Elotuzumab (Elo) is a monoclonal antibody (MoAb) targeting SLAMF7 that has improved overall survival (OS) in combination with the immunomodulatory drugs (IMiDs) lenalidomide (len) or pomalidomide (pom) and dexamethasone (D), in patients with relapsed/refractory multiple myeloma (RRMM) in the ELOQUENT 2 and 3 trials, respectively [1, 2]. However, in ELOQUENT 2, patients were not len-refractory or previously treated with daratumumab (Dara) and in ELOQUENT 3, <5% of patients were previously treated with Dara and none were pom-refractory [3, 4]. The majority of patients on these trials received 1–3 prior lines of therapy (LOT) and none were triple-class refractory (TCR). The efficacy of Elo+IMiD-based regimens in RRMM patients that are IMiD, Dara-, or TCR and have received >3 prior LOT are poorly characterized. Furthermore, clinical trials evaluating Elo-based regimens in heavily pretreated RRMM patients are lacking given the advent of highly efficacious T-cell mediated therapies such as chimeric-antigen receptor (CAR) T-cell and bispecific antibodies (BsAb) which have revolutionized the treatment of RRMM [5]. In this retrospective analysis, we aim to evaluate the real-world efficacy and the clinical outcomes of RRMM patients treated with Elo+ImiD+Dex regimens across the 3-site Mayo Clinic Comprehensive Cancer Center (MCCC).

We retrospectively analyzed the medical records of patients with RRMM treated with Elo+IMiD-based regimens between January 2016 and July 2023 at the MCCC. Patients were defined as being refractory to a treatment if they did not achieve a minimal response to therapy, progressed while on treatment or developed progressive disease within 60 days of the last treatment dose [6]. TCR RRMM was defined as patients refractory to an IMiD, a proteasome inhibitor (PI) and an anti-CD38 MoAb [7]. Clinical responses were assessed using the International Myeloma Working Group criteria [8]. Descriptive statistics were used to describe patient characteristics. Categorical variables were compared with Chi-square tests and continuous variables were compared with t tests. Outcomes were estimated using the Kaplan–Meier method.

Baseline patient characteristics are shown in Table 1. 135 patients were included in the analysis, 30 received Elo-Len-D (ERd) and 105 received Elo-Pom-D (EPd). Key differences between the ERd and EPd patient populations were that more patients treated with EPd were PI-exposed, pom-refractory, Dara-refractory and had extramedullary disease (EMM) compared to patients treated with ERd. The median time from MM diagnosis to start of an Elo-based regimen was 4.8 years. The median time to first response was 0.96 months for EPd and 1.2 months for ERd and the median time to best response was 1.8 months for both EPd and ERd. The median follow-up time for ERd treated patients was 20.5 months and 53.8 months for patients treated with EPd. At 2 years 38.8% and 53.7% of patients had ongoing sustained response for EPd and ERd, respectively. The median PFS for patients treated with EPd was 4.8 months and the median PFS for patients treated with ERd was 17.28 months (Fig. 1A). The median OS for patients treated with EPd was 2.55 years and was 5.64 years for patients treated with ERd. For Dara-refractory patients, the median time from Dara-progression to start of ERd and EPd was 3 months and 2.28 months, respectively. For Dara-refractory patients treated with EPd (n = 94), patients had received a median of 4 prior LOT and had a median PFS of 5.04 months compared to non-Dara refractory patients (n = 11) who had received a median of 3 prior LOT and had a median PFS of 2.64 mos, p = 0.84. For Dara-refractory patients treated with ERd (n = 18), patients had received a median of 4 prior LOT and had a median PFS of 7.68 months compared to non-Dara refractory patients (n = 12) who had received a median of 2 prior LOT and had a median PFS of 38.52 mos, p = 0.015. For patients treated with EPd that were Dara-refractory, the median OS was 30.6 months compared to an OS that was not reached for patients that were not Dara-refractory (p = 0.80). For patients treated with ERd that were Dara-refractory, the median OS was 13.56 months compared to a median OS of 80.16 months for patients that were not Dara-refractory (p = 0.20). For EPd treated patients who received ≥4 prior LOT the median PFS was 3.72 months compared to a median PFS of 5.88 months for patients who received ≤3 prior LOT (p = 0.07) (Fig. 1B). For EPd treated patients who received ≥4 prior LOT the median OS was 14.16 months compared to a median OS that was not reached for patients who received ≤3 prior LOT (p = 0.04). For ERd treated patients who received ≥4 prior LOT the median PFS was 5.16 months compared to a median PFS of 35.8 months for patients who received ≤3 prior LOT (p < 0.001) (Fig. 1C). For ERd treated patients who received ≥4 prior LOT the median OS was 10.2 months compared to a median OS that was not reached for patients who received ≤3 prior LOT (p < 0.001). For patients treated with EPd, the median PFS for TCR patients (n = 52) was 4.3 months compared to 5.04 months for non-TCR patients (n = 53), p = 0.29. For patients treated with ERd, the median PFS for TCR patients (n = 11) was 7.68 months compared to 28.56 months for non-TCR patients (n = 19), p = 0.20 (Fig. 1D). For patients that were pom-refractory and were treated with EPd (n = 57), their ORR was 28.7%, their median PFS was 3.72 months and their median OS was 27.12 months, compared to an ORR of 49.9% (p = 0.03), a median PFS of 8.16 months (p < 0.001) and a median OS that was not reached for patients that were not pom-refractory (n = 48) (p = 0.07). For patients that were len-refractory and were treated with ERd (n = 19), their ORR was 52.3%, their median PFS was 23.6 months and their median OS was 80.16 months, compared to an ORR of 54.5% (p = 0.90), a median PFS of 15.84 months (p = 0.90) and a median OS of 67.7 months for patients that were not len-refractory (n = 11) (p = 0.90).

Table 1 Baseline characteristics of relapsed/refractory myeloma patients treated with elotuzumab-based regimens (N = 135).
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Fig. 1: Survival outcomes.
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A PFS of patients treated with ERd and EPd. B PFS of EPd-treated patients based on ≤3 prior LOT vs. ≥4 LOT. C PFS of-ERd treated patients based on ≤3 prior LOT vs. ≥4 LOT. D PFS of ERd and EPd-treated patients based on triple-class refractory status.

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The results of our study show the real-world efficacy of ERd and EPd in RRMM. Patients in ELOQUENT 2 treated with ERd had received a median of 2 prior LOT (none were TCR), achieved a median PFS of 19.4 months, and a median OS of 48.3 months [1, 3] whereas the patients treated with ERd in our study had received a median of 3 prior LOT (37% were TCR), achieved a median PFS of 17.3 months and a median OS of 67.7 months. Patients treated with ERd in our study had similar survival outcomes despite being more refractory and heavily pretreated compared to the patients in ELOQUENT 2 and in fact had superior OS which is likely due to the advent of BCMA-directed immunotherapies which have improved the survival outcomes of patients with RRMM [9]. Patients in ELOQUENT 3 treated with EPd received a median of 3 prior LOT (none were TCR), achieved a median PFS of 10.3 months, and a median OS of 28.8 months [2, 4] whereas the patients treated with EPd in our study received a median of 4 prior LOT (49.5% were TCR), achieved a median PFS of 4.8 months, and a median OS of 30.6 months. Patients treated with EPd in our study had inferior PFS but similar OS compared to the patients in ELOQUENT 3 and a plausible explanation for this PFS difference is that the patients in our study were more heavily pretreated, TCR, and had EMM compared to patients on ELOQUENT 3. The similar OS outcomes between the ELOQUENT 3 patients and the patients on our study treated with EPd is likely due the use of BCMA-directed therapies. Having TCR disease or being Dara refractory did not appear to influence survival outcomes although non-Dara-refractory patients (median of 2 prior LOT) treated with ERd had a significantly longer PFS compared to Dara-refractory patients (median of 4 prior LOT) treated with ERd and this is likely due to the fact that the Dara-refractory patients were much more heavily pre-treated. These findings of the similar efficacy of EPd in TCR and Dara-refractory patients is consistent with reported clinical trial data [10] but is discordant with retrospective data showing that class/drug-refractory status better identifies patients with poor response to therapy, compared to LOT [11]. A plausible explanation for this might be that the modest efficacy of EPd did not allow for differences based on class/drug-refractory status to show in this heavily pre-treated patient population treated with EPd. Importantly, the results of our study show that the efficacy of Elo+IMiD-based regimens declines considerably when used after ≥4 prior LOT as patients who were treated with ERd or EPd and had received ≤3 prior LOT had a longer PFS and OS compared to patients who received ≥4 prior LOT. As expected, EPd showed greater efficacy and survival outcomes in patients that were not pom-refractory but there were no differences in outcomes amongst ERd-treated patients regardless of len-refractory status, likely due to the small number of ERd-treated patients on the study. A major limitation of our study is the small number of patients in the ERd cohort which may make the data from that cohort difficult to interpret, particularly the subgroup analyses within the ERd cohort. It appears that len-refractory patients treated with ERd had superior ORR, PFS, and OS compared to the non-len refractory patients treated with ERd. While the differences were not statistically signifiant, this is counterintuitive and likely represents a type II error due to the small number of patients treated with ERd and should be interpreted with caution.

While it is reported that the main mechanisms of resistance to IMiDs involve alterations in cereblon which inhibit the ability of IMiDs induce myeloma cell death, the role of cereblon alterations on IMiDs’ immunomodulatory functions remain unknown [12]. It is purported that immune cell exhaustion mediates resistance to IMiDs’ immunomodulatory functions [12], however, combining IMiDs with an immunostimulatory MoAb such as Dara, can enhance the adaptive immune response and overcome IMiD resistance [13]. Given Elo’s known ability to enhance innate immune responses [14], it is therefore plausible that using ERd or EPd in IMiD-refractory patients can yield clinical responses. It has been reported that CD16/CD226Low NK cells with reduced effector functions accumulate in patients with MM and negatively impact clinical outcomes [15] and this NK-cell dysfunction may explain the modest responses seen with Elo-based regimens in heavily pretreated RRMM.

It is becoming increasingly more difficult to justify the use of Elo+IMiD-based regimens in RRMM. Len and pom can be used in combination with anti-CD38 MoAbs and PIs which induce deeper and more durable responses than EPd and ERd. Furthermore, with the multitude of highly efficacious therapies available for RRMM such as BCMA/GPRC5d-directed immunotherapies, selinexor, and venetoclax-based combinations (for [t;11:14]) which can also be combined with IMiDs [5] and also induce more durable responses, using ERd or EPd have fallen out of favor. In TCR MM patients, there is essentially no role for ERd and while EPd has activity in this patient population, the aformentioned novel therapies lead to deeper and more durable responses [5]. Nonetheless, in regions where access to BCMA/GPRC5d-directed immunotherapies, selinexor, or venetoclax is limited, there is a role for Elo+IMiD-based regimens as they show modest clinical activity even in TCR, heavily pretreated myeloma patients and can serve as a bridge to a clinical trial or a salvage transplant. Additionally, there is the potential to use elotuzumab in combination with bortezomib, pomalidomide, and dexamethasone (Elo-VPd) in RRMM as a recent phase II clinical trial demonstrated an ORR of 56.3% and a median PFS of 10 months in 48 RRMM patients that had received a median of 3 prior LOT [16]. However, in triple-class exposed patients that were refractory to anti-CD38 mAb (n = 14), the ORR was 35.7% and the median PFS was 5.82 months [16]. There are ongoing clinical trials evaluating Elo in combination with the next generation IMiDs iberdomide (NCT05560399) and mezigdomide (NCT03989414) and with belantamab mafodotin (NCT05002816). In the CC-92480-MM-002 trial, 20 patients received Elo-mezigdomide-D at 0.3 mg (n = 11) or 0.6 mg (n = 9) and ORRs were 36% and 56%, respectively [17].