Plasma cells in bone marrow. Treatment of Multiple Myeloma Novel Approaches. Approach to Progressive MM. Approach to Initial Therapy

Transcription

1 Treatment of Multiple Myeloma ovel Approaches Plasma cells in bone marrow Donna E. Reece, M.D. Princess Margaret Hospital Toronto, 21 ctober 25 Adhesion Molecules and Growth Factors in Multiple Myeloma Algorithm for Cytogenetic Analysis for MM at PMH Conventional cytogenetics steoclast Plasma cells ICAM-1 VCAM-1 IL-6 TFα VEGF Deletion q1 or other change o dividing cells or normal FISH for t(11;14) VEGF βfgf Bone marrow blood vessels Positive egative Molecular testing for t(4;14) Approach to Initial Therapy Approach to Progressive MM Eligible for transplantation ot eligible for transplantation After ASCT TTP o prior ASCT TTP High-dose dexamethasone-based therapy Melphalan + prednisone 2 years < 2 years < 1 year 1 year Stem cell collection ASCT +/- Maintenance Plateau Second ASCT Thalidomide +/- steroids Dexamethasone Cyclophosphamide + prednisone Velcade Clinical trial Repeat M + P 1

2 ovel Agents in Myeloma Thalidomide in Multiple Myeloma Agents Thalidomide Bortezomib (Velcade) Lenalidomide (Revlimid) Settings Relapsed/refratory disease Part of initial therapy Maintenance First novel agent for myeloma Has apoptotic, anti-angiogenic and immunomodulatory effects In relapsed/refractory disease, response rate ~% as single agent and ~5% with dexamethasone Toxicities: sedation, constipation, rash, peripheral neuropathy and DVT Thalidomide Trials in MM Phase III Trial: Thal/Dex vs Dex in Patients With ewly Diagnosed MM ewly diagnosed patients Thal + Dex versus Dex before ASCT Combinations before ASCT MP + thal versus MP in newly diagnosed elderly patients Thalidomide as maintenance therapy after ASCT =2 ewly diagnosed MM R A D M I Z A T I Thal + Dex 4 cycles or PD n=1 Dex 4 cycles or PD n=14 Primary End Point Best response at 4 mo (ITT) *Treatment beyond 4 cycles was permitted at physician discretion Cycle duration=1 month ff Study for SCT Continue Therapy* Rajkumar SV et al. Blood. 24;14:98a Thal/Dex vs Dex in ewly Diagnosed MM Results after 4 Cycles Thal/Dex vs Dex in ewly Diagnosed MM Grade or 4 Toxicities utcome Best response (ECG) * Best response, corr Thal/Dex (n=1) (%) Dex (n=11) (%) Toxicity on-heme DVT Thal/Dex (n=1) (%) Dex (n=11) (%) 4 Median time to response (months) CR (%) Disease progression 1.1 (. 4.1) 1.1 (. 2.9) 5 Rash Bradycardia europathy Successful harvest 91 1 Any >/= gr Rajkumar SV et al. Blood. 24;14:98a Rajkumar SV et al. Blood. 24;14:98a 2

3 ew Trials of Thalidomide in ewly Diagnosed Before ASCT Thal/Dex vs Dex Combinations Velcade, thalidomide and Dex (VTD) Pegylated liposomal doxorubicin + velcade + low dose Dex + thalidomide (Doxil + VdT) VAD + thalidomide (VAD-thal) VTD-PACE in Total Therapy Cyclophosphamide + thalidomide + Dex (CTD) Adriamycin + dex (AD) followed by thalidomide + Dex (DT) Thalidomide With Melphalan and Prednisone in Elderly Patients With MM ewly diagnosed, > 65 years (n=1) Phase III Randomized Controlled Trial MPT Arm Melphalan,, 4 mg/m 2 ( days/month) Prednisone, 4 mg/m 2 ( days/month) Thalidomide, 1 mg/d (continuously)* (n=89) 6 courses MP Arm Melphalan, 4 mg/m 2 ( days per month) Prednisone, 4 mg/m 2 ( days per month) (n=88) *Thalidomide dose reduced to 5% if grade 2 toxicity; enoxaparin prophylaxis added to protocol December 2 Palumbo A et al. Blood. 24;14:6a [abstract 2] Thalidomide With Melphalan and Prednisone in Elderly MM Patients Thromboembolism in MPT Treated Elderly Patients Reduced With Prophylaxis Response CR + ncr PR 5% - 4% 5% - 99% Total MPT, % 28* MP, % Adverse Event DVT* PE Incidence, % o LMWH With LMWH 1 (n= 61) (n= 28) Median EFS, mo 25.2* 1. Arterial occlusion 1.6. *p <.1 Median follow-up, 1.6 months * p=. 1 Enoxaparin,.4 ml/day for 4 months Palumbo A et al. Blood. 24;14:6a [abstract 2] Palumbo A et al. Blood. 24;14::6a [abstract 2] MP vs MP-Thal and MP vs Mel1 in ewly Diagnosed MM Aged 65 5 Years IFM 99-6 Trial Design MP vs MP-Thal and MP vs Mel 1 x2 in ewly Diagnosed MM Aged 65 5 Years IFM 99-6 Trial Response to Treatment* ewly diagnosed MM; aged 65 5 years (=5) 2 2 MP Arm Standard MP. 12 courses at 6-wk intervals MP-Thal Arm MP as Arm 1 + Thal at MTD but 4 mg/day, stopped at end of MP MEL1 Arm VADx2; cyclophosphamide g/m 2 ; Melphalan, 1 mg/m 2 1 o Endpoint: verall survival Category of Response Complete response (%) 9% (%) 5% (%) % of Patients at 12 Months MP (n= 15) 8 4 MP-Thal (n= 95) MEL1 x2 (n= 92) All patients received clodronate Facon T et al. Blood. 24;14:6a [abstract 26] *2 nd planned interim analysis; median follow-up time = 28 months Facon T et al. Blood. 24;14(part 1):6a [abstract 26]

4 IFM 99-6 Trial: Adverse Events verview Maintenance With Thalidomide After ASCT for MM Incidence of DVT*, n (% of Patients) MP (n= 15) 8 (5%) MP-Thal (n= 99) 12 (12%) MEL 1 x2 (n= 92) 6 (6.5%) o toxic deaths related to DVT MP-Thal arm: DVT at median mos (range.1-1 mos) MP-Thal arm: 6% peripheral neuropathy Patients with stage 1, 2, or MM <65 yr old o prior therapy or 1 risk factor (n=8) VAD regimen (vincristine, doxorubicin, and dexamethasone) 4 cycles Melphalan, 14 mg/m 2, and ASCT Month Randomized if no progression n=588 o maintenance therapy n=19 Melphalan, 2 mg/m 2 Pamidronate, 9 mg/mo and ASCT n=194 Pamidronate, 9 mg/mo Thalidomide, 1 mg/day n=19 Hematologic/other adverse events as expected in each arm Patients with history of DVT were excluded from trial Facon T et al. Blood. 24;14(part 1):6a [abstract 26] Attal M et al. Blood. 24;14(part 1):155a [abstract 55] Maintenance With Thalidomide After ASCT for MM Preliminary Results Velcade (Bortezomib; PSI 41) Proteasome Inhibition Endpoint Patients, n Progression, % Median PFS, mo -yr PFS, % Bone events, % -yr risk of bone events, % o maintenance Pam Thal/Pam > p value α β 26S Proteasome 19S Cap Degrades ubiquitinated proteins Proteolysis is ATP-dependent 2S Subunit 19S Cap Cross section of β ring Chymo- tryptic Site β1 Post- β2 Tryptic Glutamyl Site Site β β6 β5 β4 β Chymotryptic site is ratelimiting in protein degradation Attal M et al. Blood. 24:14(part 1):155a [abstract 55] iquitin-proteasome Pathway Velcade (Bortezomib) H 2 Lys Protein Substrate = ubiquitin Lys = lysine H Lys Poly ubiquitinated Protein 26S Proteasome Complex Degraded proteins Dipeptidyl boronic acid H H H B H β6 Chymo- tryptic β5 Site Cross section of β ring β2 β1 Post- Tryptic Glutamyl Site Site β Bortezomib β4 β (reversible inhibitor of chymotryptic active site of proteasome B subunit) Millennium Pharmaceuticals, Inc., 2. 4

5 MM cells BMSC FAS Apoptosis Inhibitors (IAP, FLICE) Caspases 8, Block activation VELCADE Adhesion Cytokine Angiogenesis PI K antiapoptotic Increased Apoptosis TFα IGF-I VEGF IL-6 ΙκB/FκB X X X IL-6, VEGF MAPK proliferation Decreased Proliferation BM Vessels Intracellular level Inhibition DA-repair effectors (=22) 1% 9% 8% % 6% 5% 4% % 2% 1% % SUMMIT: Prior Therapy 99% 92% 8% 81% Steroids Akylating Agents Thalidomide Anthracyclines Stem Cell Transplant 64% 6 median lines of prior therapy 92% of patients received at least of the drug therapies listed (excluding stem cell transplant) 1. Millennium Pharmaceuticals, Inc., 24. SUMMIT: Response Rates with Bortezomib (=19)* 25% 2% 15% 1% 5% 4% 6% 5% 18% % 24% 5% overall response (CR+PR+MR) 2% CR+PR 24% stable disease (SD) 59% of patients SD or better SUMMIT: Response Rates Independent of the Types of Prior Therapy 1 Steroids Alkylators Anthracyclines Thalidomide Stem-cell Transplant Percent response (CR+PR) to bortezomib alone by types of prior therapy in SUMMIT trial 28% 2% 29% % % % CR ear CR PR MR SD *f 22 patients, 19 were evaluable for response and duration of response ear CR met all the criteria for a CR, with the exception of detectable M protein by immunofixation umbers rounded to nearest integer. Richardson et al. Engl J Med. 2;48: % 5% 1% 15% 2% 25% % 5% CR+PR = 2% (9% CI = (22.2,.2) ) 1. Millennium Pharmaceuticals, Inc., 2 SUMMIT: Updated Time-to-Progression Median TTP: overall ~ mo, responders ~1.9 mo, nonresponders ~1. mo Bortezomib Trials in MM Velcade versus Dex in relapsed MM (APEX study) Velcade combinations as part of initial therapy Richardson et al. EHA 24; Abstract 4. 5

6 APEX: Study Design International, randomized, open-label study in pts with relapsed or refractory MM 669 pts enrolled at 94 centers Endpoints Primary: time to progression (TTP) Secondary: survival, response rate (RR) and duration, time to skeletal events (TSE), incidence of G infection, safety Exploratory: quality of life (QL), pharmacogenomics Companion crossover study (M411-4): bortezomib for pts progressing on Dex Bortezomib 8 cycles APEX: Treatment Plan 1. mg/m 2 IV push D 1, 4, 8, 11 q -wk cycle 1. mg/m 2 IV push D 1, 8, 15, 22 q 5-wk cycle Randomization Induction Dexamethasone 2 treatment days 28 treatment days 4 cycles 4 mg P D 1 4, 9 12, 1 2 q 5-wk cycle cycles Maintenance 5 cycles 4 mg P D 1 4 q 4-wk cycle Richardson et al. ASH 24; Abstract 6.5. Richardson et al. ASH 24; Abstract 6.5. Adverse Events (All Pts) Adverse events G Adverse events G4 Serious adverse events Discontinuation due to adverse events n-study deaths Bortezomib (n = 1) % Dexamethasone (n = 2) % Richardson et al. ASH 24; Abstract

7 Treatment-Emergent Grade Adverse Events APEX Endpoints in Second Line Patients Hyperglycemia Bortezomib (n = 1) Dexamethasone (n = 2) CR + ear CR Dexamethasone 4% Pneumonia Dyspnea Fatigue Diarrhea Peripheral neuropathy Anemia eutropenia Thrombocytopenia Patients, % Richardson et al. ASH 24; Abstract 6.5. CR + PR VELCADE Dexamethasone VELCADE 12% % Responding Patients 4% of patients relapsed/refractory after 1 prior therapy (n= 251) Statistically significant survival benefit with VELCADE in second line patients Richardson et al. ASH 24; Abstract % 45% Management of Thrombocytopenia 4% overall incidence 1 of thrombocytopenia 2% Grade (1-5 x 1 9 /L) % Grade 4 (< 1 x 1 9 /L) Mean Platelet Count (1 9 /L) Platelet Recovery ver Time (=22). Time Platelet nadir is ~4% of baseline Del(1) in Multiple Myeloma APEX: Matched-Pairs Analysis Del(1) in Multiple Myeloma APEX: Matched-Pairs Analysis Del(1) is Associated with Poor Survival in Dex-Treated Patients Del(1) Has o Impact on Survival in Bortezomib-Treated Patients Proportion of Patients HR (95% CI) = 9.1 (1.88, 46.6); P =.2 o deletion (n = 24) Del(1) (n = 12) Proportion of Patients HR (95% CI) = 1.61 (.5,.46); P =.9 Del(1) (n = 9) o deletion (n = 1) Time, d Time, d Jagannath et al. ASC 25; ral Abstract 651 Jagannath et al. ASC 25; ral Abstract 651

8 Velcade Regimens Before ASCT Study Jagannath Popat Harousseau /Eval 2/2 21/21 11/9 Regimen Velcade +/- DEX PAD Velcade + Adria (2 dose levels) + DEX Velcade + DEX CR/nCR % 29% 22% 1% CR+PR 8% 95% 1% 8% Alexanian Barlogie Uy rlowski /19 VTD Velcade + thal + DEX Total Therapy T VTD-PACE Velcade after thal or anthracycline Velcade + Doxil A A % 5% 8% A 89% 8% Lenalidomide (CC-51; Revlimid ) More potent immunomodulator than thalidomide Fewer side effects: no significant constipation, neuropathy, or sedation DVT noted ot teratogenic H Lenalidomide (Revlimid) Trials Lenalidomide + Dex versus Dex alone in relapsed patients Pilot study of lenalidomide + Dex in newly diagnosed patients thers H 2 Lenalidomide + Dex vs Placebo + Dex in Relapsed/Refractory MM Interim Analysis Relapsed/refractory MM Lenalidomide 25 mg/day P, Days Dexamethasone 4 mg/day P, Days 1 4, 9 12, (n=1) Placebo 25 mg/day P, Days Dexamethasone 4 mg/day P, Days 1 4, 9 12, utcome TTP (mos) Response rate CR Lenalidomide + Dex (n=1) YR 51% 19% Placebo + Dex (n=1) 5 2% 4% (n=1) Endpoints: TTP, Response Rate, verall Survival Weber D et al.haemotologica. 25;99(s1):155a 8

9 Lenalidomide (CC-51) and Dexamethasone for ewly Diagnosed MM Lenalidomide (CC-51) and Dexamethasone for ewly Diagnosed MM ewly diagnosed MM (n=) Lenalidomide 25 mg/day Days 1 21 Dex 4 mg Days 1 4, 9 12, 1 2 Aspirin daily for DVT prophylaxis SCT Planned; off treatment CR/PR/Stable at 4 months o SCT; remain on treatment at MD discretion Progressive disease; off treatment 8% (25/) achieved PR on intent-totreat basis Combination appears active Final analysis awaited to confirm results Randomized phase III trials of lenalidomide/ Dex in newly diagnosed MM are ongoing (SWG S22, ECG E4A) Rajkumar SV et al. Blood. 24;14(part 1):98a [abstract 1] Rajkumar SV et al. Blood. 24;14(part 1):98a [abstract 1] Lenalidomide and Dex: Adverse Events Profile Hematologic toxicity, % Anemia eutropenia Lymphopenia on-hematologic toxicity, % DVT (all received prophylaxis) Constipation Sedation Rash europathy Anxiety Rajkumar SV et al. Blood. 24;14(part 1):98a [abstract 1] Grade 1/2 1 1 Grade 1/2 1 Grade /4 Grade ovel Agents in Multiple Myeloma Summary/Conclusions Effective in relapsed/refractory patients Combinations can produce high response rates (up to 89-9%) in newly diagnosed patients CR/near CR rates up to 2-% Toxicities profile different from conventional chemotherapy, but potentially manageable (DVT, peripheral neuropathy) ovel Agents as Part of Initial Therapy in MM: Unanswered Questions Will the improved response rates translate into better overall survival? Should novel agents/combinations be used upfront or reserved for relapse? Will aggressive regimens replace ASCT? Will they prove to be necessary as maintenance therapy after ASCT? ngoing/pending PMH Multiple Myeloma Trials ewly diagnosed myeloma Dex + Velcade + Doxil (DBd) Velcade in t(4;14) myeloma Relapsed disease Cyclophosphamide + prednisone + Velcade Revlimid + Dex (expanded access) BCL inhibitor (GeminX) Irreversible proteasome inhibitor Histone deacetylase inhibitor (SAHA) 9

10 Thalidomide (Thalomid ) ral immunomodulator Derivative of glutamic acid Anti-angiogenic and apoptotic properties H Thal/Dex vs Dex in ewly Diagnosed MM Conclusions Addition of thal improves depth of response compared with Dex alone Significant increases in non-heme toxicity and DVT DVT might be managed by prophylactic anticoagulation Thal + Dex is a reasonable alternative to VAD or Dex alone Rajkumar SV et al. Blood. 24;14:98a Del(1) in Multiple Myeloma APEX: Matched-Pairs Analysis Del(1) in Multiple Myeloma APEX: Matched-Pairs Analysis Del(1) is Associated with Poor Survival in Dex-Treated Patients Del(1) Has o Impact on Survival in Bortezomib-Treated Patients Proportion of Patients HR (95% CI) = 9.1 (1.88, 46.6); P =.2 o deletion (n = 24) Del(1) (n = 12) Proportion of Patients HR (95% CI) = 1.61 (.5,.46); P =.9 Del(1) (n = 9) o deletion (n = 1) Time, d Time, d Jagannath et al. ASC 25; ral Abstract 651 Jagannath et al. ASC 25; ral Abstract 651 1

11 APEX: Final Results (=669) Time to Progression: 8% improvement on bortezomib arm (p<.1) Median TTP: Bortezomib 6.2 mos, Dex.5 mos Survival: verall survival superior on bortezomib arm (p<.1) including patients on dex who crossed over to bortezomib 1 year survival: bortezomib 8%, Dex 65% 41% decreased risk of death at year on bortezomib arm (p=.5) Richardson et al. ASH 24; Abstract % 2% 15% 1% 5% % 4% SUMMIT Response Rates to VELCADE * Alone CR RR = 5% 6% ear CR 18% PR % MR 24% SD 19 evaluable patients 5% overall response (CR+PR+MR) 2% CR+PR 24% SD 59% of patients SD or better Assessed by Independent Review Committee 1 Richardson P et al. Engl J Med. 2;48: ovel Agents in Myeloma Thalidomide, Bortezomib (Velcade ), and Lenalidomide (Revlimid ) In relapsed/refractory disease As part of first line therapy Before ASCT In patients ineligible for ASCT As maintenance therapy after ASCT 11