Effectiveness and Safety of Ixazomib in Combination with Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma in a Real-Life Population in France: The Remix Study

Background Ixazomib (IXA) is an oral proteasome inhibitor (PI) used in combination with lenalidomide and dexamethasone (IXA-Rd) for patients (pts) with relapsed and/or refractory multiple myeloma (RRMM). Efficacy and safety have been demonstrated in the phase 3 Tourmaline-MM1 clinical trial (1), which has recently reported the longest median overall survival (mOS) in phase III studies of Rd-based triplets (53.6 months, mo) (2).

The REMIX study has been conducted since IXA became available in France in 2017. It is the largest cohort of RRMM pts receiving IXA-Rd combination in real life. The final analysis was performed with a median follow-up of 28.7 mo.

Methods REMIX is a non-interventional, prospective study conducted in 59 sites (public and private) in pts with RRMM in France. To be eligible pts had to receive IXA-Rd in second line or later and IXA had to be initiated concomitantly to Rd (pts who started lenalidomide (lena) more than 6 weeks before IXA were excluded). After inclusion, pts were assessed every 3 mo during 24 mo and then every 6 mo as per standard practice.

Analysis comprised OS, progression-free survival (PFS), overall response rate (ORR), very good partial response (VGPR) and tolerance. The analysis was conducted for the overall population and in subgroups of interest: age and lines of treatment (L2, L3 or L4+).

Results A total of 376 eligible pts were included. Median age was 71 years (y) with 18.4% of patients aged ≥80y. At IXA-Rd initiation, 48.8% of pts were frail and 21.8% had renal clearance ≤50 ml/min. Comorbidities were reported in 62.8% of pts, including diabetes (8.8%), renal disease (8.8%) or solid tumour (6.4%). At inclusion, the cytogenetic risk was standard, high or unknown in 44.4%, 12% and 43.6% of pts, respectively. MM was diagnosed at a median of 4y before IXA-Rd initiation.

44.5% of pts had previous autologous stem cell transplantation (ASCT). IXA-Rd was initiated in L2, L3 or advanced lines (L4+) in 60.4%, 18.1% and 21.5% of pts, respectively. Regarding previous treatment received, 66.0% of pts had received IMID (including 39.2% lena and 11.7% pomalidomide), 93.1% had received PI (including 91.7% bortezomib and 7.5% carfilzomib) and 13.9% had received daratumumab.

Most pts were previously exposed to lena in L3 (73.5% of L3, n=50/68, for a median duration of 16 mo) and L4+ (91.3% of L4+, n=73/81, for 17 mo) compared to L2 (10.6% of L2, n=24/227, for 18 mo). Out of all pts, 26, (7.9%) were considered lena-refractory during previous therapy. The median washout (WO) period between lena discontinuation and IXA-Rd start was 22.8 mo (SD: ±23.9). IXA was used for a median of 12.4 mo (13 cycles) at a 4-mg dose for 90.4% of pts.

The median PFS (mPFS) was 19.1 mo (95% CI: 14.9-21.5) for the overall cohort, with a mPFS of 21.5 mo (95% CI: 19.2-24.8) for L2 (n=213), 21.9 mo (95% CI: 16.2-28.7) for L3 (n=65) and 5.8 mo (95% CI: 4.8-9.4) for L4+ (n=80). In the subgroups of pts aged <80y (n=293) and ≥80y (n=65), mPFS were 19.1 mo (95% CI: 15.9-21.9), and 17.4 mo (95% CI: 10.8-23.0), respectively. The mOS was not reached for the overall cohort; 36mo and 48mo OS rates were respectively 58.3% (95% CI: 52.6%-63.9%) and 52.4% (95% CI: 44.2%-60.5%). The 36mo OS rates were 63.4% (95% CI: 56.1-70.8%), 68.9% (95% CI: 57.1-80.7%) and 35.3% (95% CI: 23.9-46.7%) in L2, L3 and L4+ pts respectively. Among the 331 pts with available response according to investigators, the ORR was 73.1% (79.8% in L2, 70% in L3 and 54.4% in L4+ patients) and the VGPR rate was 45% (52.7% in L2, 41.7% in L3 and 25% in L4+ pts).

IXA discontinuation was reported in 74.1% of pts (n=278). Discontinuation was related to AE in 21% of cases (n=79). Serious adverse events (SAE) were reported in 54.3% (n=204), including 57 (15.2%) pts with SAE considered related to IXA. Most frequent (>10%) AEs were diarrhoea (52%), thrombocytopenia (45.9%), asthenia (29.7%), neutropenia (23.6%) and anaemia (22.3%).

Conclusion The REMIX study reported a mPFS in real-world conditions of 19.1 mo consistent with MM1 (20.6 mo), while half of patients were considered frail and 39.2% had previously received lenalidomide. The effectiveness in third line of treatment is similar to that in second line but was lower in L4+ as expected (5.7 mo). mOS is not reached at 48mo which aligns with MM1 final analysis. Reported AEs are consistent with the known safety profile of Ixazomib. Funding

Takeda

Vincent:BMS: Membership on an entity's Board of Directors or advisory committees, Other: Financing meeting participation; Pfizer: Other: Financing meeting participation, congress participation; Sanofi: Honoraria, Other: Financing meeting participation; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Financing meeting participation; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financing meeting participation; Sandoz: Other: Education course paid by sandoz; Amgen: Membership on an entity's Board of Directors or advisory committees. Laribi:AbbVie, AstraZeneca, Beigene, Iqone, Janssen, Novartis, Takeda: Honoraria. Hulin:Amgen: Honoraria; Takeda: Honoraria; GSK: Honoraria; BMS: Honoraria; Janssen: Honoraria; Sanofi: Honoraria. Macro:Takeda: Honoraria, Other: Travel/accommodation, Research Funding; GSK: Honoraria; Sanofi: Honoraria; Janssen: Honoraria, Other: Travel/accommodation, Research Funding. Karlin:Celgene-BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial Support travel & scientific meetings; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial Support travel & scientific meetings; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barué:Takeda: Current Employment. Chouaid:Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Leleu:Janssen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Amgen, Merck, BMS, GSK, Janssen, Oncopeptide, Takeda, Roche, Novartis, AbbVie, Sanofi, Gilead, Pfizer, Harpoon Therapeutic, Regeneron, Iteos: Consultancy, Honoraria; BMS: Honoraria; Amgen, BMS/Celgene, Janssen, Takeda, Novartis, Sanofi, Merck, Oncopeptide, Karyopharm, Roche, Abbvie, Carsgen, GSK, and Harpoon Therapeutics: Honoraria.