Introduction: Historically, triplet therapy with an anti-CD38 monoclonal antibody (mAb) has been the standard (i.e., daratumumab + lenalidomide + dexamethasone [DRd]) for TIE/deferred patients with ND MM. Recently, data pertaining to anti-CD38 mAb-containing quadruplet regimens have been published (IMROZ: isatuximab ± bortezomib, lenalidomide, and dexamethasone [Isa-VRd]; NCT03319667 and CEPHEUS: daratumumab ± bortezomib, lenalidomide, and dexamethasone [Dara-VRd]; NCT03652064). It is unclear how these trials have influenced anti-CD38 preference for the management of TIE/deferred ND MM and what factors influence the decision between triplet or quadruplet therapy. The primary purpose of this study was to determine how frailty affects providers choice of triplet versus quadruplet regimens and which anti-CD38 agent was preferred in the real-world setting among providers managing patients with TIE/deferred ND MM.

Methods: In April and June 2025, US-based oncologists convened at two live meetings to discuss healthcare trends in hematology/oncology. To determine if frailty plays a role in treatment decision, the subgroup analysis of IMROZ focused on frail versus non-frail patients was presented to our participants. Additionally, the overall CEPHEUS data for all-comers was reviewed as well, given that the CEPHEUS only accrued those with frailty score 0–1 (did not accrue frail patients). An online premeeting survey was used to collect participants' demographics. Participants' experiences and management strategies surrounding TIE/deferred ND MM were captured via an audience response system during the live meeting; not all participants answered every question. Responses were aggregated and analyzed using descriptive statistics.

Results: Among the 115 myeloma-treating participants, 79.1% were community providers, who saw an average of 20 patients on clinic days, and had a median (range) of 20 (3−46) years in practice. Sixty-five percent of participants reported that ≥50% of their TIE/deferred patients with ND MM were initiated on a quadruplet regimen within the past 6 months. Participants reported age (72.8%), patient preference (50.5%), and patient frailty (45.6%) as the most common reasons a patient with ND MM is deemed ineligible for transplantation in their practices. Participants were presented with 2 standard-risk, TIE patients with ND MM who differed only in frailty status (i.e., non-frail and frail). For the hypothetical, non-frail patient, the majority of participants (73.1%) selected Dara-VRd as their preferred treatment, and for the hypothetical, frail patient, the majority of participants (58.0%) selected DRd as their preferred treatment. After reviewing both the IMROZ and CEPHEUS trials, the treatment preferences for the non-frail patient remained the same (Dara-VRd; 76.0%). While daratumumab was still the preferred anti-CD38 agent for the frail patient (DRd: 40.6%; Dara-VRd: 25.7%), preference for Isa-VRd increased following the review of the quadruplet trials (1.0% à 20.8%). Additionally, when participants were queried about which patient populations they would prefer Dara-VRd over Isa-VRd after reviewing the trials, participants reported the following preference patterns: age ≥70 years (Dara-VRd 39.8% vs Isa-VRd 12.2%), standard-risk (26.2% vs 14.3%, respectively) and high-risk disease (36.9% vs 10.2%, respectively), and non-frail patients (42.7% vs 16.3%, respectively). The only identified patient population where Isa-VRd was numerically preferred over Dara-VRd was in frail patients (33.7% vs 26.2%). Overall, 40.8% of participants indicated that they would not use Isa-VRd over Dara-VRd in any patient population.

Conclusions: The real-world data shows that Dara-VRd has emerged as the preferred regimen for non-frail, TIE/deferred patients with ND MM and that DRd is the preferred regimen for frail, TIE patients with ND MM. While interest for Isa-VRd saw a drastic increase for frail TIE patients with ND MM following review of the data, Dara-VRd was still the preferred anti-CD38 regimen if quadruplet regimens were considered. Despite the lack of a subgroup analysis of frail versus non-frail patients from CEPHEUS, Dara-VRd remains the preferred quadruplet therapy over Isa-VRd for TIE/deferred ND MM. Isatuximab is soon expected to be available via subcutaneous formulation via an on-body injector system, and it remains to be seen if this may further impact the preferences for anti-CD38 mAbs use in this space.

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2025
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