Ixazomib Maintenance Induces Deep and Durable Responses in Multiple Myeloma


Patients with newly-diagnosed multiple myeloma who did not elect to undergo stem cell transplant but remained on single agent ixazomib maintenance fared as well as those who received SCT.

Shaji Kumar, MD

Shaji Kumar, MD

Patients with newly-diagnosed multiple myeloma (NDMM) who did not elect to undergo stem cell transplant (SCT) but remained on single agent ixazomib maintenance fared as well as those who received SCT, according to findings presented during the 2017 European Hematology Association congress. All patients received a induction treatment of lenalidomide and dexamethasone plus the novel oral proteasome inhibitor ixazomib.  

In the analysis, the objective response rate (ORR) in evaluable patients was 88% for those receiving SCT versus 80% for maintenance ixazomib. Complete response (CR) was achieved by 23% versus 32%, and very good partial response (VGPR) was reported in 34% versus 32% of patients in the SCT and non-SCT cohorts, respectively. Partial response (PR) was reported in 30% of patients receiving SCT and in 17% of patients remaining on ixazomib. The best response of stringent CR was achieved by 9 patients receiving SCT and by 7 patients in the ixazomib group.

“Long-term follow-up confirmed the all oral ixazomib triplet induction regimen is active in newly diagnosed multiple myeloma and can result in deep and durable responses that improve during ixazomib maintenance,” explained lead investigator Shaji Kumar, MD, from the Mayo Clinic. “These results provide a foundation for a phase III ixazomib program in newly diagnosed multiple myeloma.”

Kumar presented updated efficacy and long-term safety data from a phase I/II study (NCT01217957) for the overall study population (SCT and non-SCT) compared with patients who did not withdraw from the study to receive SCT, and between patients receiving and not receiving SCT.

After completing 12 treatment cycles of induction therapy with weekly oral ixazomib (1.68 to 3.95 mg/m²; days 1, 8, and 15), lenalidomide (25 mg days 1-21), and dexamethasone (40 mg, days 1, 8, 15, and 22), the patients either proceeded to SCT or remained on single agent ixazomib at the last tolerated dose until disease progression or unacceptable toxicity. Of the 65 enrolled patients, 23 (35%) discontinued treatment to undergo SCT and 42 (65%) elected to forgo SCT and remain on study treatment. In the cohort not receiving SCT, 37 patients (88%) discontinued treatment, due to progressive disease (50%), adverse events (AEs; 21%), and other reasons (16%).

The after 55 months follow-up, overall survival (OS) was not reached (NR) in either cohort but the estimated landmark 1-year OS rate was 94% versus 90%, in the overall population compared with patients not receiving SCT and remaining on ixazomib, respectively. Landmark 2- and 4-year OS rates were 89% versus 87% and 84% versus 82% in the overall and non-SCT populations, respectively.

Median progression-free survival (PFS) in the overall population was 35.4 months compared with 29.4 months in patients who did not receive SCT and remained on ixazomib.

Median time to best VGPR or better was rapid at 4.9 versus 6.6 months in the overall versus non-SCT cohorts and the median time to best CR was 5.6 in both cohorts. Overall, 8 (89%) versus 6 patients (86%) achieved MRD-negative status in the overall versus ixazomib maintenance cohorts, respectively. “Deepening responses were observed in patients receiving ixazomib maintenance,” Kumar noted.

In the 25 patients receiving maintenance with single-agent ixazomib, the ORR was 100% at the end of the induction period and included a 28% CR rate, 44% VGPR rate, and 28% PR rate. The ORR of 100% was maintained during maintenance but the other responses deepened with 8 patients (32%) showing an improved response during maintenance; 7 patients in VGPR achieved CR for a CR rate of 52% and 1 patient in PR achieved VGPR for a rate of 20%.

Median PFS for patients on maintenance therapy was 24 months.

The overall safety profile comprising the induction and single agent ixazomib maintenance phases showed most adverse events (AEs) occurred early on. The most common grade ≥3 hematological treatment-related AEs (TRAEs) included neutropenia (31%) and thrombocytopenia (35%), which occurred almost exclusively during the induction period. Grade ≥3 AEs were experienced by 86% of patients, with 52% considered serious AEs. The most common grade ≥3 AEs were neutropenia, thrombocytopenia, diarrhea, back pain, vomiting, rashes, eruptions and exanthems, peripheral neuropathy, and nausea

Following treatment 74% of patients had grade ≥3 TRAEs, and 26% of the patients had serious TRAEs. One treatment-related death due to respiratory syncytial viral pneumonia occurred. Overall the incidence of grade ≥3 peripheral neuropathy and rash was 10% and 5%, respectively; however, no new events of grade ≥3 peripheral neuropathy or rash were reported during maintenance.

“Quality of life according to the EORTC scale scores was maintained during treatment and improved during ixazomib maintenance,” noted Kumar.

Ixazomib was approved by the FDA in November 2015 and in the European Commission in November 2016. In both regions, the oral proteasome inhibitor is approved in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. The agent continues to be explored in the TOURMALINE development program. TOURMALINE consists of 5 ongoing pivotal trials, 4 of which are focused on multiple myeloma and the fifth on light-chain amyloidosis.


Kumar SJ, et al. Deep and durable responses with weekly ixazomib, lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up of patients who did not undergo SCT. Presented at: 22nd Annual European Hematology Association Congress; June 22-25, 2017; Madrid, Spain. Abstract S408.

The analysis comparing the overall population of 65 patients to the cohort of 42 patients that did not proceed to SCT showed similar results between cohorts. Baseline patient characteristics in the SCT cohort versus the non-SCT cohort, respectively, were median age of 66 versus 68 years, 55% of patients in both cohorts were male, and 95% versus 93% of patients had ECOG performance status of 0 or 1.

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