ASH 2017 | Ixazomib-thalidomide-low dose dexamethasone (ITd) induction and maintenance with ixazomib in NDMM patients not eligible for transplant

The MM Hub were delighted to attend the 59th American Society of Hematology (ASH) Annual Meeting held in Atlanta, Georgia, from 9-12 December 2017. On Sunday 10 December, an oral session was held and entitled: Session: 653. Myeloma: Therapy, excluding Transplantation: Upfront Therapy for Multiple Myeloma: Induction and Maintenance. During this session, an oral abstract was presented by Sonja Zweegman from the Department of Hematology, VUMC, Amsterdam, Netherlands. The title of the talk was: Abstract 433: Ixazomib-Thalidomide-Low Dose Dexamethasone (ITd) Induction Followed by Maintenance Therapy with Ixazomib or Placebo in Newly Diagnosed Multiple Myeloma Patients Not Eligible for Autologous Stem Cell Transplantation; Initial Results from the Randomized Phase II HOVON-126/Nmsg 21.13 Trial.

Professor Zweegman began her talk by outlining the rationale for the ongoing Phase II HOVON study. With the combination of a proteasome inhibitor (PI) and an IMiD having shown significant efficacy in Newly Diagnosed Multiple Myeloma (NDMM) patients, such a combo is an obvious option for elderly patients who are not eligible for transplant. However, keeping adverse effects to a minimum is critical in this patient subset and so the use of ixazomib as the relevant PI provides the added benefit of an all-oral combination. Therefore, elderly non-transplant eligible (nte) NDMM were given ixazomib induction therapy in combination with thalidomide, followed by maintenance therapy with either ixazomib or placebo.

The primary endpoints of the study were progression free survival (PFS) for maintenance therapy with ixazomib or placebo, and the overall response rate (ORR) of induction therapy. The preliminary results of the study after an early interim analysis were outlined.

Study Design:

• Patients (pts) n= 142 were assessed; 94 expected to be randomized (subgroup analyses based on frailty and cytogenetic risk)
• Pts were treated with 9x 28 day-cycles:
  • Ixazomib 4mg (days 1, 8, 15), thalidomide 100 mg (day 1-28) and dexamethasone 40 mg (days 1, 8, 15, 22)
  • Pts were then randomized to either ixazomib or placebo groups (both treated on days 1, 8, 15 every 28 days) until progression
• Frailty was assessed using a modification of the IMWG frailty index based on age, the Charlson Comorbidity Index and the WHO performance status as a proxy for (instrumental) Activities of Daily Living (scoring WHO 0 as 0 points, WHO 1 as 1 point, and WHO 2-3 as 2 points); high risk cytogenetics was defined as del17p, t(4;14) or t(14;16)
• Inclusion criteria: previously untreated MM according to IMWG criteria, measurable disease, not eligible for stem cell transplant, WHO performance status (0-3 for pts, 75 yrs and 0-2 for pts ≥75 yrs)
• Exclusion criteria: Neuropathy grade 2 with pain or grade 3 and creatinine clearance < 30 ml/min

Key Data:

• Median follow up = 17.0 months (range 0.9-28.1 months)
• Overall Response Rate (ORR, i.e. ≥PR) post-induction = 81% (95% CI, 73-87%); VGPR = 34% (95% CI 35-54%); ≥ CR = 10% (95% CI 5-17%); PR = 37 %; ≥ VGPR = 44%
• ORR: Pts ≤75 years = 85% vs pts ≥76 years = 73% (p=0.15), ≥VGPR = 45% vs 42% (p=0.85), ≥CR = 13% vs 4% (p=0.21)
• Median time to response = 1.1 month; median time to max response = 4.7 months
• Classification: frail = 47%, unfit = 28% unfit and fit = 21%; 4% unknown
• Efficacy of ITd via pts:
  • Frail: ORR = 75%, ≥ VGPR = 43% and ≥ CR = 9% (p=0.34)
  • Unfit: ORR = 85%, ≥ VGPR = 53% and ≥ CR = 9% (p=0.43)
  • Fit: ORR = 88%, ≥ VGPR = 36% and ≥ CR = 16% (p=0.62)
• Cytogenetic risk was determined 90% of patients: high-risk = 19%
• Response rates in high vs standard risk patients:
  • ORR = 79% vs 84%
  • ≥ VGPR = 42% vs 48%
  • ≥ CR=  11% vs 10%
• Discontinuation of induction therapy = 54/120 pts (45%)
• Discontinuation rates: toxicity = 18/120 (15%) pts, neurotoxicity = 6, infection = 3, dermatological toxicity = 2, gastro-intestinal toxicity = 2 and other toxicity = 5
• Discontinuation rates before maintenance: pts ≥76 yrs = 62% vs ≤75 yrs = 35%; none of the 10 pts > 80 years reached maintenance therapy
• Early mortality was higher in older pts: ≥76 = 4/45 (9%) vs ≤75 = 1/75 (1%) and was mainly due to infections (3) and cardiac arrest (1)
• Discontinuation rate during induction: fit = 6/25 (24%), unfit = 11/34 (32%) and frail = 34/56 (60%)

The talk was concluded by Professor Zweegman summarizing the overall finding that induction treatment with ITd in NDMM led to a high ORR of 81%, with 44% ≥ VGPR. It was emphasized that this was equally effective in subgroup analyses via frailty and high-risk cytogenetics. This regimen, therefore, offers a valid and manageable frontline therapy for MM patients who are ineligible for transplant.

To listen to Professor Zweegman discussing this study click here.