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Update on Current Therapies for the Treatment of Multiple Myeloma

Update on Current Therapies for the Treatment of Multiple Myeloma. Beth Faiman , MSN, APRN-BC, AOCN ® Cleveland Clinic Taussig Cancer Institute Cleveland, OH. Multi-Drug Combinations in Multiple Myeloma. NCCN Review Categories. *Combinations recently reviewed by NCCN .

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Update on Current Therapies for the Treatment of Multiple Myeloma

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  1. Update on Current Therapies for the Treatment of Multiple Myeloma Beth Faiman, MSN, APRN-BC, AOCN® Cleveland Clinic Taussig Cancer Institute Cleveland, OH

  2. Multi-Drug Combinations in Multiple Myeloma

  3. NCCN Review Categories *Combinations recently reviewed by NCCN Generic Name Trade Name Company Bortezomib Velcade Millennium - Takeda Lenalidomide Revlimid Celgene Thalidomide Thalomid Celgene NCCN Clinical Practice Guidelines in Oncology, v.3.2010

  4. Revised Categories of Evidence and Consensus – NCCN Guidelines, 2010 NCCN Categories of Evidence and Consensus: 1 High-level evidence, uniform consensus 2A Lower-level evidence, uniform consensus 2B Lower-level evidence, non-uniform consensus NCCN Clinical Practice Guidelines in Oncology, v.3.2010

  5. NCCN: Changing Categories of Consensus • Change is a natural process secondary to constant stream of data from recent clinical studies • Categories 2A and 2B are not indicative of inferiority of the treatment: …non-uniform consensus does not represent a major disagreement, rather it recognizes that given imperfect information, institutions may adopt different approaches. A Category 2B designation should signal to the user that more than one approach can be inferred from the existing data… NCCN, “Categories of Evidence and Consensus”, 2010

  6. Future of MM Therapy: Recent and Ongoing Clinical Studies Patient Treatment Largely Determined by Transplant Status • Transplant-ineligible patients • VMP – VT vs. VTP – VP • VMPT – VT vs. VMP • MP vs. MPT • MP vs. MPR vs. MPR (continued Lenalidomide) • Lenalidomide/Dexamethasone in Smoldering Myeloma • QUIREDEX Study • New combinations and early studies • EVOLUTION Study • Pomalidomide/low Dexamethasone • Carfilzomib • Carfilzomib/Lenalidomide/Dexamethasone • Elotuzumab/Lenalidomide/Dexamethasone • Transplant-eligible patients • Lenalidomide after ASCT • MPR vs. high dose Melphalan

  7. VMP vs. VTP Followed by VT vs. VP(ASH 2009 - PLENARY SESSION) A Phase III Study of Bortezomib/Melphalan/Prednisone (VMP) vs. Bortezomib/Thalidomide/Prednisone (VTP) Followed by Bortezomib/Thalidomide (VT) vs. Bortezomib/Prednisone (VP) in Elderly Newly Diagnosed Multiple Myeloma (NDMM) Patients • Study Objective: • Testing an alkylating agent (Melphalan) and an immunomodulatory drug (Thalidomide) as a partner for Bortezomib • Study Design: • Prospective, multicenter, randomized • Induction: patients randomized to 6 cycles of VMP vs. VTP • Maintenance: patients randomized to VT vs. VP for up to 3 years Mateos et al, Blood 114, Abstract 3, 2009

  8. Conclusions from VMP – VT vs. VTP – VP • Both induction schedules are highly effective with similar overall response rate (ORR) and complete response (CR) • More neutropenia but less cardiac toxicity and peripheral neuropathy with VMP • Both maintenance therapies markedly improve responses • Combination of these regimens improves poor prognosis of high-risk cytogenic abnormalities (CA) in elderly MM patients Mateos et al, Blood 114, Abstract 3, 2009

  9. Bortezomib 1.3 mg/m2 Days 1, 15Thalidomide 50 mg/day continuously Bortezomib 1.3 mg/m2Melphalan 9 mg/m2 Days 1-4 Prednisone 60 mg/m2 Days 1-4 Thalidomide 50 mg Days 1-42 Bortezomib 1.3 mg/m2 Melphalan 9 mg/m2 Days 1-4 Prednisone 60 mg/m2 Days 1-4 No Maintenance Bortezomib/Melphalan/Prednisone/Thalidomide – Bortezomib/Thalidomide A Phase III Study of VMPT Followed by Maintenance with Bortezomib and Thalidomide for Initial Treatment of Elderly Multiple Myeloma Patients • Study Objective: • Compare VMPT with a maintenance regimen including Bortezomib and Thalidomide with VMP without a maintenance regimen • Study Design: • Prospective, randomized • Both regimens amended to 9 5-week cycles • Bortezomib modified to weekly administration (days 1,8,15,22) Palumbo et al, Blood 114, Abstract 128, 2009

  10. Conclusions from VMPT – VT vs. VMP • VMPT followed by VT was superior to VMP for response rates and PFS • The weekly infusion of Bortezomib significantly reduced the incidence of grade 3-4 peripheral neuropathy • From 18% to 4% (p=0.0002) in VMPT arm • From 13% to 2% (p=0.0003) in VMP arm • This is the first report showing the superiority of a 4-drug regimen followed by maintenance compared to standard therapy (VMP) Palumbo et al, Blood 114, Abstract 128, 2009

  11. Melphalan/Prednisone vs. Melphalan/Prednisone/Thalidomide MP vs. MPT as Initial Therapy for Previously Untreated Elderly and/or Transplant Ineligible Patients with Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials • Study Objective: • Systemic review of randomized controlled trials to compare efficacy of MP with MP+T • Clinical endpoints are Response Rate (RR), Progression-Free Survival (PFS) and Overall Survival (OS) • Study Design: • Comprehensive search of database to identify randomized controlled trials • Meta-analysis by pooling results on clinical endpoints Kapoor et al, Blood 114, Abstract 615, 2009

  12. Conclusions from MP vs. MPT • Five prospective randomized controlled trials were identified (1571 patients data analyzed) • The data indicated that MPT was better than MP in achieving at least a partial response • The pooled hazards ratios for PFS and OS were in favor of MPT • Analyses suggest that MPT is superior to MP in terms of response and survival Kapoor et al, Blood 114, Abstract 615, 2009

  13. Cycles 10+ 9 28-day cycles Melphalan 0.18 mg/kg Days 1-4 Prednisone 2 mg/kg Days 1-4 Lenalidomide 10 mg QD PO Days 1-21 Lenalidomide Lenalidomide Melphalan 0.18 mg/kg Days 1-4 Prednisone 2 mg/kg Days 1-4 Lenalidomide 10 mg QD PO Days 1-21 Placebo Progression Melphalan 0.18 mg/kg Days 1-4 Prednisone 2 mg/kg Days 1-4 Placebo Days 1-21 Placebo MP vs. MPR vs. MPR – R A Phase III Study to Determine the Efficacy and Safety of Lenalidomide in Combination with Melphalan and Prednisone (MPR) in Elderly Patients with NDMM • Study Objective: • In previous studies Lenalidomide was efficacious in relapsed/refractory MM • Compare safety and efficacy of MPR in NDMM patients • Study Design: Palumbo et al, Blood 114, Abstract 613, 2009

  14. Conclusions from MP vs. MPR vs. MPR – R • MPR – R regimen reduced risk of progression by 50% vs. MP alone • MPR followed by Lenalidomide maintenance is a new therapeutic option • This regimen can be considered a new standard for elderly patients Palumbo et al, Blood 114, Abstract 613, 2009

  15. Lenalidomide after ASCT First Analysis of a Phase III Study of the Intergroupe Francophone Du Myelome (IFM 2005 02) • Study objective: • Controlling the residual disease after high-dose therapy • Neuropathy a major limiting factor in previous study • Lenalidomide evaluated (has lower neurological toxicity) • Study design: • Prospective, randomized, placebo controlled • 1st line ASCT less than 6 months before enrollment • Consolidation with Lenalidomide, 25 mg/day, po, 21 days/month, 2 months • Maintenance until relapse: • Lenalidomide, 10-15 mg/day Attal et al, Blood 114, Abstract 529, 2009

  16. Conclusions from Lenalidomide after ASCT 2 month consolidation with Lenalidomide: • 80% of patients were able to receive the planned 2 cycles of consolidation • Significantly improved the sCR/CR rate Attal et al, Blood 114, Abstract 529, 2009

  17. Melphalan/Prednisone/Lenalidomide vs. High Dose Melphalan MPR vs. Melphalan (200 mg/m2) and Autologous Transplantation in Newly Diagnosed Myeloma Patients: An Interim Analysis • Study objective: • To compare Melphalan/Prednisone/Lenalidomide (MPR) with tandem Melphalan (200 mg/m2) in patients younger than 65 years • Study design: • Induction, 4 28-day cycles • Lenalidomide 25 mg days 1-21 • Low-dose Dexamethasone 40 mg days 1,8,15,22 • Consolidation: • MPR arm: 6 28-days cycles • Melphalan 0.18 mg/kg days 1-4 • Prednisone 2 mg/kg days 1-4 • Lenalidomide 10 mg days 1-21 • Melphalan arm: tandem melphalan 200 mg/m2 with stem cell support Palumbo et al, Blood 114, Abstract 350, 2009

  18. Conclusions from MPR vs. MEL200 • Rd is an effective and safe induction regimen • Both MPR and MEL200 improved the quality of response • At 1 year follow-up, PFS and OS are similar in both groups • Longer follow-up is needed Palumbo et al, Blood 114, Abstract 350, 2009

  19. Lenalidomide/Dexamethasone in Smoldering Myeloma Phase III trial of Lenalidomide/Dexamethasone vs. therapeutic abstention in Smoldering Multiple Myeloma (sMM) at high risk of progression to symptomatic MM • Study objective: • To investigate whether early treatment prolongs the time to progression (TTP) in sMM patients at high risk • Study design: • Multicenter, randomized, open-label • High risk population defined by Plasma Cells ≥10% and M-component ≥3g/dL • Len/Dex arm, 9 4-week cycles: • Lenalidomide: 25 mg/daily, days 1-21 • Dexamethasone: 20 mg/daily, days 1-4 and 12-15 (total dose 160 mg) • Maintenance with Lenalidomide, 10 mg on days 1-21 every 2 months until progression Mateos et al, Blood 114, Abstract 614, 2009

  20. Conclusions From Lenalidomide/Dexamethasone in Smoldering Myeloma In sMM patients, lack of treatment is associated with early progression (17.5 months) with bone disease Lenalidomide/Dexamethasone treatment prolonged TTP and induced CRs with a manageable and acceptable toxicity profile Mateos et al, Blood 114, Abstract 614, 2009

  21. Emerging New Treatments in Early Development • EVOLUTION Ph II Study • Novel 3- and 4-drug combinations: VDR, VDC, VDCR • Exploring the combination of Bortezomib and Dexamethasone with Lenalidomide and Cyclophosphamide in NDMM patients • Development of a novel proteosome inhibitor, Carfilzomib • Appears to work in patients that are resistant to Bortezomib • Prior therapy with Bortezomib doesn’t preclude a good response • Minimal neuropathy and myelosuppression • Development of Pomalidomide, an immunomodulatory drug • Evidence of efficacy in heavily pretreated patients with relapsed disease • Acceptable safety profile • Development of Elotuzumab, a monoclonal antibody against a glycoprotein that is highly and uniformly expressed in MM • Manageable toxicity profile in combinations with other agents • Promising preliminary efficacy data ASCO 2009; Kumar et al, Blood 114, Abstract 127, 2009; Lonial et al, Blood 114, Abstract 432, 2009; Richardson et al, Blood 114, Abstract 301, 2009; Siegel et al, Blood 114, Abstract 303, 2009; Wang et al, Blood 114, Abstract 302, 2009; Niesvizky et al, Blood 114, Abstract 304, 2009

  22. Future Direction of Combinations & Protocols with Novel Therapies • Evolving role of the new drug combinations for transplant eligible and ineligible patients • New 4-drug aggressive regimen (VMPT) • New strategy for Bortezomib: weekly dose with much better tolerability Treatment of Smoldering MM patients provided first evidence of efficacy in preventing progression • Two new clinical paradigms are emerging: • Control Option • Careful use of drugs, using agents sequentially • Cure Option • Aggressive treatment ASCO 2009; ASH 2009

  23. Conclusions • Novel combination therapies exhibit great potential in improving RR, TTP, PFS, and OS outcomes • Randomized clinical trials are underway to compare which of these novel combinations will offer patients better OS balanced with a good quality of life

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