2010 Annual Hematology Meeting – Multiple Myeloma « OncoFacts

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There were 2 interesting and important presentations at the American Society of Hematology (ASH) 2010 Annual Meeting regarding the E4A03 trial of induction therapy with lenalidomide plus high-dose (LD) versus low-dose (Ld) dexamethasone. In abstract 38, David Siegel compared the outcome of patients who underwent autologous stem cell transplant (ASCT) following lenalidomide-dexamethasone induction therapy to patients who continued on front-line lenalidomide-dexamethasone therapy.1 In the initial 1-year analysis of the LD versus Ld regimens, the 1-year survival for patients receiving lenalidomide-Ld dexamethasone was significantly better than for those on lenalidomide-LD dexamethasone. but after 3 years of follow-up, the curves had come together, and the survival at 3 years was 75% for both the LD and Ld dexamethasone groups. this current landmark analysis considered only those patients surviving the first 4 cycles of induction therapy. the authors examined the probabilities of survival for patients under the age of 65 and for those >65 and >70 years of age. the probabilities for survival for patients <65 were significantly better at 3 years for patients undergoing early ASCT whether they received LD or Ld regimen.

This current landmark analysis considered only those patients surviving the first 4 cycles of induction therapy. the authors examined the probabilities of survival for patients under the age of 65 and for those >65 and >70 years of age. the probabilities for survival for patients <65 were significantly better at 3 years for patients undergoing early auto-SCT whether they received LD or Ld regimen.

Landmark Survival Probability for Patients under Age 65

    1-year 2-year 3-year     N Events Survival Probability N Events Survival Probablility N Events Survival Probability No Early Transplant all 141 9 0.94 141 17 0.88 141 26 0.78 LD 65 7 0.89 65 12 0.82 65 13 0.79 Ld 76 2 0.97 76 5 0.93 76 13 0.78 Early Transplant all 68 0 1.00 68 4 0.94 68 4 0.94 LD 38 0 1.00 38 2 0.95 38 2 0.95 Ld 30 0 1.00 30 2 0.93 30 2 0.93

LD, high-dose dexamethasone; Ld, low-dose dexamethasone.

For patients >65 and >70 years of age, the percentage undergoing ASCT were significantly lower than for the <65 group. However, even in these older age groups the early use of auto-SCT led to a significantly higher probability of survival at 3 years.

Landmark Survival Probability for Patients over Age 65

    1-year 2-year 3-year     N Events

Survival Probability

N Events Survival Probability N Events Survival Probability No Early Transplant all 200 13 0.94 200 37 0.81 200 57 0.69 LD 97 8 0.92 97 22 0.77 97 28 0.70 Ld 103 5 0.95 103 15 0.86 103 29 0.67 Early Transplant all 22 1 0.95 22 2 0.91 22 3 0.83 LD 12 1 0.92 12 1 0.92 12 1 0.92 Ld 10 0 100 10 1 .090 10 2 0.75

LD, high-dose dexamethasone; Ld, low-dose dexamethasone.

This landmark analysis of the results of the E4A03 trial for patients surviving the first 4 cycles of lenalidomide-dexamethasone induction suggest that the probability of survival at 3 years following initiation of therapy is significantly better for those patients undergoing early autologous-SCT whether they are under or over 65 years of age.

In a second E4A03 analysis, David Vesole from Hackensack University examined the 2-year survival of patients receiving low-dose dexamethasone plus lenalidomide versus those patients receiving high-dose dexamethasone plus lenalidomide.2 this was an intent to treat analysis. this analysis examined the survival probability for Ld versus LD therapy with regard to age of the participants. overall survival (OS) in the E4A03 trial at 1 and 2 years was superior for low-dose dexamethasone compared to high-dose dexamethasone in all age groups (<65, >65, or >70 years of age). this was despite the higher initial response rates in the high-dose dexamethasone group. considering the increased toxicity and early deaths associated with high-dose dexamethasone in this trial, low-dose dexamethasone should be considered the best choice for all age groups.

In abstract 42, Michele Cavo provided an update of the GIMEMA trial comparing induction therapy with thalidomide-dexamethasone (TD) to TD plus bortezomib (VTD).3 At a median follow-up of 31 months, the median progression-free survival (PFS) was 42 months for TD and “not yet reached” for VTD. Randomization to VTD appeared to overcome the negative prognostic effect of the t(4;14) translocation on PFS. In a multivariate analysis, variables favorably influencing PFS were ß2M<3.5, absence of t(4;14) and/or del17p, randomization to VTD, attainment of at least a very good partial response (VGPR) and a complete response (CR). although there was no statistically significant difference in OS, the survival curves did appear to begin to diverge after 40 months follow-up.

Shaji Kumar from the Mayo Clinic Rochester provided an update of the randomized phase II EVOLUTION trial.4 Approximately 140 previously untreated symptomatic patients with myeloma were randomized to 1 of 4 regimens: bortezomib, dexamethasone, and lenalidomide (VDR), VDR plus cyclophosphamide (VDCR), bortezomib, dexamethasone, and cyclophosphamide (VDC), or VDC-modified, which added an additional cyclophosphamide dose on day 15. Baseline characteristics were similar. A median of 5-6 cycles was administered in each arm of the study. the best confirmed response rates across all cycles are noted here.

Response % VDCR N = 42 VDR N = 42 VDC N = 32 VDC-mod N = 17 ORR (>PR) 86 83 75 100 CR 24 24 22 47 sCR 14 19 9 29 CR+nCR 34 38 31 47 >VGPR 57 50 41 53

ORR, overall response rate; PR, partial response; CR, complete response; sCR, stringent complete response; nCR, near complete response; VGPR, very good partial response.

All 4 arms appeared highly active, but the 4-drug VDCR arm did not result in a substantial increase in response rates compared to the VDR arm. Safety profiles were similar and quite acceptable although there was a higher rate of adverse event–related treatment discontinuation in the VDCR arm. Moving forward, the planned Eastern Cooperative Oncology Group (ECOG) phase III trial will now compare VDR with the VDC-modified regimen.

Maintenance treatments following front-line or induction therapy followed by ASCT have garnered a great deal of interest recently. the CALGB 100104 trial was initially presented at ASCO 2010 and the 12-month results demonstrated a significant increase in time to progression (TTP) for patients receiving lenalidomide maintenance versus placebo after induction therapy and ASCT.5 In abstract 37 at ASH 2010, Philip McCarthy from Roswell Park Cancer Institute updated the results of the CALGB 100104.6 In this trial, 568 patients underwent induction therapy and the 460 patients, who successfully completed induction and agreed to participate, were then randomized to lenalidomide versus placebo. this analysis was performed after nearly 18 months of follow-up. There had been 231 events to that point: 44 events in the lenalidomide arm and 91 events in the placebo arm (P<.0001). this suggested a 61% reduction in the incidence of disease progression or death in the lenalidomide arm. Time to progression was 42 months for the lenalidomide maintenance arm versus 22 months for the placebo arm. overall survival thus far is similar for the 2 arms. As expected, hematologic adverse events and infections were more common in the lenalidomide maintenance arm. There was, however, a more concerning note from this study. the number of secondary malignancies seen in the lenalidomide arm was higher than in the placebo arm: 15 versus 10. the significance of this difference is uncertain at this time, but certainly bears further observation.

In abstract 310, Michel Attal presented the final analysis of the IFM 2005-02 trial in which patients <65 years of age with non-progressive disease following induction therapy followed by auto-SCT followed by 2 cycles of lenalidomide consolidation were randomized to lenalidomide maintenance versus placebo.7 Baseline characteristic were similar for the maintenance and placebo groups. There were also no significant differences in the induction therapy received, the post-transplant response rates and the number of transplants received. In both arms, response depth was improved by the 2 cycles of lenalidomide consolidation. this analysis took place a median of 34 months from randomization and 44 months from initiation of treatment. Progression-free survival was significantly improved with lenalidomide maintenance: 42 months versus 24 months for placebo. Progression-free survival at 4 years was 60% for the lenalidomide arm and 33% for the placebo arm. this improvement in PFS was seen in all post-consolidation response groups: CR, VGPR, and partial response (PR). Five-year post-diagnosis overall survival was 81% for both groups. Once again there was an increase in secondary malignancies in the lenalidomide maintenance arm (16) compared to the placebo arm (3). Two-thirds of these were hematologic malignancies.

A final abstract, number 622, bears discussion. this was Antonio Palumbo’s update of the international study of front-line therapy for older patients with myeloma comparing melphalan and prednisone (MP) with melphalan, prednisone, and lenalidomide (MPR), and MPR followed by maintenance lenalidomide (MPR-R).8 this study was originally presented at the 2009 ASH meeting and demonstrated superior response rates and PFS for the MPR-R arm compared to MP alone. the MPR-R arm was also significantly superior to MPR without R-maintenance. this year Dr Palumbo, from the University of Torino, presented the results of the second interim analysis with a median follow-up of 21 months. after 9 cycles of therapy the >VGPR rates for MP alone were approximately 12% compared to approximately 28% for both MPR and MPR-R.

However, median PFS was significantly greater only for the MPR-R arm at 31 months compared to 14 months for MPR and 13 months for MP alone. this represented a 69% reduction in disease progression. Sub-group analysis demonstrated that all groups derived greater benefit from MPR-R compared to MP. There was decreased dose intensity and a higher drug discontinuation rate among patients >75 years treated on the MPR-R arm. those patients >75 years of age appeared to benefit somewhat less from MPR-R than did the 65-75 year old group. There was a slight increase in solid tumors and hematologic malignancies in the lenalidomide arms compared to the MP arm, but there was no significant difference noted between the MPR and MPR-R arms. overall survival at 36 months was no different being approximately 70% for all 3 treatment groups.

  1. Siegel DSD, Jacobus S, Rajkumar SV, et al. Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in the ECOG E4A03 randomized clinical trial. Blood. 2010;116(21). Abstract 38 and oral presentation at: American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL.

  2. Vesole DH, Jacobus S, Rajkumar SV, et al. Lenalidomide plus low-dose dexamethasone (Ld): Superior one and two year survival regardless of age compared to lenalidomide plus high-dose dexamethasone (LD). Blood. 2010;116(21). Abstract 308 and oral presentation at: American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL.

  3. Cavo M, Perrone G, Buttignol S, etl. Bortezomib-thalidomide-dexamethasone compared with thalidomide-dexamethasone as induction and consolidation therapy before and after double autologous transplantation in newly diagnosed multiple myeloma: Results from a randomized phase 3 study. Blood. 2010;116(21). Abstract 42 and oral presentation at: American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL.

  4. Kumar S, Flinn IW, Richardson PG, et al. novel three- and four-drug combination regimens of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide, for previously untreated multiple myeloma: Results from the multi-center, randomized, phase 2 EVOLUTION study. Blood. 2010;116(21). Abstract 621 and oral presentation at: American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL.

  5. McCarthy PL, Owzar K, Anderson KC, et al. Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant (ASCT) for multiple myeloma (MM): CALGB 100104. J Clin Oncol. 2010;28(15s). Abstract 8017.

  6. McCarthy PL, Owzar K, Anderson KC, et al. Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma: CALGB 100104. Blood. 2010;116(21). Abstract 37 and oral presentation at: American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL.

  7. Attal M, Cances-Lauwers V, Marit G, et al. Maintenance treatment with lenalidomide after transplantation for MYELOMA: Final analysis of the IFM 2005-02. Blood. 2010;116(21). Abstract 310 and oral presentation at: American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL.

  8. Palumbo A, Delforge M, Catalano J, et al. A phase 3 study evaluating the efficacy and safety of lenalidomide combined with melphalan and prednisone in patients >65 years with newly diagnosed multiple myeloma (NDMM): Continuous use of lenalidomide vs fixed-duration regimens. Blood. 2010;116(21). Abstract 622 and oral presentation at: American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL.

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2010 Annual Hematology Meeting – Multiple Myeloma « OncoFacts


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