Efficacy of novel therapies for refractory and relapsed multiple myeloma in China

Multiple myeloma (MM) is the second leading hematologic malignancy and remains incurable. The majority are confronted with disease progression despite of treatment continuation. The latest statistics estimated that the number of MM-related mortality was 17,360 per year, being substantially increased over the past 5 years.[1,2] Since MM prevalently affects the seniors,[3] the increasing number of elderly myeloma patients is predictive of a major health concern in the following decades as aging grows in China. Over the past 20 years, the treatment options for relapsed or refractory MM (RRMM) in China can be grouped into six categories: Proteasome inhibitor (PI), immunomodulatory drug (IMiD), PI+IMiD, monoclonal antibody (mAb), chimeric antigen receptor (CAR) T-cell (CAR T), and Others (selinexor or chemotherapy).[4–10] These categories are in line with the most common therapies used globally.[11] Despite the advent of these innovative agents, there is a lack of evidence to demonstrate which new treatment regimen is best for Chinese RRMM. Herein, a scoping systematic review of the literature and conference abstracts was performed to compare treatment outcomes of all existing RRMM therapies, aiming to provide an evidence-based rationale for the treatment optimization for Chinese RRMM patients. A total of 18,218 records were gathered by searching the authoritative databases referred to in Supplementary Methods, https://links.lww.com/CM9/C628. Following the standard screening procedure, the final set of literature included 176 records/reports involving 108 studies [Supplementary Figure 1, https://links.lww.com/CM9/C628]. The 108 studies contained 6826 patients with RRMM, including 3760 in the 52 interventional studies and 3066 in the 56 non-interventional studies. Baseline demographic and clinical characteristics of all patients and study types are summarized in Supplementary Table 1, https://links.lww.com/CM9/C628. Median age was 60.5 years old (range 27.0–96.0). A total of 32.1% (2188/6826) had undergone at least two previous lines of therapy (LOT). [Supplementary Table 1, https://links.lww.com/CM9/C628]. Three eras of anti-myeloma treatment development were defined according to the central modality and the patient enrollment time. In the period of 2005–2012, PI-based regimens were the most commonly used for RRMM treatments. The subsequent era of 2013–2016 emerged as mono-drug use of IMiD or in combination with PI was increasingly prevalent. The advent of mAb and CAR T therapies led to the treatment paradigm shift into the era of immunotherapy (2017–2023). All the CAR T therapies and selinexor (a newer first-in-class agent)-based regimens were studied in the interventional approach, representing the most promising modality contemporarily [Figure 1A].Figure 1: Therapeutic response evaluations of different treatment regimens. (A) The graph illustrates the treatment regimens for relapsed and refractory multiple myeloma over one and a half of decades in China. The X axis represents the years. The right Y axis represents the number of studies for each treatment regimen; the interval of two ticks on the right Y axis refers to the number of two. (B) ORR of the interventional studies; (C) ≥CR rate of the interventional studies; (D) ≥VGPR rate of the interventional studies; (E) ORR of the non-interventional studies; (F) ≥CR rate of the non-interventional studies; (G) ≥VGPR rate of the non-interventional studies. CAR T: Chimeric antigen receptor T cell; CR: Complete response; IMiD: Immunomodulatory drug; mAb: Monoclonal antibody; PI: Proteasome inhibitor; ORR: Overall response rate; VGPR: Very good partial response.Overall survival (OS): For the 12 interventional studies with available OS data, all six categories of therapeutic approaches were evaluated. The RRMM patients who were given PI-based, IMiD-based, or a combination of PI and IMiD treatments had a median OS of 12.0–28.6, 15.8–24.3, or 25.8 months, respectively. The participants pretreated with PI and/or IMiD could achieve a median OS of 16.6–26.5 months after mAb administration. Notably, management with CAR T could extend the median OS to 55.8 months with a 5-year follow-up. In the Others regimen set, two studies adopted selinexor, and one reported a median OS of 13.2 months [Supplementary Table 2, https://links.lww.com/CM9/C628]. For the 23 non-interventional studies, the majority of data were from the patients treated with PI and/or IMiD that was able to prolong the lifespan of the chemo-resistant patients by 3 years or more. Those who failed to respond to PI and/or IMiD could further benefit from anti-CD38 mAb and obtained a median OS of over 2 years. The results demonstrate that the novel agents improve the Chinese RRMM survival to varying degrees, and that CAR T therapy confers an outstanding effectiveness [Supplementary Table 2, https://links.lww.com/CM9/C628]. Progression-free survival (PFS): The 24 interventional studies with available PFS data were predominantly involved with CAR T therapy. Most CAR T-exposed patients were previously refractory to PI and/or IMiD. The median number of prior LOTs was the highest in the CAR T cohort vs. the other regimens. The studies on CAR T with sample sizes larger than 25 subjects consistently reported a median PFS of longer than 1 year, which was evidently better than PI, IMiD, and Others [Supplementary Table 3, https://links.lww.com/CM9/C628]. In the non-interventional studies, PI and/or IMiD accounted for the most. The PFS differed in the diverse studies with PI and/or IMiD-based regimens, but did not display an obvious numerical disparity. The effectiveness prompted by mAb enabled the PI- and/or IMiD-refractory patients to have a median PFS time spanning 8.0–17.0 months [Supplementary Table 3, https://links.lww.com/CM9/C628]. It suggests that a prolonged PFS of Chinese RRMM patients can be achieved by any of the available agents, among which CAR T therapy may enable a superior efficacy. Overall response rate (ORR), complete response (CR), and very good partial response (VGPR): For the interventional studies, CAR T regimens achieved the highest median ORR (88.2%), followed by PI (72.8%) and mAb (71.3%) [Figure 1B]. Likewise, CAR T achieved the highest ≥CR rate (50.0%) and the most favorable ≥VGPR rate (77.2%) as opposed to the other treatments [Figure 1C, D]. For the non-interventional studies without a CAR T regimen included, PI+IMiD-based regimens achieved the highest ORR (80.0%), followed by PI- (75.4%) and mAb (71.4%) [Figure 1E]. However, mAb achieved the highest ≥CR rate (18.2%) and ≥VGPR rate (57.1%) [Figure 1F, G]. The data demonstrate that a CAR T regimen is potentially more powerful to fight against myeloma, aligning with the aforementioned survival outcomes. Minimal residual disease (MRD): MRD− data was only available in the interventional studies. It showed that CAR T achieved an MRD− rate of 91.2%, considerably higher than that observed in the other classes of drugs, such as mAb (32.6%) and PI (4.3%) [Supplementary Figure 2A, https://links.lww.com/CM9/C628]. It is reflective of the therapeutic advantage of CAR T over mAb- and PI. Duration of response (DOR) and time to response (TTR): For the interventional studies, the patients exposed to CAR T achieved the longest median DOR [Supplementary Figure 2B, https://links.lww.com/CM9/C628]. The median TTR was approximately 1 month for CAR T, mAb-, PI-, and PI+IMiD-based regimens, whereas IMiD and Others had a relatively longer TTR of approximately 2 months [Supplementary Figure 2C, https://links.lww.com/CM9/C628]. For the non-interventional studies, median DORs were comparable across the studies reporting on PI-, IMiD-, and Others [Supplementary Figure 2D, https://links.lww.com/CM9/C628]. PI led to shorter TTRs compared with IMiD- and Others [Supplementary Figure 2E, https://links.lww.com/CM9/C628]. Analyses of CAR T regimens: The efficacy results of the interventional studies demonstrated the superiority of CAR T treatment over the other modalities. However, the effectiveness varied across different CAR T products. Meta-analysis of the 19 studies on CAR T treatment showed that ≥CR rates ranged from 40.7% to 85.7% [Supplementary Figure 3A, https://links.lww.com/CM9/C628]. It was supposed that CAR construct, particularly the property of antigen recognition moiety, might be a potentially impactful attribute. Thus, the influence of the extracellular domain of CAR on ≥CR rate was examined. The results showed that the ≥CR rates of single- and dual-target CAR T were 56% and 66%, respectively [Supplementary Figure 3B, C, https://links.lww.com/CM9/C628]. The ≥CR rates in the studies of humanized and non-humanized CAR T were 65% and 58%, respectively [Supplementary Figure 3D, E, https://links.lww.com/CM9/C628]. The ≥CR rates for single-chain variable fragment (scFv) CAR T and heavy-chain-only antigen-binding fragments (VHH) CAR T were 59% and 70%, respectively [Supplementary Figure 3F, G, https://links.lww.com/CM9/C628]. It is important to note that the non-humanized CAR T therapies included murine-derived CAR T and llama-derived CAR T, with the former accounting for 61.3%. The llama-derived CAR T therapies were exclusively retrieved from the studies on ciltacabtagene autoleucel, which demonstrated a ≥CR rate of 77% in its pivotal clinical trial.[12] Ciltacabtagene autoleucel utilizes two distinct llama-derived VHH domains to target tumor antigen, which may contribute to its superior efficacy. The above data suggest that an optimized design of CAR featuring dual targets, experiencing humanized modification, or adopting a VHH construct is beneficial to Chinese RRMM treatment efficacy as opposed to the other types of CAR currently accessible. In conclusion, novel agents, especially CAR T- and mAb-based regimens, have shown advantages over traditional therapies in China. However, more planned studies of CAR T and mAb regimens are encouraged, as it may lead to a change in the treatment sequence of Chinese patients with RRMM and provide more benefits to this patient population. Availability of data and materials Data are available from the corresponding author upon reasonable request. The protocol is registered in INPLASY: doi: 10.37766/inplasy2022.6.0083. Acknowledgements The authors are grateful to Yan Huo from Systematic Review Solutions, Ltd. for providing professional expertise and assistance. Funding This work is supported by the National Natural Science Foundation of China (Nos. 82470206 and 82370201), the Basic-Clinical Collaborative Innovation Project from Shanghai Immune Therapy Institute, the Explorers Program of Shanghai (Basic Research Funding, No. 25TS1403900) the Innovative Research Team of High-Level Local Universities in Shanghai, and the Shanghai Shenkang Hospital Development Center (No. SHDC2020CR2066B). Conflicts of interest Chao Liu is an employee of Legend Biotech and may hold stock in Legend Biotech. The rest declare no competing interests.