Real-World Patterns of Utilization and Outcome of Market Approved Lenalidomide-Based Triplet Combinations in First Relapsed Multiple Myeloma Patients: Evidence from a Propensity Score Matched Analysis
Authors: Mangiacavalli Silvia , Galli Monica , Pezzatti Sara , Belotti Angelo , Fazio Francesca , Marcatti Magda , Cafro Anna Maria , Mina Roberto , Zambello Renato , Paris Laura , Cartia Claudio Salvatore , Barilà Gregorio , Olivares Cecilia , Pompa Alessandra , Mazza Rita , Farina Francesca , Soldarini Martina , Benvenuti Pietro , Lecci Marica , Ferretti Virginia Valeria , Petrucci Maria Teresa 
Published: November 2021

Abstract
Background: Lenalidomide (R) plus dexamethasone (d) triplet combinations have been indicated by ESMO guidelines as standard of care in first relapse for lenalidomide sensitive multiple myeloma (MM) patients (pts) (Dimopoulos et al, 2021). Meta-analysis of randomized clinical trials (RCT) shows better outcome with the combination of Daratumumab + Rd (DaraRd) over other Rd-based combinations (carfilzomib+Rd (KRd), elotuzumab+Rd (EloRd), Ixazomib+Rd (IxaRd). There are few real-life studies focusing on the pattern of utilization and outcome of different Rd triplets in first relapse MM.
Aims: To explore performances of market-approved Rd-based triplets in unselected MM pts in first relapse.
Patients and methods: After ethics committee approval, we review data of 366 MM pts in first relapse consecutively addressed to Rd-based triplets according to market-approved schedule after 2017. Rd-based therapies was distributed as follows: DaraRd 51.6% (189 pts), KRd 36.1% (132 pts), EloRd 8.7% (32 pts), IxaRd 3.6% (13 pts). Given the limited number of pts treated with IRd and EloRd, the analysis is focused only on DaraRd and KRd group after further excluding 51 pts (13%) addressed to salvage autologous stem cell transplant (ASCT) after daraRd (n=9)/KRd(n=42) fixed induction. Few pts in both groups were previously exposed to R/K/Dara (respectively 12 pts (3%), 8 (2%), 0). Treatment choice was influenced by market approval, with KRD regimen used more commonly in the IQR 2017- 2019, while DaraRd more commonly in the IQR 2018-2020. To limit the bias of a retrospective observation, we calculated a propensity score and we used it (after trimming of 5% of observations) to re-weight the data, according to the Inverse Probability of Treatment method (IPTW analysis). For the estimation of the propensity score, we used: age at Rd-triplet starting, ISS stage, presence of high-risk FISH, previous exposure to Bortezomib, previous ASCT, good response at first-line therapy (≥VGPR), time between diagnosis and relapse, myeloma defining events at diagnosis, type of relapse (symptomatic/biochemical), center. Details of these characteristics are reported in table1. Of note, pts addressed to DaraRd were slightly older (68,7 vs 63,4 years in KRd, p&lt;0.001), time from diagnosis was quite longer (3,5 vs 2,9 year in KRd, p=0.094), they received a lower rate of prior ASCT (56% vs 72% in KRd, p=0.008). After a median follow-up of 21.6 months (IQR: 9.6-32.4), response rate ≥PR were similar in both groups (92% in DaraRd vs 87,6% in KRd, IPTW analysis: OR=0.8, 95%CI: 0.4-1.5, p=0.422). No significant difference was found in terms of ≥VGPR (60% in DaraRd vs 62,9% in KRd, IPTW analysis: OR=0.7, 95%CI: 0,4-1,1 p=0.098) as well as of ≥CR (16,6% in DaraRd and 23,6% in KRd, IPTW analysis: OR=1,3, 95%CI: 0.8-2,2, p=0.340). The median number of administered cycles was higher for DaraRd (12 vs 10, IPTW analysis: β: 0.2, 95%CI: 0.1-0.4, p=0.025). Discontinuation rate was lower with DaraRd (28% vs 62% with KRd, IPTW analysis: OR: 0.3, 95%CI: 0.2-0.4, p&lt;0.001). Most patients in both groups discontinued treatment for progression (55,3% with DaraRd and 59.3% with KRd), discontinuation for TEAE was reported respectively in 38,3% in DaraRd and 31,5% in KR; 6,4% of pts in DaraRd and 9,2% in KRd discontinued treatment for pts decision. Weighted analysis shows a similar outcome. In particular, the median PFS is 28 months for DaraRd vs 23 months for KRd, (HR=0.9, 95%CI: 0.6-1.2, p=0,420) (Figure 1). At left-truncation analysis, patients with ≥VGPR, had similar PFS when comparing DaraRd vs KRd (HR=1.0, 95%CI: 0.6-1.6, p=0.896) while in patients with ≤PR, DaraRd showed a longer PFS (HR=0.5, 95%CI: 0.3-0.9, p=0.012) (Figure 2). The median TTNT was 31 and 29 months in DaraRd and KRd, respectively (HR=0.8, 95%CI: 0.5-1,1 p=0,111). No difference was found in terms of OS (HR=1.2, 95%CI: 0.8-1.8, p=0.408)(Figure 3).
Conclusions: Our real-life study shows that DaraRd represents the most commonly received regimen at first relapse followed by KRd triplet. After propensity score matching, DaraRd and KRd combinations proved to be both effective with similar outcomes when used early in the treatment history, after one line of therapy. This study, in addition, points out the possible gap of outcome between RCT and clinical practice.
Figure 1 Figure 1.

Disclosures
Mangiacavalli: BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; GSK: Honoraria. Galli: BMS, Celgene, Janssen, Sanofi, Takeda: Honoraria. Belotti: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees. Fazio: Janseen: Honoraria. Petrucci: Celgene: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; GSK: Honoraria, Other: Advisory Board; Karyopharm: Honoraria, Other: Advisory Board.