Adverse impact of 1q amplification on outcomes in patients with multiple myeloma treated with daratumumab, carfilzomib and dexamethasone in a real‐world clinical setting

Gain/amplification of 1q21 (1 q21+) are chromosomal abnormalities frequently observed in patients with multiple myeloma (MM), present in approximately 30% of patients at initial diagnosis, and increasing in frequency with disease progression.1 The 1q21+ abnormalities are poor prognostic chromosomal abnormalities, with a weight of 0.5 points assigned to 1q21+ in the R2-ISS score.2 Daratumumab is an anti-CD38 monoclonal antibody effective in patients with newly diagnosed (ND) or relapsed/refractory (RR) MM, with good responses achieved even in patients with high-risk chromosomal abnormalities (HRCAs).3 However, the effectiveness of daratumumab-based regimens for 1q21+ remains controversial. Reports regarding the impact of 1q21+ on the outcome of daratumumab, carfilzomib, and dexamethasone therapy (DKd) in particular are lacking. Therefore, we retrospectively analyzed the impact of 1q21+ on treatment outcomes in patients with MM who underwent DKd at our institution. This retrospective, noninterventional cohort study comprised existing data from electronic medical records of patients with MM who attended the Japanese Red Cross Medical Center (JRCMC). Patients included in the study underwent initial DKd. The study was approved by the JRCMC Institutional Review Board to be conducted under an abbreviated informed consent procedure, and an opt-out consent principle. None of the included participants were requested to be excluded from the study. Fisher's exact test was used for intergroup comparisons of categorical variables. Cytogenetic abnormalities were considered present if they were detected at least once between diagnosis and treatment initiation. HRCAs were defined as the presence of t(4;14), t(14;16), or deletion 17p. The 1q21+ is defined as a gain of 1q21 [gain(1q21), three copies] and amplification of 1q21 [amp(1q21), four or more copies]. Overall survival (OS) was defined as the interval between the first day of the DKd and the day of death from any cause or the last follow-up. Progression-free survival (PFS) was defined as the interval between the first day of the DKd and the day of disease progression or death from any cause. Data were censored in patients who were alive or without disease progression at their last follow-up. The data cut-off was set to 28 February 2024. Survival rates were calculated using the Kaplan–Meier method. Survival rates between groups were compared using the log-rank test. To evaluate the association of PFS and OS with the factors of interest, multivariate analysis was performed using Cox proportional hazards regression analyses to determine the hazard ratios (HRs) and associated 95% confidence intervals (CIs). p-values < 0.05 were considered statistically significant. EZR software (https://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html) was used for all the statistical analyses.4 We extracted data from 35 patients who received their first cycle of DKd at JRCMC between April 2021 and December 2023. Patient characteristics are shown in Table 1. Nineteen (54.3%) of the patients had 1q21+ and 16 (45.7%) had HRCAs, respectively. The median follow-up period from DKd was 14.6 months (range, 2.8–34.8 months). In the overall cohort, the median OS was not reached (NR) (95% CI, NR-NR), with a 2-year survival rate of 74.2%. The median PFS was 30.4 months (95% CI, 5.9 months–NR). Patients with 1q amplification had significantly shorter PFS (5.7 months vs. 20.2 months vs. 30.4 months, p = 0.0013) and OS (14.6 months vs. NR vs. NR, p = 0.0010) compared to those with 1q gain and without 1q abnormality (Figure 1A,B). Also, patients with 1q amplification showed significant shorter PFS and OS compared to those with 1q gain (p = 0.037 and 0.019, respectively). However, patients with 1q gain showed no significant difference in PFS and OS compared to those without 1q abnormalities (p = 0.10 and 0.28, respectively). The results of univariate and multivariate analyses for PFS and OS are shown in Supporting Table S1. Multivariate analysis of considering for clinically important factors including triple-class refractory disease, HRCAs, and 1q amplification showed that only 1q amplification significantly affected both PFS and OS (p = 0.023 and 0.031, respectively). Grade 3/4 hematologic toxicities were observed as follows: neutropenia in 3 patients (8.6%), anemia in 7 patients (20%), and thrombocytopenia in 8 patients (22.3%). Non-hematologic toxicities included infections in 7 patients (20%) and thrombotic microangiopathy in 1 patient (2.9%). Kaplan–Meier survival curves for progression-free and overall survival from the time of anti-CD38 ab-Kd initiation. PFS stratified by 1q amplification (A). OS stratified according to 1q amplification (B). OS, overall survival; PFS, progression-free survival. The phase 3 CANDOR study demonstrated significantly prolonged OS in patients with RRMM treated with DKd compared with those treated with carfilzomib and dexamethasone alone, even in the presence of HRCAs.5 Our overall cohort in the present study had a different median number of previous treatment lines compared to the CANDOR trial, where the median previous treatment lines were two lines, but the median PFS was almost equivalent. This indicated that DKd therapy was an effective treatment in real-world clinical practice. On the other hand, in our study, 1q amplification had a negative impact on the outcome of DKd. The impact of 1q21+ on prognosis was not evaluated in CANDOR trial. Reports on the impact of 1q21+ on prognosis in daratumumab-based treatments have been scarce. For RRMM, although a small number of cases have been reported, 1q amplification has been a significant adverse prognostic factor, and patients with RRMM who are positive for 1q21+ and classified as GEP70 high risk have had extremely poor prognosis.6, 7 On the other hand, in a subgroup analysis of the MAIA study, it was shown that while patients with 1q21 gain only did not have a poor prognosis, those with 1q amplification had worse treatment outcomes compared to those without HRCA. These results, along with our study, suggest that 1q amplification could be a poor prognostic factor in both NDMM and RRMM patients undergoing daratumumab-based treatment.8 However, recent clinical trials have reported on quadruplet treatment regimens that include daratumumab, showing favorable outcomes in patients with <1 HRCA.9 This suggests that the negative impact of 1q abnormalities can potentially be overcome with quadruplet treatment regimens. Limitations of this study include its retrospective nature and limited sample size. The feasibility of extrapolating our results to other daratumumab-based treatments awaits the findings of large-scale investigations on patients with both NDMM and RRMM yet to be performed. Our most important finding was that 1q amplification has a significant negative impact on PFS and OS in patients treated with DKd therapy. These real-world data provide insight into the optimal use and timing of DKd therapy. Taku Kikuchi treated the patients, collected and analyzed the data, and wrote the manuscript. Nobuhiro Tsukada treated the patients and provided important guidance. Chiaki Matsumoto and Osamu Hosoya provided the data. Kodai Kunisada, Moe Nomura-Yogo, Yuki Oda, Kota Sato, Tomomi Takei, Mizuki Ogura, Yu Abe, and Kenshi Suzuki treated the patients. Tadao Ishida provided important guidance. All the authors critically reviewed and approved the final version of the manuscript. We would like to thank Editage (www.editage.com) for English language editing. The authors have received no particular funding for this study. TK received personal fees from Janssen, Takeda, and Sanofi. NT received personal fees from Janssen and Sanofi. TI received honoraria from Ono, Takeda, Celgene/Bristol-Myers Squibb, and Janssen. KS received honoraria from Takeda, Celgene, Ono, Amgen, Novartis, Sanofi, BMS, AbbVie, and Janssen; consultancy fees from Takeda, Amgen, Janssen, and Celgene; and research funding from BMS, Celgene, and Amgen. The authors declare no competing financial interests related to this study. This study was approved by the JRCMC Institutional Review Board and was conducted under an abbreviated informed consent procedure and an opt-out consent principle. None of the participants requested to be excluded from the study. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1002/hon.3306. The datasets generated and/or analyzed in the current study are available from the corresponding author upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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