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Treatment with elotuzumab plus lenalidomide and dexamethasone ( ERd ) was associated with significant and clinically meaningful reductions in mortality risk , compared with lenalidomide and dexamethasone alone ( Rd ), in patients with relapsed or refractory multiple myeloma ( MM ), according to results from the phase III ELO- QUENT-2 trial . The survival benefit was particularly evident in older patients and patients with high-risk disease , lead author Meletios Dimopoulos , MD , of the National and Kapodistrian University of Athens School of Medicine in Greece , told ASH Clinical News .

“ At the time of study design , Rd was the standard of care for patients with relapsed or refractory MM ,” Dr . Dimopoulos said . “ The ERd triplet not only showed a long-standing improvement in progression-free survival [ PFS ], but also in overall survival [ OS ].”

The ELOQUENT-2 study evaluated the efficacy and safety of ERd compared with Rd in patients with relapsed or refractory MM who had received between 1 and 3 prior lines of therapy . The trial enrolled 635 participants who were randomized to receive either ERd ( n = 318 ) or Rd ( n = 317 ). PFS and overall response rate ( ORR ) were the primary endpoints and OS was a key secondary endpoint of the study , with the final OS analysis planned after 427 deaths .

In the overall cohort , the median age was 66 years ( range = 37-91 ), and 20 % of patients were 75 years or older . Approximately one-fifth of patients in each group had International Staging System stage III disease , and 35 % of patients in each arm were refractory to their last treatment .

After a minimum follow-up period of 70.6 months , which the authors noted was the longest reported to date for an antibody-based triplet in this setting , a slightly higher proportion of patients in the ERd arm remained on treatment , compared with patients in the Rd arm ( 10 % and 4 %). The most common reasons for discontinuation included disease progression ( 56 % and 57 %) and study drug toxicity ( 12 % and 14 %).

At the time of the final OS analysis , there were 212 deaths in the ERd group ( 66 %) and 225 deaths in the RD arm ( 69 %). The median OS was roughly 8.7 months longer with ERd compared with Rd

TABLE . Overall Survival in Select Subgroups

( 48.3 vs . 39.6 months , respectively ; hazard ratio [ HR ] = 0.82 ; 95 % Cl 0.68-1.00 ; p = 0.04 ).

The investigators observed an early separation of OS curves at 1 year after trial enrollment ( 91 % with ERd and 83 % with Rd ), which continued at 2 years ( 73 % vs . 69 %), 3 years ( 60 % vs . 53 %), and 4 years ( 50 % vs . 43 %). Overall , treatment with ERd was associated with an 18 % reduction in the risk of death compared with Rd .

An OS benefit was also identified in specific subgroups . For instance , the median OS was 17.4 months longer with ERd in patients who had received between 2 and 3 prior lines of treatment ( 51.0 vs . 33.6 months ; HR = 0.71 ; 95 % CI 0.54-0.92 ). The median OS was also longer in patients treated with ERd across certain age groups :

• ≥75 years : 48.5 vs . 27.4 months ( HR = 0.69 ; 95 % CI 0.46-1.03 )

• < 75 years : 47.9 vs . 43.7 months ( HR = 0.86 ; 95 % CI 0.70-1.06 )

• < 65 years : 63.5 vs . 47.7 months ( HR = 0.70 ; 95 % CI 0.52-0.96 )

In a subgroup of patients who were refractory to their most recent treatment , including 113 patients in the ERd group and 114 patients in the Rd group , treatment with ERd was associated with a 14.5-month longer OS compared with Rd ( 40.4 vs . 25.9 months ; HR = 0.67 ; 95 %

CI 0.49-0.91 ). The OS benefit with elotuzumab also was seen in the subgroup of patients with relapsed disease : Patients in the ERd group had median OS of 51.2 months , compared with 47.7 months in the Rd-alone group ( HR = 0.93 ; 95 % CI 0.73-1.18 ).

Patients with high-risk or more advanced disease also had longer OS with elotuzumab treatment ( TABLE ).

— Meletios Dimopoulos , MD

No new safety signals with elotuzumab were identified in the extended follow-up , and the most common adverse events of interest included infections ( 84 %), renal and urinary disorders ( 27 %), cardiac disorders ( 24 %), and pneumonia ( 22 %). Dr . Dimopoulos added , “ The good tolerability of the combination makes it attractive for elderly patients and for patients who had a long PFS before the treatment with ERd ,” he said .

A limitation of this study , according to the investigators , is that the prior therapy participants received may not have reflected that used in current clinical practice , as the treatment landscape for myeloma has changed since the trial first started enrolling and dosing patients . Dr . Dimopoulos also noted a limitation of ERd : the activity of this triplet combination may be less pronounced compared with combinations that include anti-CD38 monoclonal antibodies such as daratumumab .

Study authors report relationships with Bristol Myers Squibb and AbbVie , which sponsored this trial .

Reference Dimopoulos MA , Lonial S , White D , et al . Elotuzumab , lenalidomide , and dexamethasone in RRMM : final overall survival results from the phase 3 randomized ELOQUENT-2 study . Blood Cancer J . 2020 ; 10:91 .

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