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Multiple Myeloma:

Multiple Myeloma:. Upfront studies. Antonio Palumbo. Levels of Evidence/Grades of Recommendation. Transplant. Patients < 65 years. VAD. VAD  3. DCEP. VDT-DPACE. HDCTX. CAD. VDT-DPACE. EDAP. DCEP. Total Therapy (TT) Trials: Treatment Schema.

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Multiple Myeloma:

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  1. Multiple Myeloma: Upfront studies Antonio Palumbo

  2. Levels of Evidence/Grades of Recommendation

  3. Transplant Patients < 65 years

  4. VAD VAD  3 DCEP VDT-DPACE HDCTX CAD VDT-DPACE EDAP DCEP Total Therapy (TT) Trials: Treatment Schema Barlogie B et al. Blood. 1999;93:55; Shaughnessy J Jr et al. Br J Haematol. 2003;120:44; Barlogie B et al. Blood. 2005;106:337a [abstract 1154]

  5. TT1 vs TT2 (No Thal): Response Barlogie B et al. Blood. 1999;93:55; Shaughnessy J Jr et al. Br J Haematol. 2003;120:44 Barlogie B et al. Blood. 2006;107:2633

  6. TT2 Barlogie B et al. New Engl J Med. 2006;354:1021

  7. TT3 vs TT2 + Thal TT3 vs TT2 + Thal: Significantly less DVT, febrile neutropenia, somnolence, PN, and dizziness, but significantly more anorexia and renal insufficiency Barlogie B et al. Blood. 2005;106:337a [abstract 1154]

  8. New Drugs as induction for Autologous / Allogeneic transplant • VDT-PACE as induction regimen • stem cell mobilization after Cycle 1 • stem cell collection after 1° VTD-PACE >2° VTD PACE • TT3 compares favorably to TT2 as historical control • nCR 16% after 1 cycle VTD-PACE • nCR 26% after 2 cycles VDT-PACE • nCR 40% after first MEL200 • nCR 80% after second MEL200 • Estimated CR rate: 80% for TT3 (MEL200 + Tal + Vel) 60% for TT2 (MEL200 + Tal) 40% for TT1 (MEL200) Bartlogie et al. ASH 2004 Abstract 538

  9. Autologous followed by Allogeneic Transplantvs Tandem Autologous transplant Bruno B, Blood. 2005;106;18a, abstract 46.

  10. Maintenance With Thalidomide AfterASCT for MM (IFM 99-02) mo 3Randomized if no progression (n=593 as of 6/05) Arm A No maintenance therapy(n=200) Patients with stage 1, 2, or 3 MM <65 yr oldNo prior therapy 0 or 1 risk factor (n=780) VAD regimen (vincristine, doxorubicin, and dexamethasone) 3–4 cycles Melphalan,140 mg/m2, and ASCT Melphalan,200 mg/m2and ASCT Arm B Pamidronate, 90 mg/mo(n=196) Arm C Pamidronate, 90 mg/moThalidomide, 100 mg/day (n=201) Attal M et al. Blood. 2005;106:335a [abstract 1148]

  11. IFM 99-02: Results *P=0.01 for arm B vs arm C Attal M et al. Blood. 2005;106:335a [abstract 1148]

  12. Standard treatment Patients > 65 years

  13. MP vs Dexamethasone-Based Regimens (IFM 95-01 Trial) • 488 patients aged 65-75 yr randomised to MP, MD, D, or D-IFN (12 courses at 6-wk intervals) • FU 82.8 mo, OS 35.0 mo (415/488), EFS 18.3 mo (473/488) for whole series • Standard MP gold standard for treatment of older pts *P<0.001 for pts not receiving Melphalan Facon T et al. Blood. 2005 Sep 20; [Epub ahead of print]

  14. Thalidomide

  15. Thalidomide, 200 mg/day orallyDexamethasone, 40 mg/day*days 1–4, 9–12, and 17–20(n=103) Stop therapy at mo 4 for SCT or continue at physician’s discretion R A N D O M I Dexamethasone alone, 40 mg/day*days 1–4, 9–12, and 17–20(n=104) Stop therapy Z A T I O N Thalidomide/Dexamethasone vs Dexamethasone in Newly Diagnosed MM Phase III ECOG E1A00 Study Design CR/PR/stable Newly diagnosed MM (n=207)  4 cycles Any progression *Administered as 4-wk cycle All patients received monthly pamidronate or zoledronic acid No DVT prophylaxis Rajkumar SV et al. J Clin Oncol. 2006;24:431

  16. Thalidomide/Dexamethasone vs Dexamethasone: Best Response Within 4 Cycles P=0.0017 *Based on ITT, 50% reduction in serum and urine M protein, or 90% reduction in urine M protein if only urinary protein was evaluable for response †Allowing for use of serum M protein when a measurable urine M protein was unavailable at follow-up Rajkumar SV et al. J Clin Oncol. 2006;24:431

  17. Thalidomide/Dexamethasone vs Dexamethasone: Specifically Monitored Adverse Events Deaths within 4 cycles: Thal/Dex, 7; Dex, 11 *Rows do not add to total as patients could have more than 1 of these adverse events Rajkumar SV et al. J Clin Oncol. 2006;24:431

  18. MPT vs MP in Elderly Patients With MM Phase III Randomized, Controlled Trial MPT* arm (median age 72) Melphalan, 4 mg/m2 (7 days/mo) Prednisone, 40 mg/m2 (7 days/mo) Thalidomide, 100 mg/d (continuously)* (n=129†) Newly diagnosed MM patients, aged >65 yr (n=255†)   6 courses MP arm (median age 72) Melphalan, 4 mg/m2 (7 days/mo) Prednisone, 40 mg/m2 (7 days/mo) (n=126†) *Thalidomide dose reduced to 50% if grade 2 toxicity; enoxaparin prophylaxis added to protocol December 2003 †No. of patients with ≥6 mo follow-up Palumbo A et al. Lancet. 2006;367:825

  19. MPT vs MP in Elderly Patients With MM: Response PR (>50%), nCR (IF+), CR (IF–) Palumbo A et al. Lancet. 2006;367:825

  20. 1.0 09 08 07 MPT 06 Proportion of Patients 05 04 MP 03 02 HR 0.51 (95% CI 0.35–0.75) P=0.0006 01 0 MPT vs MP in Elderly Patients With MM: Event-Free Survival and Overall Survival EFS 49%  in risk of event for MPT OS 65%  in risk of death at >9 mo for MPT 1.0 09 MPT 08 MP 07 06 Proportion of Patients 05 04 03 02 HR 0.68 (95% CI 0.38–1.22) P=0.19 01 0 6 12 18 24 0 12 18 24 6 30 0 Months Months Number at risk Number at risk 129 MPT 129 106 70 43 26 MPT 111 20 79 52 38 126 97 49 27 MP 21 111 72 42 10 MP 126 13 Adapted with permission from Palumbo A et al. Lancet. 2006;367:825

  21. MPT vs MP in Elderly Patients With MM: Grade 3/4 AEs P=0.001 P=0.001 P=0.01 Patients, % Palumbo A et al. Lancet. 2006;367:825

  22. MPT in Elderly Patients With MM: Thromboembolic Events • MPT with no prophylaxis (n=65) • 56.9% (37/65) grade 3/4 adverse events* • 16.9% (11/65) thromboembolism† • MPT + enoxaparin (40 mg/day for 4 mo) (n=64) • 39.1% (25/64) grade 3/4 adverse events* • 3.1% (2/64) thromboembolism† • Both patients had evidence of thromboembolism within 2 mo of discontinuing enoxaparin *P=0.042 comparing MPT with MP †P=0.005 comparing MPT with MP Palumbo A et al. Lancet. 2006;367:825

  23. MP vs MPT and MP vs Mel 100 in Newly Diagnosed Elderly MM Patients IFM 99-06 Trial Design MP arm (n=191) Standard MP; 12 courses at 6-wk intervals 3 2 MPT arm (n=124) MP Arm + Thal at MTD but 400 mg/day, stopped at end of MP Newly diagnosed MM patients; 65–75 yr (N=436 as of 5/05) 1o endpoint: OS 2 MEL 100 arm (n=121) VAD  2; cyclophosphamide 3 g/m2 + G-CSF + PBSC harvest (melphalan, 100 mg/m2 + PBSC + G-CSF)  2 All patients received clodronate Facon T et al. Blood. 2005;106:230a [abstract 780]

  24. 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0 0 12 12 24 24 36 36 48 48 60 60 72 72 0.0 0 0 12 12 24 24 36 36 48 48 60 60 72 72 MP vs MPT and MP vs Mel 100 in Newly Diagnosed Elderly MM Patients: Response* MPT PFS OS MP MEL 100 Fraction Fraction Time From Inclusion, mo Time From Inclusion, mo <0.0001 0.0008 0.0001 0.014 *Third interim analysis (May 1, 2005); median follow-up time (±SEM) = 32.2±1.8 mo Facon T et al. Blood. 2005;106:230a [abstract 780]

  25. Lenalidomide

  26. Lenalidomide and Dexamethasone for Newly Diagnosed MM: Response Adequate stem cells were obtained in all patients who underwent ASCT *n=34 Rajkumar SV et al. Blood. 2005;106:4050

  27. Phase II Trial of Lenalidomide and Dexamethasone for Newly Diagnosed MM SCT planned; off treatment CR/PR/Stable at 4 mo Lenalidomide 25 mg/day* days 1–21, 28-day cycle Dex 40 mg/day† days 1–4, 9–12, 17–20, 28-day cycle Aspirin‡daily for DVT prophylaxis Newly diagnosed MM (n=34) No SCT; remain on treatment at MD discretion Progressive disease; off treatment *Progressively reduced for AEs to 15, 10, and 5 mg †Progressively reduced for AEs to 40 mg/day for 4 days q 2 wk, 40 mg/day for 4 days q 4 wk, and 20 mg/day for 4 days q 4 wk ‡80 mg/day or 325 mg/day at MD discretion Rajkumar SV et al. Blood. 2005;106:4050

  28. Phase I/II Trial of Lenalidomide, Prednisone,and Melphalan (RMP) in Newly Diagnosed MM Median age 71 yr ( range, 57–77) day 1 2 3 4 21 Melphalan Prednisone Lenalidomide q 4–6 wk for maximum of 9 cycles ASA (100 mg/day) given as DVT prophylaxis Palumbo A et al. Blood. 2005;106:231a [abstract 785]

  29. RMP in Newly Diagnosed Patients: Response vs MPT N=37 N=76 N=20 N=76 % of patients 60% 63% 51% 33% 10% 1%CR Cycle 1 Cycle 3 Palumbo A et al. Oral presentation at ASH Annual Meeting; December 10-13, 2005; Atlanta, GA

  30. RMP in Newly Diagnosed Patients: Toxicities ≥Grade 3 toxicities seen in cohorts 3 and 4 only Hematologic Non-hematologic Cohort 4 (0.25/10) (n=17) Cohort 3 (0.18/10) (n=21) Palumbo A et al. Presented at: ASH Annual Meeting; December 10-13, 2005; Atlanta, GA

  31. Bortezomib

  32. Reduced Dose PAD Combination TherapyNewly Diagnosed Patients • Patients: n=20 • Treatment: Induction – 4, 21 day cycles prior to transplant Bortezomib 1.0 mg/m2 days 1,4, 8, 11 Adriamycin9 mg/m2 – IV push days 1-4 Dexamethasone 40 mg PO - Cycle 1: d 1-4, 8-11, 15-18; Cycle 2 – 4: d 1-4 PBSC harvested followed by HD Mel (MEL200) and PBSCT 1Oakervee et al., Br J. Haematol 2005; 129 755-762 Popat R, et al. ASH 2005,Abstract #2554 SLIDE 33

  33. Study of VTD in Newly Diagnosed MM Followed by Early Intensive Therapy • T; 100 mg/day  q 7 days to ≤200 mg/day, D; 20 mg/m2 days1–4, 9–12, and 17–20, bortezomib (V); 1.3 mg/m2 (15 patients), 1.5 mg/m2 (11 patients) and ≥1.6 mg/m2 (10 patients) • LMWH or warfarin to keep INR between 2.0 and 3.0 • Response rates • Stringent criteria (>75%  in serum M protein and/or >99%  in urine M protein) was 78% (19% CR) • Standard criteria (>50%  in serum M protein and/or >90%  in urine M protein) was 92% • 30% higher by either criteria with VTD than TD (P<0.01) • No added benefit of bortezomib >1.3 mg/m2 • Side effects were mild and reversible (DVT in 2 patients, grade 3 neuropathy in 3 patients, serious infections in 3 patients) • After median of 4 mo, HDT-supported ASCT successful in 22 patients • Primary resistant disease responsive in 4/6 patients • PR converted to CR in 3/13 patients • 3 patients intensified in CR Wang M et al. Blood. 2005;106:231a [abstract 784]

  34. Phase I/II Study of V-MP in Untreated MM Patients 65 yr n=60; median age 74 (range, 65–85) day 1 2 3 4 5 8 11 22 25 29 32 B B B B B B B B Melphalan 9 mg/m2 60 mg/m2 Prednisone Four 6-wk cycles followed by five 5-wk cycles 2 sequential doses of B (1.0 and 1.3 mg/m2) tested (6 patients each) to define MTD in combination with MP. Expanded at MTD to 60 patients. 53 evaluable for response % of patients Mateos MV et al. Blood. 2005;106:232a [abstract 786]

  35. B B B B Bortezomib, Melphalan, Prednisone, and Thalidomide (V-MPT) in Advanced MM Median age 68 (range, 38–79) day 1 2 3 4 5 15 22 35 Melphalan Prednisone Thalidomide q 35 days for 6 cycles DLT: grade 4 neutropenia for ≥7 days; grade 4 other hematologic; ≥grade 3 non-hematologic Palumbo A et al. Blood. 2005;106:717a [abstract 2553]

  36. Phase III trial: Study Design 28 days after CTX Day 1 cycle 3 60 days after MEL200 Blood Samples for coagulation study

  37. Phase III: Study Design 9 V-MP courses No maintenance 250 pts random diagnosis Maintenance with Velcade and Thalidomide 9 V-MPT courses 250 pts

  38. V-MPT arm: Thalidomide 50 mg/day continuously Treatment Schedule • Induction: nine 6-week courses 1 2 3 4 8 11 22 25 29 32 42 Velcade 1.3 mg/sqm biweeky couses 1-4; weekly courses 5-9 Melphalan 9 mg/sqm Prednisone 60 mg/sqm • Maintenance Thalidomide 50 mg daily continuously + Velcade 1,3 mg/sqm/2 weeks. No maintenancetherapy is scheduled for patients randomized to control arm

  39. Diagnosis > 65 yr, VMPT arm < 65 yr Random LMWH WAR 1.25 mg ASA 100 mg Phase III: Study Design

  40. Treatment Administrated

  41. Phase III: Study Design 4 PAD courses 2 CY courses 2 MEL100 courses Maintenance with Revlimid Consolidation with Revlimid and Prednisone

  42. Treatment Schedule • Induction: 4 PAD courses 1 4 8 11 15 18 28 Peg-Doxorubicine 30mg/sqm Velcade 1.3 mg/sqm Cycle 1 Cycle 1 Dexamethasone 40 mg QD Cycle 1-4 • Consolidation: 4 28 days RP courses (within 6 months after ASCT) 1 21 28 Revlimid 25 mg QD Prednisone 50 mg each other day • Manteinance: R 28-days courses until progression Revlimid 10 mg QD

  43. GIMEMA ongoing trials < 60 years 60-70 years > 65 years Dexamethasone + Velcade + Thalidomide CY + PBPC Dexamethsone+ Doxorubicin + Velcade 9 cycles MP + Velcade +Thalidomide No Transplant MEL 100 ASCTransplant MEL 200 ASCTransplant Dexamethasone + Velcade +Talidomide Lenalidomide Dexamethasone Talidomide + Velcade

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