Real-Life-Setting Effectiveness of Ixazomib in Combination with Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma: The Remix Study
Authors: Clement-Filliatre Lauriane , Benboubker Lotfi , Stoppa Anne-Marie , Rodon Philippe , Laribi Kamel , Vincent Laure , Collet Philippe , Richez Valentine , Charvet-Rumpler Anne , Zerazhi Hacene , Hulin Cyrille , Maloisel Frederic , Macro Margaret , Karlin Lionel , Texier Nathalie , Chouaid Christos , Leleu Xavier 
Published: November 2020

Background
Ixazomib (IXA) is an orally-administered proteasome inhibitor approved in Europe in November 2016 for relapsed and/or refractory multiple myeloma (RRMM). It became available in France in May 2017 via a compassionate use program (CUP) and from October 2018 via the classical market access (non-CUP).
In addition to pivotal clinical trials, real-world evidence (RWE) is required to evaluate effectiveness and safety in clinical routine practices. A non-interventional study, has been conducting in France to evaluate IXA use in combination with lenalidomide and dexamethasone (IRD) in real life.
Methods
REMIX is a non-interventional, multicentric study to assess IRD effectiveness and safety, conducted in 59 sites (public and private) in patients with RRMM. IRD was initiated in second line or more during the CUP and afterwards. After inclusion, patients were assessed every 3 months (mo) during 24 mo then every 6 mo as per standard practice.
This interim analysis assessed IRD effectiveness (median Progression Free Survival (mPFS), 12 and 24-mo overall survival (OS) rates and tolerance in the CUP patients initiating IXA concomitantly to RD (patients who started lenalidomide more than 6 weeks before IXA were excluded). The analysis was conducted globally and per subgroups (age, number of lines of treatment, frailty as defined by Facon T & al.in Leukemia 2020). The CUP-patient median study follow-up was 17.4 mo for this interim analysis.
Results
The 198 eligible CUP patients were 47% of males, with a median age of 69 years (26% ≥75y). Out of them, 45% were frail and 7% had renal failure (CrCl ≤30 ml/min). Comorbidities were reported in 64% of patients including diabetes (9%), renal disease (10%), solid tumor (9%). At diagnosis, the cytogenetic risk was standard, high or unknown in respectively 46%, 13% and 41% of patients; 11% presented a plasmacytoma. 41% had multiple or severe bone lesions and 25% peripheral neuropathy. MM was diagnosed at a median of 4 years before IRD initiation.
IXA was initiated after one (L2) / two (L3) / three or more lines of treatment (L4+) in respectively 58%, 18% and 24% of patients. Of them, 38% had received lenalidomide during prior line(s), mainly in patients with L3 and L4+ (78%, 65/84) vs L2 (8%, 9/114). The median washout period between lenalidomide discontinuation and IRD start was 18 mo 95%CI [17.6 - 29.6].
The mPFS was 19.2 mo 95%CI [13.3; 21.9] for the CUP cohort. mPFS was 21.5 mo 95%CI [13.3; 21.9] for L2 (104 patients), 17,8 mo 95%CI [12.2; 26.7] for L3 (29 patients) and 5.6 mo 95%CI [4.1; 8.8] for L4+ (38 patients) (c.f. Figure1). mPFS was similar in &lt;75 YO (19.2, mo 95%CI [12.3; 24.8]) and in ≥75 YO patients (19.2 mo, 95%CI [1.7; 21.5]). In the subgroup with available frailty score (n= 124), mPFS was 21.5 mo 95%CI [12.5; -] in non-frail and 13.3 mo 95%CI [5.6 ; 19.8]) in frail patients.
12mo and 24mo-OS rates were 84% 95%CI [78%; 89%] and 73% 95%CI [65%; 80%] for the global group. Among the 166 patients with available response according to investigators, overall response rate (ORR) was 68% (66% in &lt;75 YO and 71% in ≥75 YO patients) and very good partial response (VGPR) 35% (38% in&lt;75 YO and 27% in ≥75 YO patients).
The 187 followed-up CUP patients received a median of 14 IRD cycles. IXA discontinuation was reported in 50% of patients (n=92), related to AE in 13% of cases (n= 24). Serious adverse events were reported in 34% (n=69), including 14 (7%) patients with SAE considered related to IXA. Most frequent (&gt;10%) AE were thrombocytopenia (30%), diarrhoea (28%), asthenia (20%), anaemia (18%), neutropenia (15%), nausea (14%) and peripheral neuropathy (10%).
Conclusion
Few RWE data have been published for IXA use in Europe. In this first interim analysis, estimated mPFS is consistent with MM1 results or data reported in MM1 study (19,2 mo vs 20.6 mo) even though CUP patients in REMIX were globally elder, frailer and more frequently treated in advanced lines (24% of L4+ in REMIX vs 11% of L4 in MM1). Reported adverse events were in line with known safety IXA profile.
Figure 1

Disclosures
Laribi: abbvie: Honoraria, Research Funding; amgen: Research Funding; novartis: Honoraria, Research Funding; takeda: Research Funding. Vincent:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Congress support; takeda: Membership on an entity's Board of Directors or advisory committees, Other: Congress support; janssen: Membership on an entity's Board of Directors or advisory committees, Other: Congress support. Hulin:Celgene/Bristol-Myers Squibb, Janssen, GlaxoSmithKline, and Takeda: Honoraria. Macro:sanofi: Honoraria; gsk: Honoraria; janssen: Honoraria, Other: travel accomodation, Research Funding; takeda: Honoraria, Other: travel accomodation, Research Funding. Karlin:Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Personal fees; Sanofi: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees. Texier:Kappa Santé: Other: employee of the CRO in charge of REMIX. Chouaid:pfizer: Honoraria, Research Funding; GSK: Honoraria, Research Funding; novartis: Honoraria, Research Funding; pfizer: Honoraria, Research Funding; takeda: Honoraria, Research Funding; bms: Honoraria, Research Funding; msd: Honoraria, Research Funding; astra zeneca: Consultancy, Honoraria, Research Funding; amgen: Consultancy, Honoraria, Research Funding; roche: Consultancy, Honoraria, Research Funding. Leleu:GSK: Honoraria; Amgen: Honoraria; BMS-celgene: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Oncopeptide: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Novartis: Honoraria; AbbVie: Honoraria; Karyopharm: Honoraria.