In-class Transition from Parenteral Bortezomib to Oral Ixazomib in Newly Diagnosed Multiple Myeloma: Analysis of US MM-6 By Number of Treatment Cycles Received
Authors: Richter Joshua , Girnius Saulius , Birhiray Ruemu , Lloyd Eric , Cherepanov Dasha , Noga Stephen J. , Nascimento-Ferreira Isabel , Rifkin Robert 
Published: December 2024

Background: Long-term proteasome inhibitor (PI)-based therapy can improve overall survival and delay disease progression for patients (pts) with multiple myeloma (MM), but this can be particularly difficult to achieve in pts with comorbidities. US MM-6 is a prospective, community-based phase 4 study of in-class transition (iCT) from parenteral bortezomib (V)-based induction to all-oral ixazomib-lenalidomide-dexamethasone (IRd) in pts with newly diagnosed MM (NDMM; NCT03173092). US MM-6 aims to extend the duration of PI-based therapy and improve clinical outcomes while maintaining pt quality of life (QoL). We report results by number of treatment cycles received.

Methods: Transplant-ineligible/delayed-transplant (≥24 months) pts with NDMM, who had achieved a response of stable disease or better after 3 cycles of V-based induction, were enrolled at US community sites to receive IRd for up to 39 cycles or until progression or toxicity. For this analysis, data were assessed in subgroups of pts who had received 1−3, 4−9, and &gt;9 IRd cycles (or 4-6, 7-12, and &gt;12 cycles of overall PI-based therapy, respectively). Comorbidities were assessed via a modified Charlson Comorbidity Index (mCCI); a score of 0 indicates no comorbidities, while higher scores indicate higher probability of mortality in pts with comorbidities (Charlson, J Chronic Dis 1987).

Results: At data cutoff (October 12, 2023), 140 pts had been enrolled and treated, 27 (19%) pts had received 1−3 IRd cycles, 35 (25%) had received 4−9 cycles, and 78 (56%) had received &gt;9 cycles. Most common reasons (&gt;25%) for treatment discontinuation were pt withdrawal (41%) and treatment-emergent adverse events (TEAEs, 37%) in the 1−3 cycles group; TEAEs, progressive disease, or physician decision (26% each) in the 4−9 cycles group; and AEs (31%) in the &gt;9 cycles group. In the 1−3, 4−9, and &gt;9 cycles groups, respectively, median age was 75, 73, and 71 yrs, and 52%, 46%, and 37% were aged ≥75 yrs; 59, 74, and 50% of pts were male; and 26, 20, and 38% had a baseline International Staging System score of III. Of the pts in the 1−3, 4−9, and &gt;9 cycles groups, 89, 91, and 97% had ≥1 comorbidity at baseline, respectively, including renal/urinary disorders (41, 34, and 29%), cardiac disorders (30, 20, and 32%), peripheral neuropathy (PN) or sensory PN (30, 9, and 23%), and diabetes mellitus (19, 11, and 22%); 48, 49, and 46% had an mCCI score of 0, and 52, 51, and 54% had an mCCI score of 1-5. In pts who received 1−3, 4−9, and &gt;9 IRd cycles, median PFS in months was 7.5 (95% confidence interval [CI] 2.7-not reached [NR]), 24.6 (5.8-NR), and NR (NR-NR); the 2-year PFS rates were 30% (95% CI 7−59), 51% (31−68) and 81% (69−88), respectively. Grade ≥3 TEAEs were reported in 59% of pts in the 1−3 cycles group, 60% in the 4−9 cycles group, and 78% in the &gt;9 cycles group; grade ≥3 TEAEs were treatment-related in 30, 37, and 40% of pts, respectively. Serious TEAEs were reported in 48% of pts in the 1−3 cycles group, 34% in the 4−9 cycles group, and 47% in the &gt;9 cycles group; serious TEAEs were treatment-related in 19, 9, and 13% of pts, and 2, 1, and 2 pts died on-study, respectively. Any grade TEAEs reported in ≥25% of pts were diarrhea (26%) in the 1−3 cycles group; PN not elsewhere classified (NEC; 34%), fatigue (34%), diarrhea (34%), and edema NEC (26%) in the 4−9 cycles group; and diarrhea (68%), PN NEC (53%), fatigue (42%), edema NEC (38%), arthralgia (35%), nausea (33%), and back pain (29%) in the &gt;9 cycles group. Grade ≥3 TEAEs reported in ≥5% of pts overall were diarrhea (9%), decreased neutrophil count (6%), pneumonia (6%), anemia (5%), and decreased platelet count (5%).

Conclusions: In non-transplant pts with NDMM, iCT from V-based induction to all-oral IRd permits long-term PI-based treatment while maintaining a tolerable safety profile. Despite the high percentage of pts with comorbidities, represented by mCCI scores of ≥1 across all cycle groups analyzed, the majority of pts received &gt;9 IRd cycles (or &gt;12 cycles of PI-based therapy) with no new safety concerns reported, demonstrating feasibility for longer treatment duration. As previously reported, long IRd treatment leads to clinically meaningful benefits in patients with NDMM (Facon, Blood 2021). Long-term triplet consolidation with IRd may delay progression and provide an alternative and convenient approach to induction/maintenance for community-based NDMM pts who are not eligible for upfront transplantation, including in pts with comorbidities.