exceed 100mg per day. Folic acid should be 1mg per day 400 IU daily IU daily OMEGA-3 Fatty Acids (EPA and DHA) Suggested doses include: 250mg twice a day (OTC). Alternatively 400mg daily by prescription with dose frequency dependent on serum Magnesium levels. May cause diarrhea in larger doses Either as provided by the treating physician or foods that are rich in potassium (eg bananas, oranges and potato). Drink one glass in evening and any other time cramping occurs 500mg twice a day with food. Can take up to 2000mg a day. 300mg to 1000mg a day with food 1g up to three times a day with food Apply to affected areas twice a day with gentle massage (rich in xanthenes, serotonins, Vitamin E and other emollients) Menthol Based Creams Apply to areas of numbness twice daily with gentle massage (e.g. Vick s Vapo-Rub) ** Do not take supplements on days of bortezomib infusions 1. Richardson PG et al, JNCCN 2010; 8: S4-S Perrone G, et al. Leukemia. 2009;23(9): Cately L, et al. Clin Cancer Res. 2006;12: Kim TY et al. Br J Haematol. 2009;146(3):

23 Drug-induced cytopenia Bortezomib Lenalidomide Chemotherapeutic agents Combinations Causes of Cytopenia Disease Bone marrow infiltration Drug effect Poor recovery from transplant Burnt out marrow

24 Fatigue Etiology: Disease-related cytokine (IL-6), Hyperviscocity Anemia Treatment-related - Thalidomide, bortezomib, lenalidomide Hypoadrenalism Hypogonadism Depression Some ideas to combat fatigue: short naps in the afternoon, healthy diet, plenty of fluid, exercise, try to stay active with friends and family. Discuss with healthcare team if fatigue is interfering with daily living. Treat the cause Herpes Zoster Prophylaxis With Bortezomib Treatment Immunocompromized pts at risk of developing VZV infection Bortezomib is associated with increased risk of VZV infection [1] Acyclovir and other antiviral prophylaxis appear effective at preventing VZV infection in patients treated with bortezomib for MM (with or without corticosteroids) [2] Vaccine not recommended at present 1. Chanan-Khan AA, et al. J Clin Oncol. 2008;26: Vickrey E, et al. Cancer. 2009;115:

25 ASCO Clinical Practice Guidelines for Bone Disease Bisphosphonates Indicated for MM pts w/ lytic bone disease osteopenia Useful as an adjunct for pts w/ bone pain The bisphosphonates recommended are either Zoledronic acid: 4 mg over 15 mins, IV q 3-4 wks Pamidronate: 90 mg over > 2 hrs, IV q 3-4 wks Monitoring w/ serum creatinine (both BPs) and/or urine albumin (for palmidronate only) PAM preferred in setting of renal dysfunction Re-evaluate after 2 years and consider stopping if stable disease Kyle R, et al. JCO : Summary of ASH Use of novel agents as initial, maintenance, and relapsed/refractory therapy 2. Second generation proteasome inhibitors and imids. 3. Development of novel combination therapies 4. Monoclonal antibody therapies 5. Treatment of side effects

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