To Maintain or Not to Maintain? Immunomodulators vs PIs Yes: Proteasome Inhibitors

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1 To Maintain or Not to Maintain? Immunomodulators vs PIs Yes: Proteasome Inhibitors James Berenson, MD Institute for Myeloma and Bone Cancer Research West Hollywood, CA

2 Financial Disclosures Takeda, Celgene and Onyx/Amgen Honoraria Consulting Expert testimony Research grants

3 Maintenance Therapy in Myeloma Goals Reduce the risk of relapse Extend PFS and OS Maintain response achieved following a new treatment with administration of drugs for a prolonged time period Therapy must be Convenient Safe and well tolerated LONGTERM NOT prevent use or reduce efficacy of other future treatments

4 Lenalidomide w/ or w/o Steroid Maintenance Therapy Studyher No. Dose of Len and steroids EFS/PFS OS McCarthy et al. 460 IT 10 mg 3-y PFS: 66% vs 39%; EFS 43 vs 27 mo (p<0.001) Attal et al. 614 IT 10 mg PFS: 41 vs 23 mo (p<0.001); EFS 40 vs 23 mo (p<0.001) Gay et al. NIT=202 IT= mg d1-21 every 4 weeks Combining NIT and IT groups: PFS 42 vs 18 mo (p<0.001) 85 vs 77% (p=0.028) 74 vs 76% (p=0.7) 5- OS: 68 vs 67% (NS) Palumbo et al. NIT= mg d1-21 every 4 weeks w/ or w/o IT- intensive therapy NIT- non-intensive therapy prednisone 50 mg qod Combining NIT and IT groups: 3-y PFS: LP 60% vs L 38% mo (p<0.001) Combining NIT and IT groups: 3-y OS: ND

5 Randomization 1:1:1 PD or unacceptable toxicity PD, OS, and subsequent anti-mm Tx FIRST: Lenalidomide/Dexamethasone vs MPT in NDMM SCT-Ineligible Patients Arm A Continuous Rd Active treatment + PFS follow-up phase Len + LoDex Continuously Lenalidomide 25 mg Days 1-21/28 LoDex 40 mg Days 1, 8, 15, 22/28 Phase III N = 1623 Arm B Rd18 Len + LoDex 18 cycles (72 wks) Lenalidomide 25 mg Days 1-21/28 LoDex 40 mg Days 1, 8, 15, 22/28 Arm C MPT Mel + Pred + Thal 12 cycles [2] (72 wks) Melphalan 0.25 mg/kg Days 1-4/42 Prednisone 2 mg/kg Days 1-4/42 Thalidomide 200 mg Days 1-42/42 Pts > 75 yrs: LoDex 20 mg Days 1, 8, 15, 22/28; Thal [3] 100 mg Days 1-42/42; Mel [3] 0.2 mg/kg Days 1-4. Stratification: age, country, and ISS stage. Benboubker et al. N Engl J Med 2014; 371:

6 72 wks Patients (%) FIRST Trial: Progression-Free Survival Median PFS Rd (n = 535) 25.5 mos Rd18 (n = 541) 20.7 mos MPT (n = 547) 21.2 mos HR: Rd vs MPT: 0.72 (P =.00006) Rd vs Rd18: 0.70 (P =.00001) Rd18 vs MPT: 1.03 (P =.70349) Mos Benboubker et al. N Engl J Med 2014; 371:

7 FIRST Trial: Conclusions PFS significantly superior with continuous Rd therapy vs MPT (HR: 0.72; P =.00006) and Rd18 (HR: 0.70; P =.00001) Planned interim 4-yr OS Continuous Rd 59% vs MPT: 51% (HR: 0.78; P =.02) vs Rd18: 56% (HR: 0.90; P =.31) Safety profile of hematologic & nonhematologic AEs similar across all arms Neutropenia higher in MPT than Rd; infection higher in Rd vs MPT Benboubker et al. N Engl J Med 2014; 371:

8 Tandem Autologous Transplant and Maintenance LEN Therapy in MM Randomized, phase 3 trial for newly diagnosed pts N=273 Induction therapy for 4 cycles LEN 25 mg po qd d1-21 Dex 40 mg d1, 8, 15, and 22 Randomized for consolidation to one of four arms Oral melphalan, prednisone, and LEN x 6 cycles w/o maintenance Rx Oral melphalan, prednisone, and LEN x 6 cycles w/ LEN maintenance RX Tandem autotransplant w/o maintenance RX Tandem autotransplant w/ LEN maintenance Rx Palumbo A et al. N Engl J Med 2014

9 Survival From the Time of Diagnosis No difference between the arms Palumbo et al. N Engl J Med, 2014

10 Survival From the Start of Maintenance Therapy P<0.001 P=0.14 Palumbo et al. N Engl J Med, 2014

11 The Role of IMiDs (LEN and THAL) in Maintenance Therapy for MM Patients Meta-analysis of 7730 MM pts from 18 Phase 3 trials PFS improved (HR 0.62; P = ) In both transplant and non-transplant pts Also when stratified for both LEN and THAL-treated pts However, no OS benefit (HR= 0.93; P = 0.08) No benefit in either transplant or non-transplant pts No improvement for either LEN or THAL-treated groups Grade 3/4 adverse events increased thromboembolic events, PN, neutropenia, and infection Wang et al. JNCI, in press

12 The Role of Lenalidomide in Maintenance Therapy for MM Patients Fairly consistent results showing improvement in PFS However, inconsistent results showing improvement in OS In fact, most studies show no improvement in OS except McCarthy trial which was in the transplant setting Meta analysis shows no OS advantage No studies show using lenalidomide for patients responding to non-imid- containing regimens is effective in terms of PFS or OS!!

13 The Role of Bortezomib in Maintenance Therapy for MM Patients Few randomized trials Inadequate trial design to determine the impact of bortezomib itself in the maintenance setting Induction w/ bortezomib followed by maintenance bortezomib in one arm and no bortezomib in either induction or maintenance therapy in the other arm Different induction regimens Maintenance regimens w/ both arms containing bortezomib w/ different additional drugs w/ both arms containing another drug w/ or w/o bortezomib

14 Bortezomib as Maintenance Therapy in MM: VMPT-VT vs VMP in Newly Diagnosed Elderly Pts (GIMEMA) Pts (n=511): >65 yrs old; median age 71 yrs VMPT + VT maintenance 2 different VMP alone 9 x 5-wk cycles:* Bortezomib Melphalan Prednisone Thalidomide induction regimens 9 x 5-wk cycles:* Bortezomib Melphalan Prednisone Maintenance (until relapse): Bortezomib (1.3 mg/m 2 d 1, 15) + Thalidomide (50 mg continuously) No maintenance *Protocol amendment: from twice-wkly bortezomib dosing (d 1,4,8,11,22,25,29,32) to once-wkly bortezomib dosing (d 1,8,15,22); 61 pts in VMP arm and 70 pts in VMPT arm received twice-wkly bortezomib dosing. Palumbo et al. J Clin Oncol 2014; 32:

15 Efficacy Data Median follow up: 54 mos 3-yr PFS Median PFS VMPT-VT 51% 35.3 mos VMP 32% 24.8 mos P < yr TNT Median TNT VMPT- VT 70% 46.6 mos VMP 51% 27.8 mos P < Palumbo et al. J Clin Oncol 2014; 32:

16 Survival and Time to Next Treatment According to Treatment Group OS OSpR - Palumbo et al. J Clin Oncol 2014;32:

17 Adverse Events and Treatment Discontinuation Grade 3/4 Adverse events Treatment discontinuation VMPT-VT VMP VMPT-VT VMP Neutropenia 38% 28% Thrombocytopenia 22% 20% Anemia 10% 10% PN 8% 5% Infections 13% 9% Cardiologic 10% 6% DVT/PE 5% 2% Discontinuation rate due to AEs yrs 27% 16% >75 yrs 37% 18% Median cumulative bortezomib dose yrs 61mg/m 2 42mg/m 2 >75 yrs 31mg/m 2 37mg/m 2 Palumbo et al. J Clin Oncol 2014; 32:

18 VMPT-VT vs VMP: Impact of Maintenance Therapy Landmark analysis after 9 cycles 52% reduced risk of progression w/ VMPT-VT (HR 0.48, P<0.0001) Irrespective of response (CR or PR) In pts <75 yrs old, but not 75 yrs Prognostic factors: response, age, ISS, cytogenetic abnormalities Grade 3/4 AE s during maintenance VMPT-VT Hematologic 2% DVT 1% Sensory neuropathy 6% Infection 1% Cardiologic 1% Discont. due to AE 11% Palumbo et al. J Clin Oncol 2014; 32:

19 Impact of Maintenance Therapy VMPT w/ VT maintenance therapy vs VMP w/o maintenance therapy? Palumbo et al. J Clin Oncol 2014; 32:

20 Phase III PETHEMA/GEM Trial: Bortezomib as Maintenance Therapy in Previously Untreated MM Endpoints: Primary: PFS; Secondary: response rate, OS, safety Patients: 386 pts <65 yrs of age with previously untreated MM randomized to maintenance therapy; median age yrs across arms; 53 59% ISS stage II/III across arms Dose and schedule: Induction: thalidomide/dex (6 cycles) vs VTD (6 cycles) vs VBMCP/VBAD (4 cycles) + bortezomib (2 cycles); followed by ASCT with MEL-200; then second randomization to: Maintenance: 1) bortezomib 1.3 mg/m 2 days 1, 4, 8, 11 every 3 mos + thalidomide 100 mg/day (VT) vs 2) thalidomide 100 mg/day vs 3) interferon-α2b 3 MU 3 times/week; for 3 yrs Rosinol et al. Blood 2012;120:

21 Phase III PETHEMA/GEM Trial: Bortezomib as Maintenance Therapy in Previously Untreated MM Response before and after maintenance therapy Response before maintenance, % Maintenance VT (n=89) Maintenance thalidomide (n=87) Maintenance interferon (n=90) CR VGPR PR Response improvement with maintenance, % CR post-maintenance Increase in CR Rosinol et al. Blood 2012;120:

22 Phase III PETHEMA/GEM trial: Bortezomib as Maintenance Therapy for Previously Untreated MM PFS and OS Outcomes Median follow-up of 34.9 months from onset of maintenance therapy PFS: addition of bortezomib to thalidomide maintenance resulted in significantly longer PFS vs thalidomide or interferon (p=0.0009) OS: No difference between arms (p=0.47) Bortezomib maintenance conferred a significant PFS advantage in pts with low-risk (p=0.002) but not high-risk (p=0.5) cytogenetics Rosinol et al. Blood 2012;120:

23 Phase III: VMP vs VTP in Newly Diagnosed Elderly Pts with MM (PETHEMA/GEM Study) Pts (n=260), >65 yrs old (median age 73 yrs) Multicenter, two-stage randomized trial Randomization step 1 Induction (max. 6 cycles) One 6-wk cycle, bortezomib 2x wkly Five 5-wk cycles, bortezomib 1x wkly VMP vs VTP Maintenance (up to 3 yrs) Randomization step 2 Bortezomib: 1.3 mg/m 2 (d 1, 4, 8, 11), every 3 mos + thal: 50 mg daily or pred: 50 mg every 48 hrs VT vs VP VT vs VP n=47 n=44 n=44 n=43 Mateos et al. Lancet Oncol 2010; 11(10): ; Mateos et al. Blood 2012; 120:

24 Response Data Response to induction VMP (n=130) VTP (n=130) ORR 80% 81% CR IF- 20% 28% CR IF+ 12% 8% PR 48% 45% Response to maintenance therapy VT (n=91) VP (n=87) ORR 95% 97% CR IF- 46% 39% CR IF+ 10% 11% PR 39% 47% Comparable efficacy with VMP and VTP Both maintenance regimens increased CR rate Mateos et al. Lancet Oncol 2010; 11(10): ; Mateos et al. Blood 2012; 120:

25 PFS and OS No significant difference in PFS and OS between VMP and VTP groups and not significantly different for VT or VP maintenance PFS OS VMP 3-yr OS 74% VMP 34 mos VTP 3-yr OS 65% p=0.1 VTP 25 mos p=0.3 Type of maintenance therapy (VT or VP) also did not impact outcome for either high-risk or standdard-risk patients Mateos et al. Lancet Oncol 2010; 11(10):

26 Bortezomib as Maintenance Therapy for MM Patients Responding to Salvage Therapy Dose and schedule Bortezomib 1.3 mg/m2 d1, 15 Dexamethasone 20 mg d1, 2, 15, and 16 Results (n=49) Improved responses (4 CR; 3 VGPR) TTP: 16 mo 1-y PFS and OS: 61% and 79%, respectively Safety Well-tolerated 3 pts developed grade 2 PN w/ dose reduction Benevelo et al. Cancer 2011; 117:

27 Ixazomib Oral Proteasome Inhibitors Phase 1/2 study 1 in untreated MM pts established 4 mg fixed dose w/ d1, 8 15 w/ lenalidomide and dexamethasone for up to 12 cycles of induction Maintenance therapy w/ ixazomib alone Results (N=65) 92% ORR (> VGPR 58%; CR 27%) During maintenance therapy, 5 of 25 (20%) improved depth of response Oprozomib Poor tolerability- undergoing reformulation Kumar et al. Lancet Oncology 2014; 115:

28 Lenalidomide maintenance therapy w/ or w/o steroids Is well-tolerated improves PFS but not OS among MM patients (also w/ thalidomide) and in both the transplant and non-transplant settings no data showing activity after induction w/ other drugs Bortezomib-responding patients tolerate its long-term use as maintenance therapy Responses deepen during maintenance therapy However, its efficacy in term of PFS or OS has not been clearly demonstrated due to trial design limitations Oral PIs are in clinical development Convenience makes them more ideal as maintenance drugs ongoing trials w/ ixazomib Summary

29 How I Use Maintenance Therapy Maintenance both in frontline & salvage setting Discontinue chemotherapy If patient is on IMiD, PI and/or steroid-containing regimen, continue drugs until disease progression or intolerability (DO NOT START DRUGS THAT WERE NOT PART OF TREATMENT REGIMEN) No change in dose or schedule of IMiD PI is administered qow Bortezomib 1.3 mg/m2 d1, 15 Carfilzomib 27 mg/m2 d1, 2, 15, and 16 Steroids Continue same dose intensity/month (160 mg DEX) Methylprednislone 40 mg po qod Dex 40 mg IV qow w/ methylprednisolone 20 mg po qod