Changing Landscape of Treatment for Multiple Myeloma

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  • Trends in Overall Survival of MMKumar et al studied survival in 387 patients who were treated at the Mayo Clinic from 1971–2006 and experienced a first relapse after ASCTPatients were divided into 2 cohorts, those with a relapse date on or before December 31, 2000 and those with a later relapse date Median overall survival (OS) was longer for patients who relapsed after 2000 compared with those who relapsed prior to this date (23.9 vs 11.8 months)Improved outcome of patients with MM has been observed in recent years, both in the relapsed setting as well as at diagnosisReferenceKumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and theimpact of novel therapies. Blood. 2008;111(5):2516-2520.
  • Orlowski RZ, et al. J Clin Oncol. 2002;20(22):4420-7. O'Connor OA, et al. Clin Cancer Res. 2009;15(22):7085-91.
  • Cycle1 Day1–2 doses were 20 mg/m2, followed by escalation to 56mg/m2Patients who did not achieve a partial response (PR) after two cycles of CFZ or initially responded to single agent CFZ, but later showed evidence of progression of disease (POD) had dexamethasone (40mg/week) added to their regimenMedian progression free survival was 4.6 monthsMedian overall survival has not been reached with a median follow-up among survivors of 9.6 months (range: 0.3-14.3 months)The average time to best response was two cyclesThree out of the 11 patients that had dexamethasone 40mg/week added to their regimen obtained an improved responseTwelve patients (35%) were dose reducedTreatment emergent, non-hematologic Grade 3/4 adverse events for which contribution of CFZ cannot be excluded were: HTN (n = 7), lung infection (n = 6), pulmonary edema (n = 3), reduced ejection fraction (n=1), sepsis (n=2), febrile neutropenia (n=1), bacteremia (n = 1), protothecosis (n = 1), fatigue (n=1), neuropathy (n=1), microangiopathic hemolytic anemia(n=1), nausea/vomiting/+/- diarrhea (n = 2), gastrointestinal bleed in the setting of Grade 4 thrombocytopenia (n = 1), hyperkalemia (n = 1)
  • A total of 22 patients were treated; the median age was 59.5 years (range 41−72); 17 were men and 7 were African American. The median number of prior chemotherapies was 4 lines (range 1−9), and median number of transplants was 2 (range 0−4); 96% of patients received prior bortezomib. As of May 2012, patients had received a median of 4 cycles (range 1−6), with no dose reductions reported. Thirty-minute infusion of carfilzomib at 45 mg/m2 or 56 mg/m2 in combination with dexamethasone was well tolerated. The most common AEs, irrespective of relationship to carfilzomib, were fatigue (36.4%), headache (36.4%), thrombocytopenia (36.4%), anemia (31.8%), cough (31.8%), dyspnea (31.8%), insomnia (27.3%), upper respiratory tract infection (27.3%), nausea (22.7%), and hypertension (18.2%). Non-hematologic AEs were mostly Grade 1 or 2. Grade 3 or higher AEs reported in >10% of patients were anemia (27.3%) and thrombocytopenia (27.3%). SAEs were reported in 4 (18.2%) patients, and there were no deaths on study. Seven patients discontinued therapy due to PD (n=6, all on 45 mg/m2) or SAE (n=1, on 56 mg/m2for Grade 4 increased aspartate aminotransferase). Preliminary responses in patients who completed at least 2 cycles (n=20) included VGPR (n=2) and PR (n=9), for an ORR of 55% with SD in 6 patients and PD in 3. The remaining 2 patients discontinued prior to cycle 2 (unrelated AE=1, patient decision=1).
  • Get Persmission clinical care optionsBTZ, bortezomib; DEX, dexamethasone; DLT, dose-limiting toxicity; IL, interleukin; MM, multiple myeloma.
  • Get Persmission clinical care optionsBTZ, bortezomib; ORR, overall response rate; NA, North America; PFS, progression-free survival; TTP, time to progression; WE, Western Europe.
  • Get Persmission clinical care optionsADCC, antibody-dependent cell-mediated cytotoxicity; ASCT, autologous stem cell transplantation; CDC, complement-dependent cytotoxicity; MM, multiple myeloma.

Transcript

  • 1. Changing Landscape of Treatment for Multiple Myeloma Ravi Vij MD Associate Professor Section of BMT and Leukemia Washington University School of Medicine,
  • 2. Trends in Overall Survival of MM Overall survival 1971–2006 Diagnosis period Median OS 1996–2006 45 months 1971–1996 30 months (P<0.001) Kumar SK, et al. Blood. 2008;111:2516-2520. Time from diagnosis (Months) Survival 0 0.2 0.4 0.6 0.8 1.0 0 20 40 60 80 100 120 140 2001–2006 1995–2000 2001–2006 1989–1994 1983–1988 1977–1982 1971–1976 OS, overall survival. 3 M
  • 3. Trends in 10-Year Relative Survival of MM 4 Period estimates of 10-year relative survival of patients with MM by major age groups in defined calendar periods from 1984-1986 to 2002-2004 *Relative survival reflects survival of patients with cancer compared with survival of the general population. Brenner H, et al. Blood. 2008;111:2521-2526. Calendar period 1984- 1986 1987- 1989 1990- 1992 1993- 1995 1996- 1998 1999- 2001 2002- 2004 10-yearrelativesurvival(%)* 0 5 10 15 20 25 30 35 40 45 50 15-49 50-59 60-69 70-79 80+ Age range
  • 4. Surviv al Outcom es from Tim e Zero 0% 20% 40% 60% 80% 100% 0 12 24 36 48 60 Months from Time Zero Ov erall Surv ival Ev ent-Free Surv ival Ev ents / N 173 / 291 222 / 291 M edian in M onths 9 (7,11) 5 (4,6) Kumar S. EHA 2010 Overall and Event-Free Survival in Patients Relapsing and Refractory to Bortezomib and Thalidomide/Lenalidomide
  • 5. Proteasome Inhibitors in MM R/R: relapsed/refractoryNIH clinical trials. Available at: www.clinicaltrials.gov. Accessed February 2012. Bortezomib Carfilzomib MLN9708 (oral) CEP-18770 Marizomib ONX 0912 (oral) Phase I Phase II/IIb Phase Ib/II Ph III Heme Malig. R/R R/Rw/ Rd Newly Diagnosed Phase I/II Phase I/II Phase I Phase I/II Accelerated FDA approval R/R Full FDA approval R/R FDA approval 1st-line Optimization in combination with other agents 2001 2003 2005 2007 2009 2011 2012
  • 6. Differentiation of Proteasome Inhibitors Compound Phase Compound Type Main Enzymatic Site Specificity Dissociation Kinetics t ½ (min) Route of admin. Bortezomib Approved Peptide boronate b5 110 IV Carfilzomib III Peptide epoxyketone b5 Irreversible IV CEP-18770 I Peptide boronate b5 Slowly reversible IV MLN9708 I Peptide boronate b5 18 IV Oral ONX 0912 I Peptide epoxyketone b5 Irreversible Oral NPI-0052 I b-lactone inhibitor b1, b2, b5 Irreversible IV Dick LR and Fleming PE. Drug Discov Today. 2010;15(5/6):243-249. Demo SD, et al. Cancer Res. 2007;67:6383-6391. Parlati F, et al. Blood. 2009;114(16):3439-3447. Miller CP, et al. Blood. 2007;110(1):267-277. Piva R, et al. Blood. 2008;111(5):2765-2775. Kupperman E, et al. Cancer Res. 2010;70(5):1970-1980. Chauhan D, et al. Blood. 2010;116(23):4906-4915. b1: Caspase-like site; b2: Trypsin-like site; b5: Chymotrypsin-like site. NR, not reported.
  • 7. Carfilzomib Monotherapy in Heavily Pre-Treated MM Patients, Phase IIb Carfilzomib 20 mg/m2 days 1, 2, 8, 9, 15, 16 every 28 days N = 46 MM: Progressive disease > 2 prior therapy lines for relapsed disease including bortezomib, thalidomide or lenalidomide, an alkylating agent, or an anthracycline alone or in combination Carfilzomib Dose escalation to 27 mg/m2 after cycle 1 up to 12 cycles N = 266 003-A0 003-A1 Siegel DS, et al. Blood. 2012;120(14):2817-25 Primary Endpoints: overall response rate (ORR; ≥ partial response) Secondary Endpoints: clinical benefit response rate (≥ minimal response), duration of response (DOR), progression-free survival, overall survival (OS), and safety
  • 8. Carfilzomib Monotherapy in Heavily Pre-Treated MM Patients, Phase IIb Patient Baseline Characteristics N = 266 Median age 63 years (range, 37-87) Median time since diagnosis 5.4 years (range, 0.5-22.3) ECOG < 1 87% Baseline grade 1/2 neuropathy 77% Unfavorable Cytogenetic/FISH Prognostic Markers 28% Median prior lines of therapy > 4 prior lines Median # anti-MM agents PD at study entry Refractory to last therapy Refractory or intolerant to bortezomib & lenalidomide 5 (range, 1-20) 82% 13 (range, 3-45) 100% 95% 80% Siegel DS, et al. Blood. 2012;120(14):2817-25 *** 266 patients evaluable for safety & 257 evaluable for efficacy (9 patients excluded because of missing baseline and/or post-baseline disease assessment)
  • 9. Carfilzomib Monotherapy in Heavily Pre-Treated MM, 003 Trial N ORR % Median DOR (month) Median OS (month) Median PFS (month) Response-Evaluable Patients 257 23.7% 7.8* 15.6 3.7 Bz + len-refractory 169 15.4% 7.8 11.9 NR Bz + len refractory/intolerant 214 20.1 % 7.4 13.2 NR ORR ≥ partial response * Calculated from 61 patients with partial response or better Bz, bortezomib; len, lenalidomide; imid, lenalidomide or thalidomide; mo, month; NR, not reported. Siegel DS, et al. Blood. 2012 ;120(14):2817-25. Unfavorable cytogenetics did not significantly impact response rates or DOR
  • 10. Selected Adverse Events With Carfilzomib in Heavily Pre-Treated MM Patients Adverse Event > Grade 3 N = 266 Hematologic: Anemia Thrombocytopenia Lymphopenia Neutropenia 24% 29% 20% 11% Non-hematologic: Fatigue Dyspnea Upper respiratory tract infection Headache 7.5% 3.4% 4.5% 1.9% Other: Febrile neutropenia Peripheral neuropathy* 0.8% 1.1% Siegel DS, et al. Blood. 2012 ;120(14):2817-25. * Grouped PN all events of neuropathy, peripheral neuropathy, peripheral sensory neuropathy, & peripheral motor neuropathy
  • 11. Carfilzomib in MM Patients Following 1-3 Prior Therapies 004, Phase II 1:1 Carfilzomib Cohort 1 20 mg/m2 (all treatment cycles) Relapsed / Refractory Multiple Myeloma 1-3 Prior Therapies N = 164 Carfilzomib Cohort 2 20 mg/m2 (cycle 1)→27 mg/m2 Bortezomib-treated (n=35) Bortezomib-naïve (n=59) Bortezomib-naïve (n=70) Bortezomib-naïve Bortezomib-treated N 129 35 Median age 65 years 63 years Median # prior therapies 2 3 Carfilzomib: IV, days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles Vij R, et al. Blood. 2012; 119(24):5661-70. Vij R, et al. Br J Haematol. 2012 Sep;158(6):739-48.
  • 12. Carfilzomib Monotherapy MM Patients With 1-3 Prior Therapies Bortezomib-Treated Cohort 1 (20 mg/m2 Carfilzomib) n = 35 ORR 17.1% CBR (> MR) 31.4% Median TTP 4.6 months Median DOR † >10.6 months Median PFS 4.6 months Vij R, et al. Blood. 2012; 119(24):5661-70. Vij R, et al. Br J Haematol. 2012 Sep;158(6):739-48. Bortezomib-naïve Cohort 1 (20 mg/m2) n = 59 Cohort 2 (20→27 mg/m2) n = 67 ORR (CR + VGPR + PR) 42.4% 52.2% CBR 59.3% 64.2% CR 3.4% 1.5% VGPR 13.6% 26.9% Median TTP 8.3 mo Not reached Median DOR* 13.1 mo Not reached Median PFS 8.2 mo Not reached †Precise estimate not determined since 4/6 patients with responses had DOR censored at study close * Calculated for ORR patients
  • 13. Dose Escalation of Carfilzomib • CFZ 30-minute IV infusion on days 1, 2, 8, 9, 15, and 16 + DEX 8 mg premedication (28-day cycle) – Cycle 1, day 1 and 2 20 mg/m2 followed by escalation to 56 mg/m2 • 78% BTZ-refractory; 21% prior alloHSCT • Results (N=34) – ORR (completed 4 cycles or PD prior to 4 cycles): 58% (1 CR, 7 VGPR, 6 PR) – ORR (after 4 cycles): 57% (BTZ-refractory) – ORR (ITT): 50% – Median PFS: 4.6 months – Median OS: not reached (median follow-up 9.6 months) • 35% patients required a dose reduction Lendvai N, et al. Blood. 2012;120. Abstract 947.
  • 14. Dose Escalation of Carfilzomib is Feasible • CFZ 30-minute IV infusion on days 1, 2, 8, 9, 15, and 16 – Cycle 1 (Day 1/2) 20 mg/m2 → escalation to 45 or 56 mg/m2 • DEX 20 mg prior to CFZ on Days 1, 2, 8, 9, 15, and 16 – DEX 40 mg administered on Day 22 • Median 4 lines treatment; 96% patients prior BTZ • Results (in patients completing at least 2 cycles); n=20 – ORR: 55% (VGPR: n=2; PR: n=9); SD: n=6; PD: n=3 – Discontinued due to PD: N=7 (45 mg/m2) – Discontinued due to SAE: N=1 (56 mg/m2) Badros AZ, et al. Blood. 2012;120. Abstract 4036.
  • 15. MLN9708 and Marizomib Agent MTD N Response Toxicity Notes MLN9708 (2x weekly) 2.0 mg/m2 orally 46 13% ≥ PR 2% CR 2% MR 61% SD DLT: rash, nausea, vomiting Common: thrombocytopenia, GI, rash, fatigue ≥ Gr 3: vomiting, DVT, anemia, rash, thrombocytopenia PN: 11% gr 1/2; 0% gr 3 MLN9708 (1x weekly) 2.97 mg/m2 orally 32 6 % ≥ PR 25% SD Marizomib (NPI-0052) 0.4 mg/m2 IV over 60 min 0.5 mg/m2 IV over 120 min 21 15% ≥ MR 55% SD DLT: transient hallucinations, cognitive changes, loss of balance (all reversible) Common: headache, GI, insomnia, dizziness, dyspnea No PN or myelosuppression Richardson PG, et al. ASH Annual Meeting Abstracts. 2011;118(21):301. Berdeja JG, et al. ASH Annual Meeting Abstracts. 2011;118(21):479. Richardson PG, et al. ASH Annual Meeting Abstracts. 2011;118(21):302. MTD, maximum tolerated dose; PR, partial response; CR, complete response; MR, marginal response; SD, stable disease; GI, gastrointestinal; Gr, grade; DVT, deep vein thrombosis; DLT, dose limiting toxicity; PN, peripheral neuropathy; min, minute.
  • 16. Oprozomib (ONX 0912) Phase 1b Study Design Phase 1b open-label dose escalation study Oprozomib BID Days 1 – 5 of a 14 day cycle Starting dose 60 mg BID (doses administered at least 4-6 hours apart) Escalation in 30 mg increments Hematologic malignancies 3 + 3 dose-escalation schema • Primary endpoint: • Safety and tolerability and to determine the maximum tolerated dose • Secondary endpoints • Pharmacokinetic and pharmacodynamic analyses Savona MR, et al. Blood. 2012;120. Abstract 203. Confidential: For Internal Use Only
  • 17. Lenalidomide 15-25 mg/d Myelosuppression Skin rash DVT N N H O O O NH2 Structurally similar, but functionally different both qualitatively and quantitatively N N O O O O Thalidomide 100-200 mg/d Neuropathy Constipation Sedation DVT Pomalidomide 1-4 mg/d N O O N H O O NH2 Pomalidomide
  • 18. MM-002: Phase 2 Study Design • Primary endpoint: PFS • Secondary endpoints: ORR,1,2 safety, DOR, OS • Stratification factors: Age (≤75 vs >75 yrs), prior THAL, and 2 vs >2 prior treatments 19 Aspirin (80–100 mg) or equivalent was mandated for all patients * Patients aged > 75 years had a starting DEX dose of 20 mg/week. Randomization Option to add LoDEX* (40 mg/week) Discontinue and follow up for survival and subsequent treatment Progressive disease Progressive diseasePOM (4 mg days 1–21 of 28-day cycles) + LoDEX* (40 mg/week) POM (4 mg days 1–21 of 28-day cycles) DOR, duration of response; G-CSF, granulocyte colony-stimulating factor; LoDEX, low-dose dexamethasone; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; POM, pomalidomide; RBC, red blood cell; yrs, years. 1. Bladé J, et al. Br J Haematol. 1998;102:1115-23; 2. Richardson PG, et al. N Engl J Med. 2003;348:2609-17. Progressive disease
  • 19. • Patients in both arms were heavily pretreated with a median of 5 prior therapies • Median number of cycles received was 5 (range 1-17) • Disease control (≥SD) was observed in 76% of overall patients Variable Pom Alone (n = 108) Pom + LoDex (n = 113) Hazard Ratio ORR (≥PR) (%) 9 30 - Median DOR (≥PR) , months Not reached 7.4 - ≥MR 25 45 - CR 0 1 - PR 9 29 - MR 16 15 - SD 46 35 - PD 16 6 - Median time to ORR (≥PR), months 2.0 1.9 - Median PFS, months 2.5 3.8 HR=0.73 (P=0.037) Median OS, months 13.6 14.4 HR=0.85 (P=0.449) Pomalidomide Alone or With Low-Dose Dexamethasone in RRMM Efficacy Responses assessed by IRAC review using EBMT criteria. ITT Population. Vij R, et al. ASCO 2012. Abstract 8016. Discrepancies in totals are due to rounding.
  • 20. Len refractory (n = 87) BTZ refractory (n = 82) Len-BTZ refractory (n=69) Len-BTZ refractory + prior transplant (n=47) ORR (≥PR), % 25 29 28 34 ≥MR 41 46 46 53 CR 0 0 0 0 PR 25 29 28 34 MR 16 17 19 19 SD, % 40 33 35 28 PD, % 7 7 7 6 Time to ≥PR, mo 1.9 1.9 1.8 1.6 Median DOR (≥PR), mo 7.0 5.8 6.2 5.7 Median duration of MR only, mo 3.4 3.2 3.0 5.7 OS 14.4 13.4 13.5 Not reached Pomalidomide Alone or With Low-Dose Dexamethasone in RRMM Efficacy in Refractory Patients Vij R, et al. ASCO 2012. Abstract 8016. Patients could be classified under more than one category. Discrepancies in totals are due to rounding.
  • 21. Response to Pomalidomide + Low Dose Dexamethasone According to Age ≤ 65 years N=62 >65 years N=51 Overall N=113 ≥PR, % 31 37 34 ≥MR, % 47 43 45 Median duration of response, mo* 10.1 7.7 8.3 Median PFS, mo 4.7 3.7 4.6 Median OS, mo 19.7 11.8 16.5 *For patients who achieved ≥PR. MR, minimal response; PR, partial response. Jagannath S, et al. Blood. 2012; 120. Abstract 450 (oral presentation). Confidential: For Internal Use Only
  • 22. Mayo Clinic Studies Pomalidomide / Dexamethasone by Previous Therapy Cohort N Pom (mg/day) Prior therapies ORR (%) ≥ MR (%) DOR (mo) PFS (mo) OS (mo) 1: 1-3 prior therapies 60 2 2 (1-3) 65 67 21 13.0 40 mo 2: Len refractory 34 2 4 (1-14) 32 44 9 5.0 27 mo 3: Bor/len refractory 35 2 6 (3-9) 26 49 16 6.5 17 mo 4: Bor/len refractory 35 4 6 (2-11) 29 43 3 3.3 9 mo 5: Len refractory 1-3 prior therapies 60 4 2 (1-5) 38 57 N/A 7.9 N/A Lacy MQ, et al. ASH Annual Meeting Abstracts. 2011;118(21):3963. ORR, overall response rate; MR, marginal response; DOR, duration of response; PFS, progression-free survival; OS, overall survival; len, lenalidomide; bor, bortezomib; Pom, pomalidomide; mo, month; N/A, not applicable.
  • 23. Pomalidomide / Dexamethasone: Administration Schedule 21 / 28 n = 43 28 / 28 n = 41 Total N = 84 ORR 35% 34% 34.5% Stable Disease 44% 51% 48% Median time to 1st response 2.7 mo 1.1 mo 1.8 mo Median DOR 10.5 mo 7.2 mo 8.1 mo ≥ 1 yr in responders 47.5% 36% 37.5% Leleu X. et al. ASH Annual Meeting Abstracts. 2011;118(21):812. MM, multiple myeloma; 21/28, 21 days of 4 mg pomalidomide on a 28-day cycle; 28/28, 28 days of 4 mg pomalidomide on a 28-day cycle; ORR, overall response rate; DOR, duration of response.
  • 24. Pomalidomide plus Low Dose Dex vs. High Dose Dex • Primary endpoint: PFS • Secondary endpoints: safety, OS, ORR (≥PR), DoR, TTP, QoL Continue treatment until PD or unacceptable toxicity Arm B: High dose DEX (n=153) Dexamethasone: 40 mg, D 1-4, 9-12, and 17-20 28-day cycles Arm A: POM – loDEX (n=302) Pomalidomide 4mg/day D1-21 Dexamethasone: 40 mg, D1, 8,15,22 28-day cycles Randomization (N=455) 2:1 Primary refractory or relapsed and refractory MM PD during treatment or within 60 days of last MM treatment (including ≥ cycles LEN or BTZ) Dimopoulos M, et al. Blood. 2012;120. Abstract LBA-6. Patients were stratified by age (≤ 75 vs > 75 years), disease population (refractory vs refractory and relapsed vs refractory and intolerant [intolerant to BTZ only]), and number of prior therapies (2 vs > 2).
  • 25. Pomalidomide + Low Dose Dex vs. High Dose Dex • Patient population – Median number of prior therapies: 5 (range, 1-17) – Refractory to both LEN and BTZ: 72% • Treatment results Characteristic Arm A POM+loDEX Arm B High DEX Treatment duration (median), wks 12.4 8 Remain on study, % 45 25 Deceased, % 25 38 Dimopoulos M, et al. Blood. 2012;120. Abstract LBA-6.
  • 26. Pomalidomide + Low Dose Dex vs. High Dose Dex • Efficacy Characteristic Arm A POM+loDEX Arm B High DEX Progression-free survival, wks 15.7 8* Overall survival, wks Not reached 34* *P<.001 Safety Characteristic, % Arm A POM+loDEX Arm B High DEX Neutropenia 42 15 Thrombocytopenia 21 24 Febrile neutropenia 7 0 Infection 24 23 1% of patients in each group developed neuropathy (Grade 3/4); 1% Arm A developed VTE. Dimopoulos M, et al. Blood. 2012;120. Abstract LBA-6.
  • 27. Immunomodulatory Agents Immunomodulatory Tumor micro-environment CEREBLON BINDING ↓ IRF-4 Direct anti-tumor effects T cell co- stimulation Treg suppression Th1 cytokine NK and NKT cell activation ADCC Induce p21, p27, & p15 cell cycle arrest Alterations in (ERG)-1,2 3 and SPARC ↓ NFkB Inhibit caspase 3,8,9 Anti-angiogenesis Anti-inflammatory ↓ adhesion molecules Anti-osteoclastogenic
  • 28. Tai YT, et al. Cancer Res. 2005;65(13):5898-5906. Hideshima T, et al. Clin Cancer Res. 2005;11(24 Pt 1):8530-8533. Catley L, et al. Blood. 2006;108(10):3441-3449. Blockade of Ubiquitinated Protein Catabolism with HDAC inhibitors HDAC6 HDAC6 HDAC6 Protein Protein aggregates (toxic) Ub 26S Proteasome Ub Ub Ub Aggresome Tubacin LBH, vorinostat Dynein Dynein Microtubule Autophagy Bortezomib Ub Ub Ub Lysosome Ub Ub Ub Ub UbUb Ub Ub Ub
  • 29. Vorinostat / Bortezomib VANTAGE 088, Phase III Bortezomib + Placebo Bortezomib + Vorinostat Multiple Myeloma 1-3 Prior Therapies N = 637 R Bortezomib + Vorinostat Bortezomib + Placebo P ORR 56% 41% < 0.0001 CBR 71% 54% < 0.0001 Median PFS 7.63 mo 6.83 mo < 0.01 Median OS NR 28.1 mo 0.35 Dimopoulos MA, et al. ASH Annual Meeting Abstracts. 2011;118(21):811. ORR, overall response rate; CBR, clinical benefit rate; PFS, progression-free survival; OS, overall survival.
  • 30. PANORAMA 2 Study Design Phase II, Simon 2-stage study in BTZ-refractory MM a Response measured according to modified European Group for Blood and Marrow Transplantation 1998 criteria. CR, complete response; nCR, near CR; DOR, duration of response; OS, overall survival; PD, disease progression; PFS, progression-free survival; PR, partial response; TTP, time to progression; TTR, time to response. • Adult pts • Relapsed and BTZ-refractory MM • ≥ 2 prior lines of therapy • Exposed to IMiDs Panobinostat BTZ Dexamethasone Panobinostat BTZ Dexamethasone Screening Treatment Phase 1 Eight 3-wk cycles Treatment Phase 2 6-wk cycles until PD After 8 cycles, continuation into treatment phase 2 in pts with clinical benefit Primary endpoint: overall response rate (CR + nCR + PR)a Key secondary endpoints: PFS, TTP, OS, MR, TTR, DOR Alsina et al. ASCO 2012. ABSTRACT 8012.
  • 31. Preliminary Response Data Activity in BTZ-refractory MM patients Best confirmed response (confirmed at 6 wks) N = 55 Overall response (CR + nCR + PR), n (%) 17 (31) Complete response – Near complete response 1 (2) Partial response 16 (29) Clinical benefit (CR + nCR + PR + MR), n (%)1-3 28 (51) Minimal response 11 (20) • VGPR observed in 3 pts • Responses were typically observed after 1 to 2 cycles • Stable disease observed in 3 pts, progressive disease in 18 pts; 3 pts not evaluable, 3 pts with unconfirmed response 1. Anderson KC, et al. Leukemia. 2008;22:231-239. 2. Richardson PG, et al. Br J Haematol. 2009;144:895-903. 3. Niesvizky R, et al. Br J Haematol. 2009;143:46-53. Alsina et al. ASCO 2012. ABSTRACT 8012.
  • 32. Current Phase III PANORAMA I Placebo Bortezomib Dexamethasone Panobinostat Bortezomib Dexamethasone Relapsed or Refractory MM R National Institutes of Health. Available at: www.clinicaltrials.gov. Accessed March 2011. Clinical trial ID: NCT01023308 Trial has met accrual goals
  • 33. Perifosine / Bortezomib / Dex N = 73 CR 4% PR 13% MR 19% SD 41% Median PFS 6.4 months Median OS 25 months MM, multiple myeloma; CR, complete response; PR, partial response; MR, marginal response; SD, stable disease; PFS, progression-free survival; OS, overall survival; dex, dexamethasone. AKT Inhibitors Perifosine, Bortezomib, and Dexamethasone Richardson PG, et al. ASH Annual Meeting Abstracts. 2011;118(21):815.  Common grade 1/2 AE • Nausea, diarrhea, fatigue and musculoskeletal pain, upper respiratory infection, anorexia, constipation  Grade 3/4 AE • Thrombocytopenia (23%), neutropenia (15%), anemia (14%), pneumonia (12%), musculoskeletal pain (11%), bleeding (10%)
  • 34. MONOCLONAL ANTIBODIES
  • 35. • CS1 is highly and uniformly expressed on MM cells – Restricted expression on NK cells – Little to no expression on normal tissues • In an MM xenograft mouse model lenalidomide enhanced the anti-tumor effect of elotuzumab Elotuzumab: Anti-CS1 Hsi ED, et al. Clin Cancer Res. 2008;14(9):2775-2784. Tai YT, et al. Blood. 2008;112(4):1329-1337. van Rhee F, et al. Mol Cancer Ther. 2009;8(9):2616-2624. Lonial S, et al. Blood. 2009;114. Abstract 432. MM, multiple myeloma; NK, natural killer.
  • 36. Elotuzumab, Lenalidomide, and Dexamethasone in RR Lenalidomide-naïve MM RRMM Phase 2 (1 – 3 prior therapies) Elotuzumab (10 mg) Lenalidomide Dexamethasone Elotuzumab (20 mg) Lenalidomide Dexamethasone Elotuzumab:10 or 20 mg/kg IV, d1, 8, 15, 22 cycles 1-2; d1, 15 for subsequent cycles Lenalidomide: 25 mg, daily, days 1-21 Dexamethasone: 40 mg, weekly. Premedication Regimen: 30-60 minutes prior to each elotuzumab infusion Methylprednisolone 50 mg IV or dexamethasone 8 mg IV, diphenhydramine 25-50 mg PO or IV (or equivalent), ranitidine 50 mg IV (or equivalent), acetaminophen 650-1000 mg PO Richardson P, et al. Blood. 2012;120. Abstract 202. Moreau P, et al. J Clin Oncol. 2012;30. Abstract 8020.
  • 37. Best Response (IMWG Criteria) Elotuzumab 10 mg/kg n = 36 Elotuzumab 20 mg/kg n = 37 Total N = 73 ORR (≥ PR)1 92% 76% 84% CR / stringent CR2 14% 11% 12% VGPR2 47% 35% 41% Median PFS1 26.9 mo 18.6 mo 25 mo CR, complete response; IMWG, International Myeloma Working Group; ORR, objective response rate; PFS, progression-free survival; PR, partial response; VGPR, very good partial response; len / dex, lenalidomide and dexamethasone. Historical Controls N ORR to len / dex* CR to len / dex MM009, Weber et al.3 177 61% 14% MM010, Dimopoulos et al.4 106 60% 16% *High-dose dex. 1. Richardson P, et al. Blood. 2012;120. Abstract 202 (oral presentation). 2. Moreau P, et al. J Clin Oncol. 2012;30 (15 suppl):8020. 3. Weber DM, et al. N Engl J Med. 2007;357:2133-2142. 4. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132. Elotuzumab, Lenalidomide, Dex in RR Lenalidomide-naïve MM Confidential: For Internal Use Only
  • 38. Siltuximab + BTZ vs BTZ Alone in Relapsed/Refractory MM • Siltuximab: chimeric IgG1k anti–human IL-6 antibody – High affinity, half-life ≈ 3 wks – Tolerability: no DLT up to ≥ 15 mg/kg • Study design: phase II, randomized, double-blind, placebo-controlled – Patients:1-3 previous lines of therapy; no previous BTZ – Treatment – BTZ 1.3 mg/m2, 8 x 42-day cycles on Days 1, 4, 8, 11, 22, 25, 29, 32 followed by maintenance, 4 x 35-day cycles on Days 1, 8, 15, 22 – Placebo or siltuximab 6 mg/kg every 2 wks – Patients progressing had option to end BTZ and start DEX 40 mg on Days 1-4, 9- 12, 17-20 and maintenance therapy at 40 mg on Days 1-4 Orlowski R, et al. ASCO 2012. Abstract 8018.
  • 39. Siltuximab + BTZ Efficacy • Nonsignificant trend toward improved ORR with siltuximab • Nonsignificant, marginal effect on overall PFS • Regional differences in PFS noted – Significant increase in NA and WE (P = .01) vs no effect for rest of world – Patients outside of NA and WE less often pretreated, which was thought to obviate benefit of adding siltuximab • Siltuximab continues to be developed for frontline therapy Orlowski R, et al. ASCO 2012. Abstract 8018.
  • 40. Daratumumab: Phase I/II Study in Relapsed/Refractory MM • Daratumumab: anti-CD38 antibody; kills MM cells via ADCC, CDC, and induction of apoptosis • Patients: relapsed/refractory MM (≥ 2 different therapies), not eligible for ASCT; 3 patients/dosing group • Efficacy based on serum and/or urine M-component analyses • At the highest dose (4 mg/kg), patients had a 49%, 55%, and 64% reduction in serum M-component and a 80%, 89%, and 97% reduction in plasma cells • Adverse events were manageable Plesner T, et al. ASCO 2012. Abstract 8019.
  • 41. Targeting Myeloma Cells in the Bone Marrow Microenvironment Bone marrow Targeting MM cell stromal cells Targeting bone marrow milieu Proteosome Inhibitors (CEP 18770, NPI 0052, MLN 2238) Other targets FGFR3 IGF-1 Hsp-90 DAC PI-3-Akt-Mtor, bcl-2 CDK IKK /p38MAPK Aurora kinases Met HGF Monoclonal antibodies( CD 138, CD40, CD56,1L-6, TRAIL-R)
  • 42. •Massively parallel sequencing of 38 tumor genomes and their comparison to matched normal DNAs. •Mutation of : •genes involved in protein translation (seen in nearly half of the patients), •genes involved in histone methylation, •genes involved in blood coagulation. •in 11 members of the NF-kB pathway •kinase BRAF in 4%of patients, 4 M A R C H 2 0 1 1 | VO L 4 7 1 | N AT U R E | 4 6 7
  • 43. Key Genetic Changes
  • 44. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides Egan et al Blood. 2012;120(5):1060-1066)
  • 45. Clonal competition with alternating dominance in multiple myeloma ( Keats et al. Blood. 2012;120(5):1067-1076)
  • 46. 47 The Goal: CureTumorVolume→ Time → Ineffective treatment High-Dose Therapy Alkylators Dexamethasone Goal of newer therapy options Limit of detection