Upfront Therapy in Myeloma Sundar Jagannath, MD Professor of Medicine New York Medical College St Vincent’s Comprehensive Cancer Center New York, New York

clinicaloptions.com/oncology Upfront Therapy in Myeloma Upfront Therapy: Old Paradigm  Induction chemotherapy choice depends on transplant status –Transplant candidates induced with nonalkylating agents –Nontransplant candidates treated with alkylating agents  Depth of response to induction therapy –Not critical in transplant –CR, PR, or SD acceptable Induction Chemotherapy Transplant Nonalkylating Agent No Transplant Alkylating Agent Kyle RA, et al. N Engl J Med. 2004;351:

clinicaloptions.com/oncology Upfront Therapy in Myeloma Upfront Therapy: New Paradigm  Start induction therapy with novel agents  Aim for CR or PR –May improve efficacy in nontransplant candidates –May make stem cell transplant optional –May allow transplant decision to be deferred –If indicated, may optimize stem cell transplantation Induction Novel Agents Transplant No Transplant

clinicaloptions.com/oncology Upfront Therapy in Myeloma Availability of Novel Agents  Immunomodulators –Thalidomide –Lenalidomide  Proteasome inhibitor –Bortezomib

clinicaloptions.com/oncology Upfront Therapy in Myeloma  ECOG E1A00: phase III, randomized, controlled trial Newly diagnosed untreated symptomatic MM (N = 207) Thal/Dex arm Thalidomide 200 mg/day PO + Dexamethasone 40 mg/day on Days 1-4, 9-12, (n = 103) Dex alone arm Dexamethasone 40 mg/day on Days 1-4, 9-12, (n = 104) Repeated monthly for 4 mos Stem cell transplant or continue therapy at physician’s discretion Stop therapy Note: Use of prophylactic anticoagulant not required. CR/PR/SD Any progression Rajkumar V, et al. ASH Abstract 205. Dexamethasone With or Without Thalidomide in Frontline Therapy

clinicaloptions.com/oncology Upfront Therapy in Myeloma CR n = 104n = DexThal/Dex PR  DVT grade ≥ 3 –Dex 3% vs thal/dex 17%  Neuropathy grade ≥ 3 –Dex 4% vs thal/dex 7%  Deaths –Dex 11% vs thal/dex 7%  All grade ≥ 4 toxicity –Dex 18% vs thal/dex 34% Rajkumar SV, et al. J Clin Oncol. 2006;24: Dexamethasone With or Without Thalidomide in Frontline Therapy (cont’d)

clinicaloptions.com/oncology Upfront Therapy in Myeloma Bortezomib: Mechanisms of Action and Pharmacokinetics  Large protein complex 26S proteasome –Degrades intracellular proteins –Maintains cellular homeostasis –Responsible for 80% of intracellular protein turnover  Bortezomib a reversible inhibitor of 26S proteasome complex –Prevents targeted proteolysis –Affects multiple cellular signaling cascades –Leads to cell death –Half-life: 9-15 hours in doses ranging from mg/m 2

clinicaloptions.com/oncology Upfront Therapy in Myeloma (Cycle 2) (Cycle 6) N = 48 patients Response Rate (%) BortezomibBortezomib ± Dex PR nCR CR  Bortezomib alone for first 2 cycles; bortezomib ± dex for total of 6 cycles  ORR: 90% (20% CR/nCR)  Peripheral blood stem cell harvest with G-CSF in 23 patients –Median CD34+ cell count: 12.6 x 10 6 /kg  Stem cell transplant in 23 patients –Estimated survival at 12 mo: 100%  Grade 3 neuropathy: 12%  Early discontinuation: 26% Jagannath S, et al. ASH Abstract 783. Bortezomib + Dexamethasone as First-Line Therapy in MM

clinicaloptions.com/oncology Upfront Therapy in Myeloma Bortezomib + Dexamethasone as First-Line Therapy in MM (cont’d) n = 48n = 42 N = 48 patients Response Rate (%) Cycles Bort/Dex Post-SCT PR vgPR CR  Bort 1.3 mg/m 2 Days 1, 4, 8, 11  Dex 40 mg Days 1-4, 9-12; cycles 1-2  Dex 40 mg Days 1-4; cycles 3-4  Peripheral blood stem cell harvest with G-CSF in 45 patients –Median CD34+ cells: 6.7 x 10 6 /kg –Cytapheresis: median 2 (1-4) –Sufficient for 2 transplants in 33/42  Serious adverse events: 16%; therapy discontinued: 6%  Death: 1 (2%)  Overall response rates –After 4 cycles bortezomib/dex: 67% –With ASCT: 90% Harousseau, et al. ASCO Abstract 6653.

clinicaloptions.com/oncology Upfront Therapy in Myeloma Bortezomib, Doxorubicin, and Dex (PAD) as First-Line Therapy in MM  PAD: 21-day cycles x 4 –Bortezomib 1.3 mg/m 2 Days 1, 4, 8, 11 –Dex 40 mg Days 1-4, 8-11, (cycle 1); Days 1-4 (cycles 2-4) –Doxorubicin 0, 4.5, or 9.0 mg/m 2 Days 1-4  High-dose melphalan (MEL200) with PBSC transplantation Oakervee HE, et al. Br J Haematol. 2005;129:

clinicaloptions.com/oncology Upfront Therapy in Myeloma Bortezomib, Doxorubicin, and Dex (PAD) as First-Line Therapy in MM (cont’d)  Median time (days) to –ANC > 500: 13 –Platelet counts > 20,000: 15  Grade 3 neuropathy: 5%  SAE: 57%; therapy discontinued: 14%  Response, PAD only: 95% –PAD + PBSCT: 95%  PBSC mobilization in 20/21 –MEL200/PBSCT in 18/20 N = 21 patients Response Rate (%) n = 21n = After 4 Cycles After Mel 200 PR nCR CR Oakervee HE, et al. Br J Haematol. 2005;129:

clinicaloptions.com/oncology Upfront Therapy in Myeloma Total N = 19 patients n = 19n = 13  Open-label, phase I/II study –Reduced dose of bortezomib  Induction: 21-day cycles x 4 –Bortezomib 1.0 mg/m 2 Days 1, 4, 8, 11 –Doxorubicin 9 mg/m 2 Days 1-4 –Dex 40 mg Days 1-4, 8-11, (cycle 1); Days 1-4 (cycle 2-4)  No PBSCT in 6 patients –1 PD –2 declined –1 deaths –1 alternative therapy –1 pending  No Grade 3 neuropathy Popat R, et al. ASH Abstract PAD as First-Line Therapy in MM: Reduced Bortezomib Dose CyclesMel 200 PR nCR CR Response Rate (%)

clinicaloptions.com/oncology Upfront Therapy in Myeloma  Previously untreated patients with multiple myeloma eligible for transplant  BTD given in 28-day cycles x 2 followed by SCT –Bortezomib 1.3 to 1.7 mg/m 2 Days 1, 4, 8, 11 –Thalidomide mg/d –Dexamethasone 20 mg/m 2 Days 1-4, 9-12,  ORR: 92% (35/38) –CR: 18%; PR: 74%  Among 26 pts successfully transplanted, 6 additional CRs post-SCT *1 patient inadvertently received 1.9 mg/m 2 without incident. Bortezomib + Thalidomide + Dex (BTD) Wang, et al. ASH Abstract 784. Dose (mg/m 2 ) Patients (n) *1 Total38

clinicaloptions.com/oncology Upfront Therapy in Myeloma Lenalidomide + Dexamethasone as First-Line Therapy in Multiple Myeloma  28-day cycle –Lenalidomide 25 mg daily x 21 days –Dex 40 mg Days 1-4, 9-12,  PBSC harvest w/G-CSF: 10/15 pts –Median CD34+ cell count: 7.9 x 10 6  Nonhematologic toxicity, gr ≥ 3: 47% –Fatigue: 15% –Pneumonia: 6% –Rash: 6% –Muscle weakness: 6%  Overall response rate: 91% –CR: 6%; vgPR + nCR: 32% N = 34 patients Response Rate (%) Rajkumar SV, et al. Blood. 2005;106: Cycles PR VGPR CR

clinicaloptions.com/oncology Upfront Therapy in Myeloma  28-day cycle –Lenalidomide 25 mg daily x 21 days –Dex 40 mg weekly –Clarithromycin 500 mg 2x daily  Adverse events, grade ≥ 3: 54% –DVT ± PE: 13.5% (1 death) –Anemia: 4.5% –Stevens-Johnson syndrome: 4.5% –Colonic perforation: 4.5% n = 22 Response Rate (%) Niesvizky R, et al. ASH Abstract 642. Clarithromycin + Lenalidomide + Dex as First-Line Therapy in MM Cycles PR nCR CR N = 35 patients

clinicaloptions.com/oncology Upfront Therapy in Myeloma Palumbo A, et al. ASH Abstract 779. Facon T, et al. ASH Abstract 780. Outcome Palumbo, et al. > 65 yrs of age Facon, et al yrs of age MP n = 126 MPT n = 129 MP n = 191 MPT n = 124 CR, % ORR, % PFS, mo OS2 yr: 65%2 yr: 82%30 mo> 55 mo Melphalan/Prednisone (MP) vs MP + Thalidomide (MPT) in Elderly Patients

clinicaloptions.com/oncology Upfront Therapy in Myeloma N = 20 patients Response Rate (%) After 3 Cycles PR CR  21-day course, every 4-6 wks  Cohort 1: n = 6 –Lenalidomide 5 mg daily x 21 –Melphalan 0.18 mg/kg daily x 4 –Prednisone 2 mg/kg daily x 4  Cohort 2: n = 6 –Lenalidomide 5 mg daily x 21 –Melphalan 0.25 mg/kg daily x 4 –Prednisone 2 mg/kg daily x 4  Cohort 3: n = 6 –Lenalidomide 10 mg daily x 21 –Melphalan 0.18 mg/kg daily x 4 –Prednisone 2 mg/kg daily x 4  Cohort 4: n = 6 –Lenalidomide 10 mg daily x 21 –Melphalan 0.25 mg/kg daily x 4 –Prednisone 2 mg/kg daily x 4  MTD –Melphalan 0.18 mg/kg –Lenalidomide 10 mg Palumbo A, et al. ASH Abstract 785. Lenalidomide + MP as First-Line Therapy in Multiple Myeloma

clinicaloptions.com/oncology Upfront Therapy in Myeloma Mateos MV, et al. ASH Abstract 786.  Bortezomib 1.0 or 1.3 mg/m 2 Days 1, 4, 8, 11, and 22, 25, 29, 32; 6-wk cycle x 4; followed by:  Bortezomib Days 1, 8, 15, 22; 5-wk cycle x 5  MP: M 9 mg/m 2 and P 60 mg/m 2 x 4; Days 1-4 Response Best Response* (n = 56) Historical Control MP x 6 Cycles CR IF-30%**NR CR IF+13%3% PR43%38% CR + PR86%41% Bortezomib + MP as Initial Therapy: Phase I/II Study in Elderly Patients  Grade 3/4 toxicities manageable; included myelosuppression, neuropathy IF, immunofixation *Median 5 cycles**Half by immunophenotype

clinicaloptions.com/oncology Upfront Therapy in Myeloma DVd, liposomal doxorubicin, vincristine, dexamethasone; VMCP/BVAP, vincristine, melphalan, cyclophosphamide, prednisone, carmustine, and doxorubicin. StudyNRegimen CR/ nCR CR + PR Stem Cell Harvest Ref Rajkumar100Dex0%50%Yes JCO 2006 Gold- schmidt 203VAD3%63%Yes ASH 2005 Rifkin97DVd3%43%Yes Cancer 2006 IFM90100 VMCP/ BVAP 5%52%Yes/No NEJM 1996 Palumbo126MP7%48%No ASH 2005 First-Line Therapy in MM: Traditional

clinicaloptions.com/oncology Upfront Therapy in Myeloma Upfront Therapy in MM: Novel Agents + Dex StudyNRegimen CR/ nCR CR + PR Stem Cell Harvest Ref Jagannath48Bort ± dex18%89%Yes BrJH 2005; ASH 2005 Harousseau48Bort + dex21%67%Yes ASCO 2005 Rajkumar99Thal + dex4%63%Yes JCO 2006 Rajkumar34Len + dex6%91%Yes Blood 2005 Niesvizky35 Len + dex + clarithro 36%86%No ASH 2005 *CR/vgPR

clinicaloptions.com/oncology Upfront Therapy in Myeloma Upfront Therapy in MM: Novel Agents + Combinations StudyNRegimenCR/nCR CR + PR Stem Cell Harvest Ref Oakervee40PAD29%95%Yes BrJH 2005 Wang36Bort/TD19%92%Yes ASH 2005 Gold- schmidt 203TAD7%80%Yes ASH 2005 Palumbo129MPT28%76%No ASH 2005 Mateos53Bort + MP43%85%No ASH 2005 Palumbo20Len + MP10%70No ASH 2005

clinicaloptions.com/oncology Upfront Therapy in Myeloma Response After High-Dose Chemotherapy StudyNRegimenCR/nCRCR + PRRef IFM90100Autograft x 138%81% NEJM 1996 Child200Autograft x 144%86% NEJM 2003 IFM96 200Autograft x 142%84% NEJM Autograft x 250%88% Total Therapy I 231Autograft x 238%81% Blood 1999 Oakervee21 PAD/ autograft x 1 57%95% BrJH 2005 Harousseau42 Bort/dex/ autograft x 1 54%90% ASCO 2005

clinicaloptions.com/oncology Upfront Therapy in Myeloma MP Standard MP, 12 courses at 6-wk intervals (n = 191) MP-T MP + Thal at MTD but  400 mg/day, stopped at end of MP (n = 124) MEL100 VAD x 2; Cyclophosphamide 3 g/m 2 + G-CSF + PBSC harvest; (Melphalan 100 mg/m 2 + PBSC + G-CSF) x 2 (n = 121) Newly diagnosed MM patients aged yrs (N = 436 as of 5/05) Primary endpoint: overall survival Facon T, et al. ASH Abstract 780. IFM 99-06: MP vs MP-T vs Mel100 in Newly Diagnosed Elderly MM Patients

clinicaloptions.com/oncology Upfront Therapy in Myeloma IFM 99-06: MP vs MP-T vs Mel100 in Newly Diagnosed Elderly MM Patients *Neuropathy with MPT: 30%. P =.0008 P =.014 Facon T, et al. ASH Abstract 780. Outcome MM Patients, yrs ( N = 436) MP n = 191 MPT * n = 124 Mel 100 x 2 n = 121 Death < 3 mo, %839 DVT, % CR, %21517 vgPR, %53424 PR, % Median OS, mo30.3>

clinicaloptions.com/oncology Upfront Therapy in Myeloma *3rd interim analysis (5/1/2005); median follow-up time (± SEM) = 32.2 ± 1.8 mo Fraction Time From Inclusion, mo MP-T MP MEL100 PFSOS Facon T, et al. ASH Abstract 780. TreatmentPFS, moP ValueOS, moP Value MP17.2 ± 1.5 < ± MP-T29.5 ± 3.6> 56 MEL ± ± 3.0 IFM 99-06: MP vs MP-T vs Mel100 in Newly Diagnosed Elderly MM Patients (cont’d)

clinicaloptions.com/oncology Upfront Therapy in Myeloma VAD regimen (vincristine, doxorubicin, and dexamethasone) 3-4 cycles; followed by Melphalan 140 mg/m 2 plus ASCT; followed by Melphalan 200 mg/m 2 plus ASCT Arm A No maintenance therapy (n = 200) Arm B Pamidronate 90 mg/mo (n = 196) Arm C Pamidronate 90 mg/mo Thalidomide 100 mg/day (n = 201) Patients with stage I, II, or III MM < 65 yrs of age No prior therapy 0-1 risk factors (N = 780) Month 3: Randomized if no progression (n = 593 as of 6/05) Attal M, et al. ASH Abstract Maintenance With Thalidomide After ASCT for MM (IFM 99-02)

clinicaloptions.com/oncology Upfront Therapy in Myeloma IFM 99-02: Results *P=0.01 for Arm B vs Arm C Attal M, et al. ASH Abstract Endpoint Arm A: No Maintenance Arm B: Pam Arm C: Thal/Pam P Value Patients, n17.2 ± ± 5.8 VGPR or CR, %  After VAD  At randomization  After randomization Events, % Median EFS, mo38 > 48 4-yr EFS, % yr OS, %7874*87*.04 Bone events, %242018NS *P =.01 for Arm B vs Arm C

clinicaloptions.com/oncology Upfront Therapy in Myeloma Treatment of High-Risk MM  High-risk characteristics –Elevated beta-2 microglobulin –High plasma cell labeling index –Del(13) –Independent adverse prognostic factor in MM 1 –Predicts worse response to treatment 1 1. Zojer N, et al. Blood. 2000;95:

clinicaloptions.com/oncology Upfront Therapy in Myeloma  Dexamethasone-treated patients: associated with poor survival –HR: 9.31 (95% CI: ) –P =.002  Bortezomib-treated patients: no difference in survival –HR: 1.61 (95% CI: ) –P = NS  Bortezomib may overcome adverse impact of Del(13q) Richardson PG, et al. N Engl J Med. 2005;352: APEX: Impact of Del(13) on Survival in Bortezomib- and Dex-Treated Patients

clinicaloptions.com/oncology Upfront Therapy in Myeloma Bortezomib in Treatment-Naive High-Risk MM  ECOG E2A02 –Nonrandomized, open-label, phase II study –Previously untreated high-risk MM (N = 43) –Induction: bortezomib 1.3 mg/m 2 Days 1, 4, 8, 11 every 21 days x 8 –Maintenance: bortezomib 1.3 mg/m 2 every other week –PR + minor response (MR) in 15/19 evaluable patients (median 5 cycles in responders) –Median time to response: 0.8 months Dispenzieri A, et al. ASH Abstract 2546.

clinicaloptions.com/oncology Upfront Therapy in Myeloma Conclusions  Addition of a novel agent to induction therapy –Improves overall response rate and CR –High CR rates not seen with chemotherapy alone –Durability of responses not tested –No evidence yet that improved response translates into longer survival –Increases posttransplant CR –Obviates need for transplant in elderly  Novel agents may overcome poor prognostic factors – eg, del 13q, t(4;14)  Novel agents as maintenance therapy –Maintenance with thalidomide prolongs EFS and OS

clinicaloptions.com/oncology Upfront Therapy in Myeloma Newly diagnosed for treatment Transplant candidate Nontransplant candidate HOVON coop study IFM coop study ( ) Italian coop study Induction therapy Bort/Dex vs VAD BMT T or Bort maintenance Induction therapy ± DCEP BMT Induction therapy TD vs Bort/TD Registration study MPV vs MP San Miguel Bortezomib Frontline Trial Strategy

clinicaloptions.com/oncology Upfront Therapy in Myeloma IFM : Bort/Dex vs Vincristine/Doxorubicin/Dex (VAD)  Open-label randomized phase III study (N = 480) –VAD (4 cycles) –VAD (4 cycles)  DCEP (2 cycles) –Bortezomib/dexamethasone (4 cycles) –Bortezomib/dexamethasone (4 cycles)  DCEP (2 cycles)  Followed by autograft  Primary endpoint: CR at end of induction National Institutes of Health. Available at: Accessed March 6, DCEP: dexamethasone, cyclophosphamide, etoposide, and cisplatin.

clinicaloptions.com/oncology Upfront Therapy in Myeloma Bortezomib/Melphalan/Prednisone Vs Melphalan/Prednisone  Randomized, controlled, open-label study (N = 680) –Patients with previously untreated multiple myeloma –KPS ≥ 60% –Ineligible for HDT/SCT (advanced age or comorbidities)  Primary endpoint: time to disease progression  Secondary endpoints –Overall and progression-free survival –CR, overall response rate, time to response, duration of response National Institutes of Health. Available at: Accessed March 6, 2006.

Upfront Therapy in Myeloma: Supplemental Slides

clinicaloptions.com/oncology Upfront Therapy in Myeloma N = 60 patients Toxicity  Grade 4 events –Fluid overload –Meningitis  Grade 3 events –Peripheral neuropathy  All other AEs were grade 1-2 Response Rate (%) Richardson, et al. ASH Abstract 2548 Bortezomib Alone as First-Line Therapy in Multiple Myeloma Cycles PR VGPR CR

clinicaloptions.com/oncology Upfront Therapy in Myeloma Day Bortezomib 1.3 mg/m Cycle Dexamethasone 40 mg Doxorubicin* Day Bortezomib 1.3 mg/m Cycles Dexamethasone 40 mg Doxorubicin* Oakervee HE, et al. Br J Haematol. 2005;129: Dose escalation by cohort. *Dose escalation by cohort. PAD: Treatment Plan for Newly Diagnosed MM

clinicaloptions.com/oncology Upfront Therapy in Myeloma  29 patients with newly-diagnosed MM  CALGB treatment regimen: recommended from phase I testing –Bortezomib (▼) 1.3 mg/m 2 on Days 1, 4, 8, and 11 –PLD (▼) 30 mg/m 2 on Day 4 –10-day rest period, with 1 cycle ▼ given every 21 days Orlowski, et al. IMW Abstract 730. CALGB 10301: Bortezomib + Pegylated Liposomal Doxorubicin ▼ ▼▼▼▼ Week 1Week 2Week 3

clinicaloptions.com/oncology Upfront Therapy in Myeloma  Preliminary response –Planned accrual of 55 patients; current accrual 29 patients; 15 patients evaluable for response Modified EBMT criteria *PLD: Pegylated liposomal doxorubicin  12 of 15 patients have had ≥ PR  No patients with PD so far Orlowski, et al. IMW Abstract 730. CALGB 10301: Bortezomib + PLD Response (n = 15) Bortezomib + PLD Completed Therapy n = 6 Still on Therapy n = 9 Overall to Date n (%) CR1--1 (7) nCR--11 (7) PR4610 (66) CR + PR12 (80)

clinicaloptions.com/oncology Upfront Therapy in Myeloma  Previously untreated patients with multiple myeloma eligible for transplant  28-day treatment cycle, 2 cycles  Institutional experience of 30 patients –Bortezomib 1.0 to 1.9 mg/m 2 Days 1, 4, 8, 11 every 28 days –Thalidomide mg each evening –Dexamethasone 20 mg/m 2 Days 1-4, 9-12, every 28 days  80% response rate, ≥ 75% reduction in M protein, > 95% reduction in Bence-Jones proteins Alexanian, et al. ASH Abstract 210. Bortezomib + Thalidomide + Dex, (VcTD) Methods Dose (mg/m 2 ) Patients (n) Total30