Introduction: Achieving prolonged therapy with parenteral proteasome inhibitors (PIs) in MM can be challenging in routine practice due to issues relating to poor tolerability and the burden of repeated, clinic-based treatment administration, particularly for older patients and those with comorbidities. US MM-6 is a prospective, community-based phase 4 study of iCT from parenteral bortezomib-based induction to all-oral ixazomib-lenalidomide-dexamethasone (IRd) therapy in patients with NDMM (NCT03173092). US MM-6 aims to extend the duration of PI-based therapy and improve clinical outcomes while maintaining patient quality of life (QoL). Results for the fully accrued dataset were reported previously (N=141; Yimer IMW 2022). Here, we report a subgroup analysis by patient age.

Methods: Transplant-ineligible/delayed-transplant (≥24 months) NDMM patients with ≥stable disease after 3 cycles of bortezomib-based induction were enrolled at US community sites to receive IRd for up to 39 cycles or until progression or toxicity (Manda CLML 2020). Key secondary endpoints, including rates of partial, very good partial, and complete response (PR, VGPR, and CR), duration of therapy (DOT), and other endpoints, including safety (secondary), QoL (secondary), and actigraphy (exploratory), were analyzed in subgroups of patients aged <75 and ≥75 years (yrs).

Results: Of 140 patients who received IRd as of Feb-28-2022, 81 (58%) were <75 yrs and 59 (42%) were ≥75 yrs of age. For patients aged <75 yrs vs ≥75 yrs, median age was 69 yrs (range 48-74) vs 77 yrs (range 75-90), 60% vs 54% were male, 19% vs 17% were Black/African American, 11% vs 5% were Hispanic/Latino, 30% vs 34% had International Staging System stage III disease, and 47% vs 44% had lytic bone disease. A total 91% of patients aged <75 yrs and 97% of those aged ≥75 yrs had ≥1 comorbidity at the start of IRd, including hypertension (51% vs 64%), fatigue (37% vs 34%), anemia (31% vs 37%), gastroesophageal reflux disease (30% vs 22%), insomnia (27% vs 29%), back pain (27% vs 20%), and constipation (23% vs 25%). Overall response rate (ORR) increased from 60% at the end of 3 cycles of bortezomib-based induction to 79% after iCT to IRd in patients aged <75 yrs, and from 64% to 76% in patients aged ≥75 yrs (Table). In the <75 yrs vs ≥75 yrs groups, treatment was discontinued due to progressive disease in 20% vs 19% of patients, adverse events in 29% vs 17% patients, and 'other reasons' in 35% vs 38% patients. With a median follow-up of 20.0 months at data cut-off, 22% of patients aged <75 yrs and 17% aged ≥75 yrs were ongoing on study treatment. Median DOT was 11.8 and 8.5 months for IRd (Table), and 14.8 and 11.1 months for total PI-based therapy, respectively. In the <75 and ≥75 yrs groups, respectively, treatment-emergent adverse events (TEAEs) were observed in 98% and 95% (treatment-related in 81% and 75%), and serious TEAEs in 41% and 47% (treatment-related in 14% in both age groups) of patients; on-study deaths occurred in 2 patients in each age group. The most common any-grade TEAEs were diarrhea (<75 yrs: 47%; ≥75 yrs: 49%), peripheral neuropathy not otherwise classified (<75 yrs: 43%; ≥75 yrs: 34%), and fatigue (<75 yrs: 36%; ≥75 yrs: 31%). In the <75 and ≥75 yrs groups, respectively, grade ≥3 TEAEs were observed in 67% and 64% of patients (treatment-related in 33% and 39%). The most common grade 3 TEAEs in patients aged <75 yrs were diarrhea (7%), neutropenia (6%), anemia (6%), and decreased platelet count (6%). Among patients aged ≥75 yrs, most common grade 3 TEAEs were diarrhea (10%), pneumonia (8%), and hypokalemia (7%). TEAEs led to modification/discontinuation of any of the 3 study drugs in 60%/16% of patients aged <75 yrs and 58%/14% of patients aged ≥75 yrs. Overall, QoL (EORTC QLQ-C30 Global Health Status/QoL score) was maintained during IRd therapy in the <75 yrs and ≥75 yrs groups, in patients with sufficient patient-reported data. Activity (hours/day) and sleep (hours/day) were generally maintained with IRd therapy in both age groups.

Conclusions: These data suggest that iCT to IRd allows long-term, tolerable PI-based treatment with improved responses in both older and younger community-treated patients with NDMM. No adverse impact on QoL, daily activity, or sleep was observed in either age group.

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Birhiray:Hematology Oncology of Indiana/American Oncology Network, PA: Current Employment; Abbvie: Consultancy; Janssen Biotech, Inc., Amgen Inc., Puma Biotechnology, Inc., Lilly Usa, Llc, Incyte Corporation, Pharmacyclics Llc, an Abbvie Company, Genzyme Corporation, Dova/Sobi Pharmaceuticals, Exelixis Inc., E.R Squibb & Sons, L.l.c., Astrazeneca Pharmaceuticals: Honoraria; Janssen Biotech, Inc., Amgen Inc., Puma Biotechnology, Inc., Lilly Usa, Llc, Incyte Corporation, Pharmacyclics Llc, an Abbvie Company, Genzyme Corporation, Dova/Sobi Pharmaceuticals, Exelixis Inc., E.R. Squibb & Sons, L.l.c., Astrazeneca Pharmaceuticals: Speakers Bureau; Array Biopharma Inc., Lilly Oncology, Janssen Scientific Affairs, Llc, Epizyme, Tg Therapeutics, Regeneron, Janssen, Abbvie, Takeda, Sanofi: Membership on an entity's Board of Directors or advisory committees; Sanofi, Diachi Sancho, Morphosys, Regeneron, Glaxo Oncology, Seagen, CTI, Blue Medicines: Speakers Bureau; Diachi Sancho, Morphosys, Regeneron, Glaxo Oncology, Seagen, CTI, Array Biopharma Inc., Lilly Oncology, Janssen Scientific Affairs, Llc, Epizyme, Tg Therapeutics, Regeneron, Janssen, Abbvie, Takeda, Sanofi: Honoraria. Rifkin:Fresenius/Kabi: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS (celgene): Honoraria, Membership on an entity's Board of Directors or advisory committees; GenMab: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; McKesson: Current Employment, Current equity holder in publicly-traded company; Coherus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Yasenchak:Seagen Inc.: Consultancy, Research Funding; Beigene: Speakers Bureau; Takeda: Research Funding. Fields-Meehan:Takeda: Research Funding. Lyons:Incyte Corporation: Consultancy, Other: Research Consulting Services; Texas Oncology/The US Oncology Network: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Other: Leadership; Celgene: Honoraria. Bogard:Takeda Pharmaceuticals: Current Employment. Tran:Takeda Pharmaceuticals U.S.A, Inc.: Current Employment. Cherepanov:Takeda: Current Employment, Current equity holder in private company. Noga:Takeda Oncology: Current Employment. Girnius:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria; Adaptive: Honoraria. Noga:Takeda Oncology: Current Employment.

Real-world evaluation of long-term use of the oral proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone for the treatment of newly diagnosed multiple myeloma in non-transplant patients with stable disease after 3 cycles of a bortezomib-based induction

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2022
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