Rapid Readout: Community-Based United States MM-6 Study: Updated Efficacy and Safety, and Reasons for Premature Discontinuation

Leon Bernal-Mizrachi, MD, discusses efficacy and safety updates to the US MM-6 study that was presented at the ASH 63rd Annual Meeting in 2021, as well as reasons for premature discontinuation, for patients with newly diagnosed multiple myeloma (NDMM).

OncLive® Rapid Readout from Extended Characterization of Newly Diagnosed Multiple Myeloma (NDMM) Patients with In-Class Transition (iCT) from Parenteral Bortezomib to Oral Ixazomib Proteasome Inhibitor (PI) Therapy in the Community-Based United States (US) MM-6 Study: Updated Efficacy and Safety, and Reasons for Premature Discontinuation

Segment Description: Leon Bernal-Mizrachi, MD, discusses efficacy and safety updates to the US MM-6 study that was presented at the ASH 63rd Annual Meeting in 2021, as well as reasons for premature discontinuation, for patients with newly diagnosed multiple myeloma (NDMM). (Abstract 2726)

Segment Body Content:

  • Use of long-term PI-based therapy can improve outcomes across treatment settings in MM. However, there are various physical, geographical, and/or socioeconomic barriers to prolonged therapy with parenteral PIs in community practice.
  • The US MM-6 study (NCT03173092) is assessing in-class transition (iCT) from parenteral bortezomib (V)-based induction to all-oral ixazomib-based therapy with ixazomib-lenalidomide-dexamethasone (IRd) in the diverse US community population. The objective of the study is to increase the duration of PI-based treatment, while maintaining quality of life and improving outcomes.
  • We previously reported efficacy and safety results for the first 101 US MM-6 patients (Girnius Blood 2020). Here, we have analyzed updated data for this patient subset with an additional 11 months of follow-up to further evaluate efficacy and safety and to determine reasons for premature (within 4 cycles of IRd) discontinuation.

Methods

  • Transplant-ineligible/delayed-transplant (≥ 24 months) NDMM patients at US community sites who had achieved stable disease or better after 3 cycles of V-based induction received IRd (ixazomib 4 mg, days 1, 8, 15; lenalidomide 25 mg, days 1–21; dexamethasone 40 mg, days 1, 8, 15, 22) for up to 39 × 28-day cycles or until disease progression or unacceptable toxicity.
  • The primary endpoint is 2-year progression-free survival (PFS). Rates of partial response (PR), very good PR (VGPR), and complete response (CR), and duration of therapy are key secondary endpoints.
  • For the current analysis, sites with patients who discontinued US MM-6 were queried for more detailed information.

Results

  • As of June 1, 2020, 101 patients had been enrolled and treated at 21 sites. Median age was 73 years (range, 48–90 years), with 81% aged > 65 years; ninety-seven percent had ≥ 1 comorbidity at the start of IRd therapy.
  • Efficacy data after an additional 11 months of follow-up (data cut-off: May 4, 2021) showed that iCT to IRd improved responses.
  • Overall response rate (ORR) had improved from 65% (CR 9%, VGPR 25%, PR 32%), at the end of 3 cycles of V-based induction, to 78% (molecular CR [mCR] 1%, stringent CR [sCR] 3%, CR 32%, VGPR 25%, PR 17%) following iCT to IRd. Thirty-three patients (33%) were still ongoing on therapy at the latest data cut-off; median duration of IRd was 11.7 months, and overall median duration of therapy (for all PI-based therapy, including V-based induction) was 14.6 months. At a median follow-up of 18.5 months, the 18-month PFS rate was 84%.
  • The safety profile of IRd was consistent with previous clinical studies. Grade ≥ 3 treatment-emergent adverse events (TEAEs) were reported in 64% of patients and treatment-related serious TEAEs in 12% (including 4 on-study deaths), while 16% of TEAEs led to study drug discontinuation. Sixty-eight patients (67%) had completed or discontinued the study since first patient enrolment on November 15, 2017. Among these patients, 14 (21%) discontinued within 2 cycles of IRd, and 27 (40%) discontinued within 4 cycles.

Conclusions

  • With longer follow-up, use of iCT from V-based induction to IRd to achieve long-term PI-based therapy in NDMM patients demonstrates efficacy via improved response rates and acceptable PFS in this real-world setting. Over 80% of US MM-6 patients were aged > 65 years and most had ≥ 1 comorbidity prior to study entry. The rate of patients discontinuing within 4 cycles of iCT (7 cycles of PI-based therapy in total) is concerning because these patients may not receive the full benefit of long-term PI-based treatment. To date, the majority of premature discontinuations were reported as being due to patient request (44%), followed by TEAEs (30%). Expanded site education and closer patient follow-up to reduce premature discontinuations will be addressed in the planned US MM7 iCT study in relapsed/refractory MM.