No abstract

The introduction of novel agents, characterized by favorable toxicity profiles and higher manageability compared to conventional drugs employed in the past, has considerably changed the treatment paradigm for multiple myeloma. Continuous therapy currently represents the standard approach for myeloma patients both at diagnosis and at relapse. In younger patients, long-term maintenance after autologous transplantation significantly improved progression-free survival and overall survival compared to observation. Also in transplant-ineligible patients, continuous treatment with combinations of newer agents and maintenance treatment following a more intense induction phase proved to be superior as compared to fixed-duration therapy. Maintenance and continuous therapy at diagnosis have shown to deepen responses and suppress minimal residual disease. At relapse, continuous therapy allowed better disease control over time. This review covers the main evidence supporting the use of continuous therapy in multiple myeloma as well as the open issues, such as the optimal agents to be used and the optimal candidates for receiving them.

Cardiovascular adverse events (CVAEs) are linked to Carfilzomib (CFZ) therapy in multiple myeloma (MM); however, no validated protocols on cardiovascular risk assessment are available. In this prospective study, the effectiveness of the European Myeloma Network protocol (EMN) in cardiovascular risk assessment was investigated, identifying major predictors of CVAEs. From January 2015 to March 2020, 116 MM patients who had indication for CFZ therapy underwent a baseline evaluation (including blood pressure measurements, echocardiography and arterial stiffness estimation) and were prospectively followed. The median age was 64.53 ± 8.42 years old, 56% male. Five baseline independent predictors of CVAEs were identified: office systolic blood pressure, 24-h blood pressure variability, left ventricular hypertrophy, pulse wave velocity value and global longitudinal strain. The resulting ‘CVAEs risk score’ distinguished a low- and a high-risk group, obtaining a negative predicting value for the high-risk group of 90%. 52 patients (44.9%) experienced one or more CVAEs: 17 (14.7%) had major and 45 (38.7%) had hypertension-related events. In conclusion, CVAEs are frequent and a specific management protocol is crucial. The EMN protocol and the risk score proved to be useful to estimate the baseline risk for CVAEs during CFZ therapy, allowing the identification of higher-risk patients.

INTRODUCTION. Elderly patients (pts) with newly diagnosed multiple myeloma (NDMM) are a heterogeneous population. The IMWG frailty score stratifies pts ≥65 years into 3 categories (fit, intermediate-fit and frail), according to chronological age, comorbidities and functional abilities, with different prognosis. We previously reported results from the phase II EMN10-Unito study investigating 4 Ixazomib-based induction regimens followed by Ixazomib maintenance in elderly NDMM pts. Here we present a post-hoc analysis of safety and efficacy of ixazomib-based induction regimens and maintenance according to IMWG frailty score. METHODS. NDMM, transplant-ineligible pts ≥65 years were enrolled. Treatment consisted of 9 induction cycles of Ixazomib combined with dexamethasone (Id), Cyclophosphamide-dexamethasone (ICd), Thalidomide-dexamethasone (ITd) or Bendamustine-dexamethasone (IBd), followed by single-agent Ixazomib maintenance for up to 2 years. Pts were stratified into 3 groups (fit, intermediate-fit and frail) according to IMWG frailty score. The aim of this analysis was to evaluate the efficacy (TTP, PFS, PFS2 and OS) and safety of ixazomib-based induction regimens and single-agent ixazomib maintenance in the 3 patient subgroups. RESULTS. 171 pts were enrolled in the study and started treatment; of these, 75 (44%) were classified as fit, 53 (31%) as intermediate-fit and 43 (25%) as frail. As expected, the median age was higher in frail (79 years) as compared with fit (71 years) and intermediate-fit (76 years) pts, and a worse ECOG score (1-2) was reported in frail (67%) as compared with fit (46%) and intermediate-fit pts (46%). Frail pts were also more likely to have ISS 2-3 myeloma (82%) compared with fit (59%) and intermediate-fit (77%) ones. The median follow-up for the entire population was 27 months. The ORR and VGPR rates after the induction were similar in fit (71%; 42%), intermediate-fit (74%; 38%) and frail pts (76%; 40%), although fit (8%) and intermediate-fit (13%) pts were more likely to achieve a CR than frail ones (2%). No significant differences in median PFS were observed among fit (14.1 months; HR: 0.75, p=0.27), intermediate-fit (14.8, HR: 0.68, p=0.12) as compared to frail pts (12.2 months). The median PFS2 was significantly longer in fit (41.1, HR: 0.48; p=0.04) and intermediate-fit (35.6, HR: 0.47, p=0.03) in comparison with frail pts (28.6 months). OS was longer in fit pts (NR; HR: 0.36, p=0.02) and intermediate-fit (NR; HR: 0.58, p=0.15) as compared to frail ones (36.7 months). The rates of grade 3-4 adverse events (AEs) and grade 3-4 non-hematological AEs during the induction phase were higher in frail pts (47% / 37%) as compared to fit (28% / 24%) and intermediate-fit (32% / 26%) ones. Similarly, the risk of treatment discontinuation was higher in frail (21%) as compared to fit (11%) and intermediate-fit pts (9%). When comparing PFS with three- vs two-drug ixazomib-based induction, both fit (HR: 0.75) and intermediate-fit (HR: 0.69) pts benefited from the use a triplet over a doublet; whereas, no difference between three- and two-drug combinations was observed in frail pts (HR: 1.01). Overall, 102 pts (60%) completed the induction phase and proceeded to ixazomib maintenance: of these, 46 (45%) were fit, 35 (34%) intermediate-fit and 21 (21%) frail. The median PFS from start of maintenance in the overall population was 15 months, without significant differences in intermediate-fit (HR: 0.92) and frail (HR: 1.14) pts as compared to fit ones. Concerning the safety of ixazomib maintenance, grade 3-4 non-hematological AEs were infrequent, occurring in 15% of fit pts (15%), 3% of intermediate-fit and 5% of frail (5%) ones. Ixazomib dose reductions were more frequent in frail (24%) as compared to fit (13%) and intermediate-fit (11%) pts, although a similar percentage of pts discontinued ixazomib due to AEs in the three groups (fit: 11%; intermediate-fit: 15%; frail: 10%). CONCLUSIONS. Ixazomib-based regimens had similar efficacy in terms of ORR and PFS, irrespective of frailty status, although AEs, dose modifications and treatment discontinuation were more frequent in frail pts. Importantly, frail pts did not seem to benefit from the addition of a third drug over the use of a doublet induction therapy. Single-agent ixazomib maintenance was effective and well tolerated in fit, as well as in intermediate-fit and frail pts, thus representing an appealing maintenance option in elderly MM. Disclosures Mina: Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Larocca:Amgen: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Offidani:Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Galli:BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. De Sabbata:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Cavo:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boccadoro:Mundipharma: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Bringhen:Bristol-Myers Squibb: Honoraria; Takeda: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including ixazomib, dexamethasone, cyclophosphamide, thalidomide and bendamustine).