Dear Editor,Patients with relapsed refractory multiple myeloma (RRMM) having progressed after three prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, have a dismal prognosis, with a median overall survival (OS) of <1 year [1, 2]. With impressive efficacy and reasonable safety seen in pivotal clinical trials, two B cell maturation antigen (BCMA) directed chimeric antigen receptor (CAR) T-cell products, idecabtagene vicleucel (ide-cel) [3] and ciltacabtagene autoleucel (cilta-cel) [4], have now been approved for use in RRMM after only 1–2 prior lines of therapy. However, these were two different randomized controlled trials with several distinct differences in the patient populations, disease biology, and prior treatment characteristics. This is particularly pertinent regarding anti-CD38 monoclonal antibody exposure and refractoriness which was seen in 23% of the patients in CARTITUDE-4 (median of 2 prior lines of therapy) and 95% of the patients in KarMMa-3 trial (median of 3 prior lines of therapy). While it is postulated that patients who are daratumumab exposed but not refractory may have better outcomes compared to those who are daratumumab refractory [5], irrespective of number of prior lines of therapy, there is no data to support this hypothesis in patients receiving CAR T-cell therapy. Therefore, we conducted a single-center retrospective study comparing the clinical outcomes of RRMM patients who received BCMA-directed CAR T-cell therapy based on their daratumumab refractoriness status. Daratumumab refractoriness was defined as disease progression per International Myeloma Work Group (IMWG) criteria within 60 days of the last dose of daratumumab. The primary objective of the study was to determine efficacy outcomes including best overall response rates (ORR), PFS, and OS in the daratumumab refractory and daratumumab non-refractory patients. Responses to therapy were determined using the IMWG criteria [6]. CRS and ICANS were graded based on American Society for Transplantation and Cellular Therapy criteria [7]. Other hematologic and non-hematologic adverse events were graded based on the CTCAE v5.0 criteria. Extramedullary disease (EMD) in this study was defined as bone-independent tumors of plasma cells growing at anatomic sites outside of the bone marrow prior to CAR T. High risk cytogenetics were defined as the presence of genomic aberrations such as deletion [17p], t(4;14), and or t(14;16) on fluorescence in situ hybridization (FISH) testing at any time prior to initiation of therapy. High disease burden was defined as bone marrow plasma cell percentage (immune histochemical analysis) of ≥50% prior to CAR T infusion. Categorical variables were compared between the two groups using the chi-square or Fisher exact test, and continuous variables were compared using the Mann–Whitney U test. Kaplan–Meier (KM) survival curves were used to examine PFS and OS. Cox regression analysis was performed to show the impact of daratumumab refractoriness on PFS and OS with univariate and multivariate analyses.

At the time of study cutoff in 7/2024, a total of 171 patients were treated with CAR T from 4/2018 until 7/2024 with 144 (84%) daratumumab refractory and 27 (16%) daratumumab non-refractory patients. Patient, disease, and treatment characteristics are described in Table 1A. A total of 88 (51%), 51 (30%), and 32 (19%) patients had received cilta-cel, ide-cel, and investigational BCMA directed autologous CAR T product, respectively. The cohort included 61 (36%) patients with EMD, 37 (22%) with high disease burden, and 88 (51%) with high-risk cytogenetics. Median prior lines of therapy received was 6 (2–14), with 73% of patients with penta-drug exposed disease. Baseline characteristics were balanced between the daratumumab refractory and daratumumab non-refractory groups except for lower number of median prior lines of therapy (4 versus 6, p = 0.011), more patients with ECOG performance status 2 (15% versus 0.7%, p = 0.001), and lower rates of EMD (19% versus 39%, p = 0.043) in the daratumumab non-refractory group (Table 1A). With the median follow-up of 19 (range 16–21, reverse KM estimate) months for the entire patient population, the best ORR was 82% with 31 (18%) achieving stringent complete remission, 48 (28%) complete remission, 41 (24%) very good partial remission, and 21 (12%) partial remission. No differences were seen in the best ORR (81% versus 89%, p = 0.4) between the two groups (Table 1A). The median PFS was 11 (95% CI 8.1–14) months for the entire population with 12-month PFS of 46% (95% CI, 39–55) (Fig. 1A). The median PFS were 9.2 and 12 months (p = 0.08), with 12-month PFS of 43% and 47% in the daratumumab non-refractory and daratumumab refractory groups, respectively (Fig. 1B). On multivariate analysis, CAR T product other than cilta-cel (hazard ratio (HR) ide-cel 4.16, 95% CI 2.50–6.91, p = <0.001), prior BCMA therapy (HR 2.69, 95% CI 1.54–4.68, p = <0.001), high risk cytogenetics (HR 1.79, 95% CI 1.16–2.77, p = 0.008), EMD (HR 2.61, 95% CI 1.69–4.01, p = <0.001), and high disease burden (HR 2.264, 95% CI 1.46–3.51, p = <0.001) were associated with inferior PFS (Table 1B). At the data cutoff, median OS was 34 months with 12-month OS of 82% (95% CI, 76–88%) for the entire cohort (Fig. 1C). The median OS was 25 and 34 months (p = 0.18), with 12-month OS of 88% and 81% in the daratumumab non-refractory and daratumumab refractory groups, respectively (Fig. 1D). On multivariate analysis, high risk cytogenetics (HR 1.82, 95% CI 1.04–3.21, p = 0.034), EMD (HR 2.67, 95% CI 1.51–4.73, p = <0.001) and high disease burden (HR 2.31, 95% CI 1.21–3.74, p = 0.012) were associated with inferior OS (Table 1C). CRS was observed in 134 (78%) patients with 7 (4%) patients experiencing grade 3+ events. ICANS was observed in 19 (11%) patients with 2 (1%) experiencing grade 3+ events. Infectious events within 90 days of CAR T were noted in 77 patients (45%) with 33% of the patients experiencing grade 3+ infections. Persistent grade 3+ cytopenias at day 90 after CAR T were accounted by 7 patients with anemia (4%), 17 patients with neutropenia (8%), and 21 patients with thrombocytopenia (12%). A total of 69 (40%) patients had hypogammaglobulinemia (IgG < 500 ug/L) at time of lymphodepletion and 118 (69%) had hypogammaglobulinemia at day 90 post CAR T. A total of 59 patients had died at the time of data cut off with disease progression (61%), infection (15%), and organ failure (8%) being the most common causes of death.

Fig. 1: Survival outcomes for DN and DR patients.
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A Progression free survival (PFS) for the entire patient population. B PFS for the daratumumab non refractory (DN) and daratumumab refractory (DR) patients. C Overall survival (OS) for the entire patient population. D OS for the DN and DR patients.

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Table 1 A Baseline patient, disease, and CAR T characteristics for entire cohort, daratumumab non-refractory, daratumumab refractory patients; B Multivariate Analyses for association of Progression Free Survival (PFS) in daratumumab non-refractory (DN) daratumumab refractory (DR) patients; C Multivariate Analyses for association of Overall Survival (OS) in daratumumab non-refractory (DN) daratumumab refractory (DR) patients.
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To our knowledge, this is the first real world study evaluating the outcomes of CAR T-cell therapy in daratumumab non-refractory patients. As shown, compared to the daratumumab refractory patients, daratumumab non-refractory patients were less heavily pre-treated with fewer prior lines of therapy and lower rates of EMD. However, type of CAR T product, rates of prior BCMA therapy, high risk cytogenetics, and disease burden were similar between the two groups. Despite equitable distribution of patient, disease, and CAR T related characteristics, there were no significant differences in efficacy seen between the two groups. The use of CAR T in the earlier lines of therapy where patients were not as heavily pretreated did not negate the negative influence of these risk factors. While it remains unclear whether all patients with MM need CAR T at the time of first relapse, our study highlights that for patients who are daratumumab naïve or non-refractory, daratumumab based therapies can be a viable option for initial salvage while CAR T can be considered for later relapses without having a negative impact on outcomes. In our study, high risk cytogenetics, EMD, high disease burden, and prior BCMA therapy as per previous reports [8, 9] continue to be associated with inferior PFS and OS. EMD is considered a high risk disease feature associated with early progression and overall poor prognosis after BCMA directed CAR T [10, 11]. Similarly, the inferior efficacy seen in patients with prior BCMA exposure in our cohort has been previously demonstrated as a risk factor for early progression [12] and could potentially be explained by emergence of clones with structural or functional loss of BCMA [13] or terminally differentiated exhausted T cell phenotype [14]. While there has been no direct head-to-head comparison between different CAR-T products in the pivotal clinical trials, there has been real world evidence-based comparison [15] highlighting the superior efficacy and survival with cilta-cel for RRMM as per our report.

Limitations of our study include its retrospective design and relatively small sample size of daratumumab non-refractory patients. However, being a single center study, management of these patients was more standardized according to the institutional guidelines and all clinically relevant variables were accurately captured and evaluated in multivariable analyses. Overall, despite some limitations, our data represents a real-world population and answers important clinical questions regarding use of CAR T in earlier lines of therapy. Longer follow up and more patients with daratumumab non-refractory disease may help confirm the findings of our study. In summary, refractoriness to prior treatment with daratumumab may not be associated with inferior efficacy after CAR T for RRMM. However, use of CAR T products other than cilta-cel, prior use of BCMA therapy, presence of EMD, high risk cytogenetics, and high disease burden continue to be associated with inferior outcomes after CAR T.