Efficacy and Safety of Anti-CD38 Monoclonal Antibodies in Patients with Relapsed or Refractory Multiple Myeloma: A Meta-Analysis of Randomized Clinical Trials

The benefit of associating anti-CD38 monoclonal antibodies to proteasome inhibitor (PI)/immunomodulatory agent (IA) and dexamethasone in the treatment of patients with relapsed or refractory multiple myeloma (MM) remains unclear. PubMed, Embase, and Cochrane Library databases were searched for randomized controlled trials that investigated the addition of anti-CD38 monoclonal antibodies to a therapy composed of PI/IA and dexamethasone versus PI/IA and dexamethasone alone for treating relapsed or refractory MM. Hazard ratios (HRs) or risk ratios (RRs) were computed for binary endpoints, with 95% confidence intervals (CIs). Six studies comprising 2191 patients were included. Anti-CD38 monoclonal antibody significantly improved progression-free survival (HR 0.52; 95% CI 0.43–0.61; p < 0.001) and overall survival (HR 0.72; 95% CI 0.63–0.83; p < 0.001). There was a significant increase in hematological adverse events, such as neutropenia (RR 1.41; 95% CI 1.26–1.58; p < 0.01) and thrombocytopenia (RR 1.14; 95% CI 1.02–1.27; p = 0.02), in the group treated with anti-CD38 monoclonal antibody. Also, there was a significant increase in non-hematological adverse events, such as dyspnea (RR 1.72; 95% CI 1.38–2.13; p < 0.01) and pneumonia (RR 1.34; 95% CI 1.13–1.59; p < 0.01), in the group treated with anti-CD38 monoclonal antibody. In conclusion, the incorporation of an anti-CD38 monoclonal antibody demonstrated a promising prospect for reshaping the established MM treatment paradigms.

MM accounts for 1% of all cancers and is the second most common hematologic neoplasm in the world, representing 30,000 new cases per year, with an estimated incidence of 5 cases per 100,000 [14][15][16].The implementation of emerging therapies has increased the overall survival of patients with MM since the 21st century [17][18][19].Before 2000, the average survival for MM was only 12 months, whereas after 2000, it increased to 24 months [20][21][22].
Thus, this meta-analysis of phase III randomized controlled trials (RCTs) aimed to clarify the benefit of treatment with anti-CD38 monoclonal antibodies combined with proteasome inhibitors or immunomodulatory agents for patients with relapsed or refractory MM.

Protocol and Registration
This research followed the recommendations outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (Tables S1 and S2) [34].The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD42024507495.

Eligibility Criteria
Included studies must have met the following eligibility criteria: (1) phase III RCTs; (2) enrolling adult patients (≥18 years) with documented relapsed or refractory MM; (3) treatment regimens with dexamethasone and immunomodulatory agent/proteasome inhibitor for intervention and control groups and an anti-CD38 humanized IgG1-κ monoclonal antibody for the intervention group only; and (4) Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2. Studies with no outcomes of interest, overlapping populations, or non-randomized clinical trials were excluded.The eligibility criteria for each of the RCTs included in this systematic review and meta-analysis are detailed in Table S3.
The question we sought to answer was as follows: How effective is the addition of anti-CD38 monoclonal antibody to dexamethasone and immunomodulatory agent/proteasome inhibitor therapy for the treatment of patients with relapsed or refractory MM?

Search Strategy
PubMed, Embase, and Cochrane Library were searched on 29 January 2024.The search strategies utilized for each database are summarized in detail in Table S4.
To identify potentially relevant future studies, we checked the references of the included articles and systematic reviews in the literature.Additionally, we set up alerts in each database to notify us of new publications related to the topic of interest.The studies found in the databases and in the references of the articles were incorporated into the reference management software (Rayyan) [35].Two reviewers (F.A.K. and V.M.S.) selected the studies found in the databases individually.Discordances in selection were solved by a general agreement between three authors (F.A.K., V.M.S., and F.C.A.d.M.).

Data Extraction
To summarize the main findings, two authors (A.d.O.M.L. and V.K.T.S.) independently collected the data extracted from the included articles.The following baseline characteristics were extracted: (1)  The ensuing outcomes of interest were extracted: (1) progression-free survival (PFS), defined as the time elapsed from patient randomization to the occurrence of death from any cause or disease progression; (2) overall survival (OS), defined as the length of time, counted from the start of treatment, that patients are still alive; and (3) adverse events, defined as an untoward medical occurrence related to a treatment.These were evaluated according to the Common Terminology Criteria for Adverse Events, version 5.0 [36].

Risk of Bias Assessment
To assess the quality of individual randomized studies, the Cochrane risk of bias tool for randomized trials (RoB-2) was used [37].A score of low, high, or unclear risk of bias was assigned to each trial across five domains: (1) randomization process; (2) deviations from intended interventions; (3) missing outcomes; (4) measurement of outcomes; and (5) selection of reported results.To further examine the possibility of publication bias, funnel-plot analyses were employed.Two authors (V.K.T.S. and F.C.A.d.M.) performed an independent evaluation of the risk of bias for all included RCTs and any disagreements were resolved by consensus.

Statistical Analysis
Hazard ratios (HRs) or risk ratios (RRs) were computed for binary outcomes, with 95% confidence intervals (CIs).Cochran Q-test and I 2 statistics were utilized to evaluate heterogeneity; p values < 0.10 and I 2 > 25% were indicative of a statistically significant heterogeneity between the included RCTs [38].The Sidik-Jonkman estimator was used to determine the Tau 2 variance between studies [39].For all endpoints, DerSimonian and Laird random effect models were used [40].To assess publication bias, contour-enhanced funnel plots were visually inspected and assessed using Egger's regression asymmetry [41].The statistical analyses were executed through the R Software version 4.3.

Search Results and Characteristics of Included Studies
The selection was described in a PRISMA flow diagram (Figure 1).A total of 2047 references were found in the systematic search.After the elimination of identical references and the evaluation according to the content in the title and abstract, 20 studies were deemed fit for the full-text reading, which encompassed a thorough evaluation of the inclusion and exclusion criteria.Out of these, six RCTs were included, comprising a total of 2191 patients [42][43][44][45][46][47].
A total of 1162 patients with relapsed or refractory MM were randomized to receive anti-CD38 monoclonal antibodies and 1029 patients were assigned to the control group.The majority of patients had an ECOG performance status score of 0 (770 patients) and 811 patients had an ECOG ≥ 1. Regarding the type of measurable MM, 979 were IgG positive and 641 were non-IgG.The median age ranged from 28.0 to 90.0 years.Baseline patient and study characteristics are summarized in Tables 1 and S5.A total of 1162 patients with relapsed or refractory MM were randomized to receive anti-CD38 monoclonal antibodies and 1029 patients were assigned to the control group.The majority of patients had an ECOG performance status score of 0 (770 patients) and 811 patients had an ECOG ≥ 1. Regarding the type of measurable MM, 979 were IgG positive and 641 were non-IgG.The median age ranged from 28.0 to 90.0 years.Baseline patient and study characteristics are summarized in Tables 1 and S5.PFS was evaluated in six RCTs, comprising a total of 2191 patients.Anti-CD38 monoclonal antibodies significantly improved PFS compared to the control group (HR 0.52, 95% CI 0.43-0.61;p < 0.001; I 2 = 57%; Figure 2).
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The individual quality assessment of each study included in the meta-analysis is depicted in Figure 4.The six studies included had a low risk of bias in all five domains of Rob 2, which represents a high quality of RCTs included in the analysis.As shown in Figures S4 and S5, the funnel plots of PFS and OS outcomes present a symmetrical distribution of similar-weight studies, indicating no evidence of significant publication bias and a lower variance among the studies included.

Discussion
In this systematic review and meta-analysis involving six RCTs and 2191 patients, we compared dexamethasone and immunomodulatory agent/proteasome inhibitor for both intervention and control groups and an anti-CD38 humanized IgG1-κ monoclonal antibody intervention for Relapsed or Refractory Multiple Myeloma.The main results of the pooled analyses were as follows: (1) PFS was better in patients in the anti-CD38 group; (2) OS showed a significant difference in favor of the anti-CD38 group; and (3) adverse events grade ≥ 3 such as neutropenia, thrombocytopenia, diarrhea, dyspnea, and pneumonia occurred in a significantly higher proportion of patients in the anti-CD38 group compared to the control.
CD38 is a type II transmembrane protein that is involved in cellular calcium signaling, lymphocyte activation, and the migration of these immune cells [43].In the normal state, CD38 expression is low, while in MM it is remarkably high in plasma cells [44].Thus, the use of targeted therapies such as daratumumab is justified due to the inhibition of tumor growth by binding to the CD38 glycoprotein with high affinity, with the activation of immune-mediated molecular mechanisms [47].Its use in clinical practice is currently approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) as a standard single treatment or in combination with other antitumor therapies for MM [43].
In addition, isatuximab is an IgG1 monoclonal antibody responsible for the enzymatic regulation of CD38, and treatment with this agent is justified because it induces caspase-dependent apoptosis and can act synergistically by invigorating T cells and natural killer cells [43].Although similar to daratumab, the mechanisms of action of these two drugs differ because they have different target epitopes [46].Furthermore, isatuximab can induce cell death directly, whereas daratumab requires additional antitumor combinations; therefore, its treatment is based on the kinergic effect of the combined protocols [46,47].
The mechanism of action of anti-CD38 monoclonal antibodies is important for the treatment of MM because they act on specific receptors (Fc) for antibodies, which are very expressed in this disease [26,48,49].Their use for treating MM is justified mainly due to complement-dependent cytotoxicity (CDC), in which the binding of C1q complex to the

Discussion
In this systematic review and meta-analysis involving six RCTs and 2191 patients, we compared dexamethasone and immunomodulatory agent/proteasome inhibitor for both intervention and control groups and an anti-CD38 humanized IgG1-κ monoclonal antibody intervention for Relapsed or Refractory Multiple Myeloma.The main results of the pooled analyses were as follows: (1) PFS was better in patients in the anti-CD38 group; (2) OS showed a significant difference in favor of the anti-CD38 group; and (3) adverse events grade ≥ 3 such as neutropenia, thrombocytopenia, diarrhea, dyspnea, and pneumonia occurred in a significantly higher proportion of patients in the anti-CD38 group compared to the control.
CD38 is a type II transmembrane protein that is involved in cellular calcium signaling, lymphocyte activation, and the migration of these immune cells [43].In the normal state, CD38 expression is low, while in MM it is remarkably high in plasma cells [44].Thus, the use of targeted therapies such as daratumumab is justified due to the inhibition of tumor growth by binding to the CD38 glycoprotein with high affinity, with the activation of immunemediated molecular mechanisms [47].Its use in clinical practice is currently approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) as a standard single treatment or in combination with other anti-tumor therapies for MM [43].
In addition, isatuximab is an IgG1 monoclonal antibody responsible for the enzymatic regulation of CD38, and treatment with this agent is justified because it induces caspase-dependent apoptosis and can act synergistically by invigorating T cells and natural killer cells [43].Although similar to daratumab, the mechanisms of action of these two drugs differ because they have different target epitopes [46].Furthermore, isatuximab can induce cell death directly, whereas daratumab requires additional antitumor combinations; therefore, its treatment is based on the kinergic effect of the combined protocols [46,47].
The mechanism of action of anti-CD38 monoclonal antibodies is important for the treatment of MM because they act on specific receptors (Fc) for antibodies, which are very expressed in this disease [26,48,49].Their use for treating MM is justified mainly due to complement-dependent cytotoxicity (CDC), in which the binding of C1q complex to the Fc tail of the therapeutic antibody initiates the complement cascade and causes the generation of the membrane attack complex [50][51][52][53].This leads to the deposition of complement factors on the membrane, triggering the engulfment and destruction of tumor cells by phagocytes, which is further elevated by the synergy with increased expression of Fcγ receptors [53][54][55].
Other Fc-dependent cellular mechanisms include antibody-dependent cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) [56].ADCC mainly involves natural killer (NK) cells, which recognize tumor cells and then release cytotoxic granules such as perforin and granzymes, which induce the death of target cells [57][58][59].On the other hand, ADCP involves the phagocytosis of cells by macrophages, which recognize the target cells by antibodies bound to the surface of the tumor cells; thus, this marking by Fc receptors leads to the destruction of these cells [60][61][62].The combination of these mechanisms, ADC and ADCP, plays a crucial role in the efficacy of daratumumab and isatuximab, although the latter can also induce cell death by direct mechanisms that are independent of Fc [63][64][65].
Our findings provide compelling evidence that incorporating anti-CD38 therapy into the treatment regimen of multiple myeloma (MM) patients significantly improves PFS.The analysis revealed an HR of 0.5, indicating a 50% reduction in the risk of disease progression for patients receiving anti-CD38 treatment compared to those who did not.This is statistically significant, with a p-value of less than 0.01, highlighting the robust nature of this benefit.These results are particularly encouraging when compared to the outcomes of other emerging therapies for MM.In the KarMMa trial, a phase 2 study investigating the efficacy and safety of idecabtagene vicleucel, a chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA), notable results were observed.The trial enrolled heavily pretreated patients with relapsed and refractory myeloma, who had received at least three prior treatment regimens.Among the 128 patients who received CART-cell, the median progression-free survival was 8.8 months (95% confidence interval, 5.6 to 11.6), indicating a substantial benefit in delaying disease progression.This stands in stark contrast to the substantial PFS benefit observed in our study with anti-CD38 therapy [66].
Our study also revealed a significant improvement in OS for patients treated with anti-CD38 monoclonal antibodies.The analysis yielded an HR of 0.72, indicating a 28% reduction in the mortality risk for patients receiving this therapy compared to the control group.This finding holds strong statistical significance with a p-value of less than 0.01, emphasizing the positive impact of anti-CD38 treatment on patient longevity.The observed benefit in OS aligns with the results of the KarMMa trial, which investigated the efficacy and safety of idecabtagene vicleucel (ide-cel, also known as bb2121), a chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA).In the KarMMa trial, the Kaplan-Meier estimated median overall survival was 19.4 months (95% CI, 18.2 could not be estimated), with an overall survival of 78% at 12 months.These data underscore the promising potential of anti-CD38 therapy in improving overall survival outcomes for patients with refractory and relapsed myeloma [66].
For patients with MM undergoing chemotherapy, treatment-related adverse events can significantly impact their well-being and quality of life, affecting their daily routines and emotional state [67,68].Our meta-analysis suggests that while anti-CD38 monoclonal antibodies may be associated with an increased risk of severe lymphopenia, neutropenic infections, and thrombocytopenia, they also offer improved clinical efficacy in MM treatment.Notably, other serious non-hematological adverse events include diarrhea, dyspnea, and pneumonia.Nonetheless, considering the potential benefits to clinical outcomes, the further investigation and incorporation of anti-CD38 as a treatment option for MM may be warranted, with careful consideration of both the risks and benefits.
The main limitation of this meta-analysis is the high heterogeneity (I 2 > 25%) present in most of the analyzed outcomes, such as progression-free survival and overall survival.This suggests that there may be significant differences between the populations included in the studies.However, despite this limitation, this meta-analysis was able to draw robust conclusions demonstrating the significant benefit of anti-CD38 for patients with relapsed or refractory MM.

Conclusions
This is the first meta-analysis of randomized clinical trials to evaluate the efficacy and safety of anti-CD38 therapy for the treatment of patients with relapsed or refractory multiple myeloma.Our results suggest that this therapy represents a potential treatment option, and its application in clinical practice should be encouraged.

Figure 1 .
Figure 1.Flow diagram of the articles included in the meta-analysis.

Figure 1 .
Figure 1.Flow diagram of the articles included in the meta-analysis.

Figure 4 .
Figure 4. Critical appraisal of randomized controlled trials according to the Cochrane Collaboration tool for assessing risk of bias in randomized trials [42-47].

Figure 4 .
Figure 4. Critical appraisal of randomized controlled trials according to the Cochrane Collaboration tool for assessing risk of bias in randomized trials [42-47].

Table 1 .
Design and characteristics of studies included in the meta-analysis.

Table 2 .
Adverse events of any grade.