The 60th American Society of Hematology (ASH) Annual Meeting was held in San Diego, California, from 1–4 December 2018. On Saturday 1 December 2018, an oral abstract session was held entitled: Clinical Autologous Transplantation: Results: Multiple Myeloma: Upfront Autologous Transplantation, which focused on updates of advanced clinical trials for newly diagnosed multiple myeloma (NDMM). During this session, Ravi Vij from Washington University School of Medicine, St. Louis, US, reported on the safety and efficacy of the triplet combination that includes ixazomib, lenalidomide, and dexamethasone (IRd).
This all-oral regimen is being studied in a phase II clinical trial as consolidation treatment after an autologous stem cell transplant (ASCT) and prior to maintenance with ixazomib or lenalidomide in patients with NDMM. The primary endpoint of this trial is to determine improvement in minimal residual disease (MRD) after four cycles of IRd consolidation. Secondary endpoints include toxicity, IMWG response rate, progression-free survival (PFS), and overall survival (OS).
The current presentation focused on results related to the MRD assessment from the consolidation phase only.
- Total number of NDMM patients to be enrolled in the trial = 240
- Age = 18–70 years
- Consolidation treatment = 80–120 days after ASCT; four 28-day cycles of IRd (ixazomib: 4 mg, days 1, 8, and 15; lenalidomide: 15 mg, days 1–21; dexamethasone: 40 mg, days 1, 8, and 15)
- Maintenance therapy = One month after the last consolidation cycle, patients are randomized with single-agent ixazomib (4 mg, days 1, 8, and 15) or lenalidomide (15 mg daily).
- MRD assessment: After 12 cycles of ixazomib or lenalidomide maintenance using ClonoSEQ or multi-color flow cytometry (MFC) if ClonoSEQ is not available
- Number of patients enrolled so-far = 191 started on IRd; 145 randomized to maintenance: 74 to ixazomib; 71 to lenalidomide
- Number of patients with data for pre- and post-consolidation = 169
- Median age = 57 (range, 28–70)
- Gender: 67% male
- Race: 76% white; 10% African-American/Black; 13% another race
- International Staging System (ISS) stage: 41% ISS I; 27% ISS II; 19% ISS III; 14% unreported
- Treatment history:
- Induction treatment with a combination of a proteasome inhibitor and an immunomodulatory drug = 83% of patients
- Number of cycles = 4 (range, 2–13)
- Median start of ASCT treatment = 170 days (range, 83–428) post diagnosis
- Median start of consolidation treatment = 110 days (range, 80–138) post ASCT
- Grade 3 hematologic-related toxicities: 7% neutropenia; 3% thrombocytopenia; 1.8% anemia
- Grade 4 hematologic-related toxicities: None
- Grade 1 non-hematologic-related toxicities: 30% gastrointestinal; 35.5% fatigue; 14.8% edema; 16.6% insomnia; 26.6% hyperglycemia; 12.4% upper respiratory/lung infections; 40.8% peripheral neuropathy; 11.8% skin rash
- Grade 3 non-hematologic-related toxicities: Very low percentages with no cases of peripheral neuropathy
- Grade 4 non-hematologic-related toxicities: None, except for one case of sepsis
- Discontinuation of consolidation = 8.3% of patients (4.1% due to toxicity; 2.4% due to disease progression; 1.2% due to other reasons)
- Clinical response rate:
- Complete response (CR) and/or stringent CR (sCR): Pre-consolidation = 47%; post-consolidation = 63%, P < 0.0001
- Very good partial response or better ( VGPR): Pre-consolidation = 81%; post-consolidation = 86%, P = 0.0495
- MRD negative rate (using clonoSEQ; n = 125 patients): Pre-consolidation = 22%; post-consolidation = 30%, P = 0.0389
- MRD negative rate (irrespective of assessment method; n = 153 patients): post-consolidation = 38%
- Median follow-up from start of IRd consolidation = 19 months
- Median follow-up on maintenance = 15 months
- Number of patients who relapsed/progressed = 36
- Deaths = 6 (1 death on study and 5 on follow-up)
The all-oral combination regimen IRd appears to be safe and effective as consolidation treatment and results in improvement in MRD negative rates. The clinical significance of this improvement remains to be determined. An interim analysis of this study is planned for 2019 comparing for the first time ixazomib and lenalidomide maintenance treatments.
Vij R. et al. Ixazomib-Lenalidomide-Dexamethasone (IRd) Consolidation Following Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma: A Large Multi-Center Phase II Trial. 2018 Dec 1; Oral Abstract #123: ASH 60th Annual Meeting and Exposition, San Diego, CA.