Patients non-eligible for transplant

ASH 2017 | Treatment strategies for NDMM patients not undergoing transplant

The MM Hub is pleased to share research findings from the 59th American Society of Hematology (ASH) Annual Meeting in Atlanta, Georgia.  On Monday 11 December 2017, an evening oral abstract session took place: Session 653. Myeloma: Therapy, Excluding Transplantation II. This session was moderated by Kenneth H. Shain from the Moffit Cancer Center, Tampa, FL and Elisabet E. Manasanch from the MD Anderson Cancer Center, Texas. Several of the talks in this session covered treatment options for Newly Diagnosed Multiple Myeloma (NDMM) patients and are summarized below. The data is based on that presented at the live sessions and may supersede that in the pre-published abstracts.

Abstract 901: Long-Term Outcome of Lenalidomide-Dexamethasone (Rd) vs. Melphalan-Lenalidomide-Prednisone (MPR) vs. Cyclophosphamide-Prednisone-Lenalidomide (CPR) as Induction Followed by Lenalidomide-Prednisone (RP) vs Lenalidomide (R) as Maintenance in a Community-Based Newly Diagnosed Myeloma Population: Updated Analysis of EMN01 Phase III Study

The first talk in this session was delivered by Sara Bringhen from University of Torino, Torino, Italy, in which she presented updated data from the phase III EMN01 study. Continuous lenalidomide, induction and maintenance therapy has shown improvement in progression-free (PFS) survival for elderly, non-transplant eligible patients. Prior studies including MM-015 trial and the FIRST trial have both demonstrated this benefit.  The aims of the current study were to assess the impact on outcomes for non-transplant eligible MM patients, comparing triplet versus doublet induction and single versus 2 drug maintenance therapy.

Key Findings:
Induction Phase
  • N = 654 patients
  • Treatment Regimens
    • n = 217 lenalidomide, dexamethasone (Rd)
    • n = 217 melphalan, prednisone, lenalidomide (MPR)
    • n = 220 cyclophosphamide, prednisone, lenalidomide (CPR)
  • Median age: Rd = 74 years, MPR = 74 years, CPR = 73 years
  • High-risk disease: Rd = 26%, MPR = 23%, CPR = 26%
  • PFS
    • MPR = 22.2 months vs Rd = 18.6 months, HR 0.83; 95% CI 0.67-1.03, p = 0.09
    • MPR = 22.2 months vs CRP = 18.9 months, HR 0.78; 95% CI 0.64-0.97, p = 0.02
  • PFS not impacted by frailty or fitness factor
  • Overall survival (OS) not significantly different among 3 induction arms
  • Adverse events (AEs)
    • Grade 3/4 AEs similar regardless of frailty or fitness
    • Most common non-hematologic toxicities: infection, fatigue, fever, cardiac, secondary malignancies
    • MPR resulted in significantly higher rates of grade 3/4 neutropenia and thrombocytopenia
    • Dose reduction and discontinuation due to AEs highest in MPR group
Maintenance Phase
  • Treatment Regimens
    • n = 198 lenalidomide, prednisone (RP)
    • n = 204 lenalidomide (R)
  • High risk: RP = 19% vs R = 18%
  • PFS from start of maintenance: RP = 22.2 months vs R = 18.6 months, HR 0.82; 95% CI 0.66-1.03, p = 0.08
  • time to next therapy: RP = 32.4 months vs R = 29.8 months
  • No significant difference in OS at 5 years
  • AEs:
    • dose reduction highest in lenalidomide group
    • same rate of drug discontinuation due to adverse events in both groups

Professor Bringhen concluded that alkylator-based 3-drug regimens have a higher rate of grade 3/4 toxicities, and may be best suited for fit elderly patients. The added risk of toxicity from alkylator therapies does not offer significant improvements in PFS in this cohort of patients, based on the data presented. Mature data for OS is not available at this time.

Abstract 902: Efficacy and Safety of Long-Term Ixazomib Maintenance Therapy in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Not Undergoing Transplant: An Integrated Analysis of Four Phase I/II Studies

Meletio Dimopoulos of National and Kapodistrian University of Athens, Greece presented an analysis of ixazomib maintenance therapy in NDMM patients not undergoing autologous stem cell transplant (ASCT).  This summary of four studies prescribed standard MM therapy combinations of lenalidomide-dexamethasone (Rd), melphalan-prednisone (MP) or cyclophosphamide-dexamethasone (Cd) in addition to ixazomib induction and continued maintenance therapy. Ixazomib, the first oral proteasome inhibitor, was dosed once or twice weekly.  This study examined the impact on progression-free survival (PFS) and overall survival (OS) with long-term ixazomib maintenance.

Key Findings:
  • N = 121
  • Median age: 72 years
  • High-risk cytogenetics: 10%
  • Ixazomib treatment characteristics
    • Weekly dosing: 26.7 weeks
    • Twice weekly dosing: 12 weeks
    •  Dose reductions: 16%
    • Therapy discontinuation: 78%
  • IRd PFS from study entry
    • Weekly dosing: 37.2 months; twice weekly dosing: 37.6 months
  • IRd PFS from start of maintenance
    • Weekly dosing: 25.8 months; twice weekly dosing: 26.3 months
  • Three-year OS from start of maintenance for patients with weekly ixazomib maintenance: 92%
  • Response greater than or equal VGPR: 63%
  • Adverse events (AE)
    • AE during induction: 93%; AE during maintenance: 74%
    • Severe drug-related AE: Induction = 19%; Maintenance = 5%
    • AE leading to study discontinuation: Induction = 2%, Maintenance = 5%
    • AE that were severe or clinically significant were less common during maintenance than induction therapy
    • Most common clinically significant AE: cardiac arrhythmia and peripheral neuropathy
  • Maintenance therapy did not adversely affect immune reconstitution of IgA or IgG

This analysis demonstrated good outcomes for NDMM patients with prolonged ixazomib maintenance therapy. Ixazomib provided good results in terms of response rate and survival, with an acceptable AE profile. Professor Dimopoulos concluded that his data provides support for the ongoing phase III trial of the safety of ixazomib in MM patients not undergoing ASCT.

Abstract 906: Bortezomib, Lenalidomide and Low-Dose Dexamethasone (VRD) Versus Lenalidomide and Low-Dose Dexamethasone (Ld) for Newly-Diagnosed Multiple Myeloma - a Randomized Phase III Study

The last talk in this series was given by Anjali Mookerjee from AIIMS New Delhi, India, who presented data from a phase III trial to determine differences in efficacy for a bortezomib triplet versus doublet therapy in NDMM patients. The triplet regimen was bortezomib-dexamethasone-lenalidomide (VRD) compared to lenalidomide-dexamethasone (Rd).  Prior trials have compared Rd to thalidomide-dexamethasone and yielded no significant difference in clinical outcomes. 

Patients included in this study had not received prior treatment with immunomodulatory agents or proteasome inhibitors, could not have diabetes, psychiatric disorders, active infections or be pregnant. The evaluation was after 4 cycles, each of 28 days in length.

Key Findings:
  • N = 135 total patients
    • n = 70 bortezomib, lenalidomide, dexamethasone (VRD)
    • n = 65 lenalidomide, dexamethasone (Rd)
  • Median age: VRD = 56 years vs Rd = 52 years
  • No significant difference in any clinical outcomes, including overall PFS; PFS stratified by ISS, OS, VGPR, ORR or death
  • Therapies after 4 cycles
    • ASCT: VRD = 27.1% vs Rd = 27.7%
    • Maintenance therapy: VRD = 47.1% vs Rd = 32.3%
    • Salvage therapy: VRD = 10% vs Rd = 12.3%
  • Fewer than 4 cycles of therapy: VRD = 5.7% vs Rd = 13.8%
  • Adverse events (AEs)
    • Most common grade 3 or 4 toxicity was anemia: VRD = 3% vs Rd = 8%
    • Toxicity leading to treatment discontinuation: VRD = 4% vs Rd = 0%

This study adding bortezomib to induction therapy in NDMM patients demonstrated no difference in survival or disease progression outcomes and is consistent with other historical studies.  The AE profile was tolerable, but a higher rate of VRD patients discontinued therapy due to secondary to toxicity. 

References
  1. Bringhen S. et al. Long Term Outcome of Lenalidomide-Dexamethasone (Rd) vs. Melphalan-Lenalidomide-Prednisone (MPR) vs. Cyclophosphamide-Prednisone-Lenalidomide (CPR) as Induction Followed by Lenalidomide-Prednisone (RP) vs Lenalidomide (R) as Maintenance in a Community-Based Newly Diagnosed Myeloma Population: Updated Analysis of EMN01 Phase III Study. Abstract #901. 59th American Society of Hematology (ASH) Annual Meeting in Atlanta, GA, December 2017.
  2. Dimopoulos M. et al. Abstract 902: Efficacy and Safety of Long-Term Ixazomib Maintenance Therapy in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Not Undergoing Transplant: An Integrated Analysis of Four Phase 1/2 Studies. Abstract #902. 59th American Society of Hematology (ASH) Annual Meeting in Atlanta, GA, December 2017.
  3. Mookerje A. et al. Bortezomib, Lenalidomide and Low-Dose Dexamethasone (VRD) Versus Lenalidomide and Low-Dose Dexamethasone (Ld) for Newly-Diagnosed Multiple Myeloma- a Randomized Phase III Study.  Abstract #906. 59th American Society of Hematology (ASH) Annual Meeting in Atlanta, GA, December 2017.
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