Multiple myeloma (MM) is the second most common hematological malignancy in the world (1), with high morbidity and mortality (2). The development of novel treatments for MM has been conducive to enhanced survival and quality of life for patients (3). The immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) have primarily driven the significant advancements in the therapeutic outcomes of MM patients over the past twenty years (4, 5). Shortly after these two drug classes established themselves as the cornerstone of MM treatment, a comprehensive study by the International Myeloma Working Group (IMWG) highlighted the grim prognosis for patients whose conditions exhibited resistance to both IMiDs and PIs. MM patients who received treatment before 2017 and were concurrently resistant to both an IMiD and a PI, had a median overall survival (OS) of 13 months, with a slim 33% probability of a positive response to the ensuing therapeutic line (6). Subsequent research revealed a variance in the median progression-free survival (PFS) and OS among MM patients receiving first-line treatment with IMiDs or PIs, depending on their International Staging System disease stage (7). Despite the improvements brought about by the introduction of several new drugs, almost all patients with MM ultimately become relapsed/refractory multiple myeloma (RRMM) (8). In order to address the unmet clinical requirements of RRMM patients, the spectrum of new agents has greatly expanded in the past decade (9, 10).

Monoclonal antibody (mAbs) targeting CD38 (e.g., daratumumab and isatuximab) have been generated because of the need for new approaches to treat RRMM (11, 12). Daratumumab is a human IgGκ mAb targeting CD38, which has direct effects on tumor (13, 14) and immune regulation mechanisms (15, 16), inducing induction of greater cytotoxicity of MM cells in vitro than other CD38 antibody analogues (17). Isatuximab is an IgG1 mAb targeting a unique epitope of CD38 (18). Isatuximab exerts its anti-myeloma effects through various mechanisms, such as direct induction of apoptotic cell death, complement-dependent cytotoxicity, and antibody-dependent cell-mediated cytotoxicity (19, 20). Previous study has reported the milestones of RRMM treatment included either a double-, triple-, or quadruple-drug combination on the basis of IMiDs and/or PIs and dexamethasone plus the anti-CD38 mAbs isatuximab or daratumumab, with or without chemotherapy (21).

Given the extensive research on anti-CD38 mAbs treatment for MM and the limited studies on the application of anti-CD38 mAbs in RRMM patients, there is an urgent need for healthcare stakeholders to compare the relative efficacy and safety of daratumumab or isatuximab versus standard therapy for RRMM. Several previous meta-analyses have reported the efficacy and safety of the triplet regimens containing daratumumab for treating MM (22–24). However, multiple related RCTs (e.g., POLLUX, CASTOR, CANDOR, and LEPUS) have subsequently updated their analysis results (25–28). Hence, we conducted a meta-analysis to systematically update the efficacy of anti-CD38 mAbs (daratumumab and isatuximab) for RRMM, and to supplement safety outcomes, including respiratory system treatment-emergent adverse events (TEAEs), digestive system TEAEs, and other nonhematologic TEAEs. Additionally, we performed subgroup analyses with the aim of providing new evidence for clinical practice.

MM is a plasma cell malignant disorder characterized by uncontrollable and progressive proliferation of plasma cell clones, leading to the excessive production of nonfunctional intact immunoglobulins or immunoglobulin chains (43). The accumulation of these immunoglobulins and the interaction between abnormal monoclonal plasma cells and other cells in bone marrow result in many AEs including bone injury, renal failure, hypercalcemia, infections, anemia, pain and fatigue (44). In the early 2000s, the introduction of IMiDs and PIs altered the outcomes of MM patients. Later, detecting CD38 as appropriate target resulted in immunotherapy methods using mAbs such as daratumumab and isatuximab (45). Although people have gained a better recognition of the biology of the disorder and introduced treatment options with new mechanisms, current treatments cannot cure MM. The majority of patients still experience disease relapse and frequently exhibit tolerance to previously used medications (46). RRMM is defined as a disorder that does not respond or progresses in patients who have had the least or better response to previous treatment within 60 days after the last treatment or the last treatment (47). Due to the poor therapy prognosis, drug resistance, and severe impairment of patients’ quality of life, RRMM has become a major problem currently faced by clinical doctors (48–50). The insignificant treatment effects of prior medications have promoted the development of the next generation of PIs and IMiDs, as well as regimen with anti-CD38 mAbs, further expanding the therapeutic range of RRMM (51, 52). Therefore, the development of novel therapeutic drugs targeting CD38 has become a hot direction for the treatment of RRMM.

CD38 is a type II transmembrane protein, which is expressed in immune cells and regulates calcium signaling, leukocyte activation and migration process (45). CD38 is expressed at a low level in immune cells under normal circumstances (53), while obviously higher CD38 expression in plasma cells is shown in healthy individuals and MM patients (20). Daratumumab binds to transmembrane glycoprotein CD38 with high affinity (54) and inhibits tumor cell growth through immunemediated direct on-tumor (55) and immunomodulatory mechanisms of action (15). It has been approved by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) as both single drug therapy and combined with standard treatment for RRMM, following intravenous and SC subcutaneous. Isatuximab is a novel IgG1 monoclonal antibody, which can directly regulate the enzyme activity of CD38, induce MM cell death by caspase-dependent apoptosis, and improve the immune response mediated by T cells and natural killer cells (20). Despite the similar action of daratumumab and isatuximab, the mechanism of both anti-CD38 mAbs is somewhat different. On one side, daratumumab and isatuximab target different CD38 epitopes. Additionally, isatuximab can directly induce cell death, whereas daratumumab must be in combination with cross-linking agents to induce cell apoptosis (20, 53).

Daratumumab has been used as a single drug in clinical practice and in combination with PIs (i.e., carfilzomib and bortezomib) or IMiDs (i.e., pomalidomide and lenalidomide) and demonstrated activity in patients with RRMM (56–59). All RRMM patients in this meta-analysis had received ≥ 1 lines of therapy and gained clinical benefits from daratumumab plus IMiDs or PIs plus dexamethasone. In present analysis, the addition of daratumumab to IMiDs (or PIs) and dexamethasone significantly improved PFS and OS in patients with RRMM. Thus, the addition of daratumumab to subsequent treatment regimens of IMiDs (or PIs) and dexamethasone may provide an alternative salvage treatment option for patients with RRMM. Real-world data also support early medication of daratumumab to induce sustained and deep responses, and extend disorder control to potentially delay clonal evolution and subsequent drug resistance (26). However, subgroup analysis suggested that the addition of daratumumab to IMiDs (or PIs) and dexamethasone had no beneficial effect on OS. This finding warrants further validation, as the results of the subgroup analysis were obtained from only two RCTs, rendering the findings unstable and not generalizable to the entire population. Moreover, to our knowledge, several trials are still ongoing (28, 39), resulting in the absence of subgroup analysis for OS. Consequently, the subgroup analysis results concerning OS in this study await future updates. In addition, patients with RRMM who received daratumumab plus IMiDs (or PIs) and dexamethasone achieved higher VGPR or better rate than those receiving IMiDs (or PIs) and dexamethasone alone. The rates of overall response, complete response or better, and MRD-negative were also higher in the daratumumab in combination with IMiDs (or PIs) plus dexamethasone group than in the IMiDs (or PIs) plus dexamethasone group. Previous study has shown that the primary and acquired drug resistance of daratumumab is associated with tumor-related characteristics (60). It has been demonstrated that the therapeutic efficacy of daratumumab depends in part on baseline expression of CD38 on MM cells (61). Nevertheless, the effect of CD38 in acquired drug resistance remains uncertain, as CD38 is rapidly and consistently downregulated on MM cells in both responding and non-responding patients upon initiation of daratumumab therapy (62, 63).

Infections were one of the most common AEs among RRMM patients receiving daratumumab plus IMiDs (or PIs) and dexamethasone or IMiDs (or PIs) and dexamethasone, including viral infections and respiratory tract infections (41). Our meta-analysis demonstrated that the rates of URTI, pneumonia, bronchitis, and pyrexia were higher in the daratumumab in combination with IMiDs (or PIs) plus dexamethasone group than IMiDs (or PIs) and dexamethasone alone. The respiratory tract AEs may be explained by the expression of CD38 in airway muscle cells (11). Administration of antipyretics, steroids, and antihistamines is clinically suggested for standard premedication of daratumumab to prevent serious respiratory AEs (64). The updated consensus guidelines recommend considering prevention and antiviral or antibacterial vaccination, together with other means to reduce the infection risk in patients with MM (65). Moreover, RRMM patients receiving daratumumab plus IMiDs (or PIs) plus dexamethasone achieved higher rates of thrombocytopenia, neutropenia, diarrhea, back pain, fatigue, and insomnia than those receiving IMiDs (or PIs) and dexamethasone alone. It is worth noting that these TEAEs did not result in higher treatment interruption rates or fatal AEs, revealing that these hematologic and nonhematologic TEAEs were manageable. It is essential to carefully monitor patients and combine prophylaxis according to clinical assessment to manage these potential TEAEs (39).

Combined medication, including isatuximab as a backbone, can effectively treat MM. The FDA has approved combination of isatuximab with pomalidomide plus dexamethasone for the therapy of patients with MM who have received ≥ 2 previous treatments (66) or with carfilzomib and dexamethasone, for the therapy of MM patients who have received 1 to 3 prior lines of treatments (67). The pooled results of isatuximab in present study suggested that isatuximab plus IMiDs (or PIs) and dexamethasone improved PFS and OS in RRMM patients, and achieved higher rates of neutropenia, URTI, bronchitis, dyspnea, and diarrhea than IMiDs (or PIs) and dexamethasone alone. Only two studies included in this meta-analysis reported the efficacy and safety of isatuximab plus pomalidomide and dexamethasone, and isatuximab plus carfilzomib and dexamethasone, respectively. The benefits of PFS and OS can be obtained with a favorable AEs profile. Addition of isatuximab to pomalidomide increased anti-MM activity because of the direct toxicity and lysis of effector cells to tumor plasma cells. Moreover, the combination of isatuximab-PIs (i.e., carfilzomib) affects MM and microenvironmental cells (20). Given that only two studies were included in the meta-analysis of isatuximab, the pooled results of isatuximab are unstable and not convincing, and more studies need to be included to further improve the results.

There were some important limitations in our work that should be acknowledged. First, all included RCTs were the open-label design, and the potential bias due to lack of blinding may affect the outcomes. Second, the TEAEs caused by anti-CD38 mAbs cannot be ignored, and the present study did not explore in detail whether these TEAEs are associated with IMiDs (or PIs) and dexamethasone. Third, TSA results suggested that the sample size for the TEAEs, such as anemia, thrombocytopenia, lymphopenia, constipation, arthralgia, asthenia and hypertension, did not reach the required sample size to achieve a definitive conclusion. Therefore, future inclusion of studies with large sample size is needed to further let the results of these TEAEs more reliable.

Taken together, our meta-analysis demonstrated that anti-CD38 mAbs in combination with IMiDs (or PIs) and dexamethasone improved PFS and OS in patients with RRMM, and achieved higher rates of overall response, complete response or better, VGPR or better, and MRD-negative compared with IMiDs (or PIs) and dexamethasone alone. The rates of hematologic and nonhematologic TEAEs, including thrombocytopenia, neutropenia, URTI, pneumonia, bronchitis, dyspnea, diarrhea, pyrexia, back pain, arthralgia, fatigue, insomnia, and hypertension, were also higher in the anti-CD38 mAbs in combination with IMiDs (or PIs) and dexamethasone group than in the IMiDs (or PIs) and dexamethasone group.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

LZo, NH, and LYa participated in research design. YX, QY, RJ, and LZ searched the literature, selected studies for inclusion, and collected the data. DC and MX analyzed the data. LYe and FZ prepared the manuscript. LZh, NH, and XY edited the manuscript. All authors contributed to the article and approved the submitted version.