Daratumumab Versus Control Treatment: A Systematic Review and Meta-analysis Study of Survival Outcomes Among Multiple Myeloma Patients : Survival Outcomes of Multiple Myeloma Treatment with Daratumumab.

Introduction

Multiple myeloma (MM) is a malignant disorder of plasma cells characterized by abnormal monoclonal protein production, bone marrow infiltration, and a complex array of clinical symptoms including bone pain, anemia, and renal dysfunction [ 1 ][ 2 ]. Representing the second most common hematologic malignancy, multiple myeloma accounts for approximately 1% of all cancers and 10% of hematologic cancers worldwide. Despite advancements in diagnosis and treatment, multiple myeloma remains an incurable disease, with most patients experiencing multiple relapses and developing resistance to standard therapies over time [ 3 ][ 4 ]. Current therapeutic strategies focus on extending progression-free survival (PFS) and achieving deeper, longer-lasting responses to improve overall survival. The introduction of novel agents like proteasome inhibitors, immunomodulatory drugs (IMiDs), and autologous stem cell transplantation (ASCT) has markedly improved outcomes for many patients, yet the need for more effective therapies remains, especially for those with relapsed/refractory multiple myeloma (RRMM) or those who are ineligible for aggressive treatments [ 5 ][ 6 ]. In this context, monoclonal antibodies targeting specific antigens on myeloma cells, particularly CD38, have emerged as promising additions to the therapeutic landscape.

Daratumumab, a human monoclonal antibody targeting CD38, has transformed the treatment paradigm for multiple myeloma due to its direct anti-myeloma effects and ability to modulate the immune microenvironment [ 7 ][ 8 ][ 9 ]. CD38 is a glycoprotein highly expressed on myeloma cells, making it an ideal target for therapy. By binding to CD38, Daratumumab induces cell death through multiple mechanisms, including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis [ 10 ][ 11 ][ 12 ]. Additionally, Daratumumab has been shown to reduce the number of immunosuppressive cells in the tumor microenvironment, such as regulatory T cells and myeloid-derived suppressor cells, thereby enhancing the body’s immune response against myeloma cells [ 13 ][ 14 ][ 15 ].

Clinical trials have demonstrated that Daratumumab, both as monotherapy and in combination with other agents, leads to significant improvements in survival outcomes. These effects are especially pronounced when Daratumumab is added to standard-of-care regimens, such as bortezomib, lenalidomide, and dexamethasone, providing a potent synergistic effect that extends the duration of response. However, despite these promising results, the efficacy of Daratumumab can vary across different patient subgroups, and its safety profile necessitates careful monitoring due to an increased risk of infections and other adverse effects [ 16 ][ 17 ][ 18 ]. Although several meta-analyses have assessed Daratumumab’s efficacy in multiple myeloma— in high-risk cytogenetic patients, in overall myeloma populations, and specifically in relapsed/refractory RCTs. However, none has concurrently quantified its effects on minimal residual disease negativity, and overall response rate, or examined how the rapidly expanding annual literature (now > 30 studies/yr) influences pooled estimates over time. By integrating both randomized and observational data and focusing on minimum residual disease (MRD) —an increasingly recognized surrogate for long-term outcomes—our meta-analysis fills this gap, providing the most comprehensive synthesis of Daratumumab’s multi-dimensional benefit in multiple myeloma to date.

This study therefore aims to (1) pool all available trials and observational cohorts to estimate the effect size of Daratumumab on overall response rate (ORR), progression or death (PRD), MRD negativity, and mortality; and (2) explore whether these effects differ between relapsed/refractory, transplant-ineligible, and transplant-eligible patient groups, thereby filling a critical gap in the current evidence.

Materials and Methods

Design

This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [ 19 ] and at the time we began, we did not prospectively register because our project timeline did not allow for the PROSPERO review process before data extraction began. Nevertheless, we strictly adhered to PRISMA throughout our project. The objective was to evaluate the treatment outcomes of Daratumumab compared to control treatments among patients with multiple myeloma. The methodology was structured to provide a thorough and objective synthesis of the existing literature on this topic.

Systematic Search

A comprehensive literature search was conducted across several electronic databases, including PubMed, Web of Science, and Scopus. The search included all records available up to [September, 2024]. Relevant Medical Subject Headings (MeSH) and keywords were utilized, focusing on terms like "multiple myeloma," "Daratumumab," "anti-CD38 therapy," and "immunotherapy." Additionally, we manually reviewed the reference lists of relevant articles and prior systematic reviews to identify any studies that might have been missed in the database search (Appendix 1).

Inclusion and Eligibility

Eligibility criteria were defined using the PICO framework. The Population (P) included clinical studies on human patients diagnosed with multiple myeloma. The Intervention (I) was treatment with Daratumumab, either as monotherapy or in combination with other agents.

The Comparison (C) group involved control treatments, such as standard care or alternative therapies without Daratumumab. The primary Outcomes (O) assessed were treatment efficacy, measured by parameters such as overall survival (OS), progression-free survival (PFS), death, hazard ratio, and minimum residual disease (MRD). Studies were excluded if they were cross-sectional, involved animal models, were case reports, or lacked sufficient clinical outcome data for analysis. Studies focusing on other cancers or conditions were also excluded. Studies without control group or studies that exposed both groups to Daratumumab were also excluded. We considered Phase II-III randomized controlled trials as well as prospective and retrospective observational cohort studies to capture both high-level efficacy and real-world effectiveness.

Data Extraction and Outcome Measures

Data extraction was independently conducted by two reviewers using a standardized data collection form. Information collected included study characteristics (author, publication year), patient demographics (age, gender, stage of multiple myeloma), treatment details (dosing, duration, regimen specifics), and outcomes measured (overall survival, progression-free survival, HZ, MRD, or death). Discrepancies between reviewers were resolved through discussion or, if necessary, by involving a third reviewer.

Statistical Analysis and Data Synthesis

All analyses were performed in R (version 4.x) using the meta package (R Foundation for Statistical Computing) and RStudio. We assessed between-study heterogeneity with the I² statistic, interpreting 25%, 50%, and 75% as low, moderate, and high heterogeneity, respectively. Regardless of I², all pooled effect estimates were calculated using a DerSimonian-Laird random-effects model to yield conservative confidence intervals. Time-to-event outcomes (e.g. PFS) are presented as hazard ratios (HRs) with 95% confidence intervals (CIs), whereas dichotomous outcomes (e.g. MRD negativity, ORR) are reported as odds ratios (ORs) or risk differences (RDs) using the Mantel-Haenszel method. Statistical significance of pooled estimates and subgroup differences was evaluated by z-tests. Predefined sensitivity analyses—omitting one study at a time—assessed robustness, and subgroup analyses were conducted by study design (RCT vs. observational) and by disease status (RRMM, ND/ISCT, ND/ESCT).

We examined publication bias via funnel plots and Egger’s regression test. Finally, study quality was independently rated by two reviewers using the Cochrane Risk of Bias 2 tool for randomized trials and the Newcastle-Ottawa Scale for observational cohorts, with discrepancies resolved by consensus and quality scores explored as potential moderators in meta-regression.

Results

Our search across PubMed, Scopus, and Web of Science yielded 24,984 studies from inception until September, 2024. Overall, 7,177 studies duplicates, hence, after removing, 17,807 studies were screened based on the title only at first. Afterwards, 449 studies were selected for abstract evaluation which resulted in selection of 93 articles for full-text evaluation. Among the 93 full texts that were evaluated, 58 had inappropriate design which included case reports and case series, animal studies, and studies that did not evaluate the clinical outcome of daratumumab treatment, and histological or histomorphological studies. Our final screening resulted in the inclusion of 35 studies in our systematic review and 35 studies [ 8 ][ 9 ][ 10 ][ 15 ][ 17 ][ 18 ][ 20 ][ 21 ][ 22 ][ 23 ][ 24 ][ 25 ][ 26 ][ 27 ][ 28 ][ 29 ][ 30 ][ 31 ][ 32 ][ 33 ][ 34 ][ 35 ][ 36 ][ 37 ][ 38 ][ 39 ][ 40 ][ 41 ][ 42 ][ 43 ][ 44 ][ 45 ][ 46 ][ 47 ][ 48 ] in the meta-analysis (Figure- 1 ). Full detail on the study characteristics of the final studies that were included is available in Table- 1 .

We included 35 studies (published 2015-2024) enrolling a total of 22,439 patients: 21 studies (n=7,604) in relapsed/refractory multiple myeloma, 12 studies (n=10,216) in newly diagnosed, transplant-ineligible patients, and 6 studies (n=4,619) in newly diagnosed, transplant-eligible patients. Fifteen were Phase II-III randomized controlled trials comparing Daratumumab (alone or with backbone regimens such as lenalidomide or bortezomib) versus placebo or standard therapy, with the remainder comprising prospective (n=2) and retrospective (n=2) observational cohorts. Sample sizes per study ranged from 45 to 1,800 patients. Studies were conducted across North America, Europe, and Asia, and reported outcomes on PFS, MRD negativity, ORR, and safety endpoints, with follow-up durations of 6-48 months.

Using the Cochrane Risk of Bias 2 tool, we found that 28 of the 31 randomized controlled trials were judged at low risk of bias across all domains, while three trials raised ‘some concerns’ (primarily due to unclear allocation concealment or missing outcome data); none were rated at high risk. For the 4 observational cohorts assessed with the Newcastle-Ottawa Scale, total scores ranged from 6 to 9 (out of 9), with a median score of 8: 3 studies were deemed high quality (NOS ≥ 7), and 1 were of moderate quality (NOS=6), most commonly losing points in the comparability domain due to limited adjustment for confounders. These assessments indicate an overall low-to-moderate risk of bias in the pooled data, supporting the robustness of our meta-analytic findings.

Hazard Ratio

The overall pooled HR for Daratumumab versus control treatment across all patients was 0.50 (95% CI: 0.46-0.55), indicating a statistically significant reduction in hazard (P<0.01). Subgroup analysis showed an HR of 0.48 (95% CI: 0.41-0.57) for RRMM with high heterogeneity (I²=77%, [P<0.01]), an HR of 0.52 (95% CI: 0.46-0.59) for ND/ISCT with moderate heterogeneity (I²=42%, [P=0.06]), and an HR of 0.55 (95% CI: 0.42-0.62) for ND/ESCT with low heterogeneity (I²=31%, [P=0.21]). The overall heterogeneity was considerable (I²=67%, τ²=0.0521, [P<0.01]), but the test for subgroup differences was not statistically significant (χ² (df=2)=0.58, [P=0.75]), indicating consistent treatment effects across the subgroups (Figure- 2 ).

Overall Response

The model, employing a random-effects model, analyzed a total of 4,923 patients in the Daratumumab group and 4,956 patients in the control group across three subgroups: RRMM, ND/ISCT, and ND/ESCT. The pooled OR for ORR with Daratumumab versus control was 2.58 (95% CI: 2.26-2.93), showing a significant benefit in favor of Daratumumab with [P<0.01]. Subgroup analyses revealed an OR of 2.43 (95% CI: 1.81-3.26) for RRMM with high heterogeneity (I²=78%, [P<0.01]), an OR of 2.00 (95% CI: 1.35-2.63) for ND/ISCT with no significant heterogeneity (I²=0%, [P=0.46]), and an OR of 2.76 (95% CI: 1.37-5.56) for ND/ESCT with moderate heterogeneity (I²=39%, [P=0.18]). Overall heterogeneity was substantial (I²=70%, τ²=0.3522, [P<0.01]), and subgroup differences were statistically significant (χ² (df=2) = 6.50, [P=0.04]), suggesting variability in treatment effects among the subgroups (Figure- 3 ).

Overall Survival

The pooled number of patients was 5,364 in the Daratumumab group and 4,870 in the control group (Figure- 4 ). Across all participants, the odds of mortality were lower with Daratumumab, yielding a pooled OR of 0.73 (95% CI: 0.66-0.81, [P<0.01]). Among the subgroups, patients with RRMM showed an OR of 0.75 (95% CI: 0.66-0.85) with moderate heterogeneity (I²=45%, [P=0.03]). ND/ISCT patients had an OR of 0.76 (95% CI: 0.45-0.72), also showing moderate heterogeneity (I²=44%, [P=0.13]). ND/ESCT patients exhibited the most homogeneous results, with an OR of 0.67 (95% CI: 0.46-0.88) and low heterogeneity (I²=12%, [P=0.33]). While overall heterogeneity was present (I²=45%, τ²=0.0208, [P=0.01]), differences across subgroups were not statistically significant (χ² (df=2)=5.24, [P=0.07]).

Minimal Residual Disease Negativity

The random-effects model included 4,097 patients receiving Daratumumab and 3,528 in the control group (Figure- 5 ). The overall pooled risk difference (RD) favoring Daratumumab was 0.20 (95% CI: 0.19-0.22, [P<0.01]). In subgroup analyses, ND/ISCT group had an RD of 0.17 (95% CI: 0.15-0.19) with low heterogeneity (I²=15%, [P=0.32]). ND/ESCT group showed a higher RD of 0.20 (95% CI: 0.16-0.24), with moderate heterogeneity (I²=51%, [P=0.11]). RRMM patients exhibited the highest RD at 0.27 (95% CI: 0.21-0.29), accompanied by substantial heterogeneity (I²=76%, [P<0.01]). Overall heterogeneity was significant (I²=73%, τ²=0.0032, [P<0.01]), with a notable difference across subgroups (χ² (df=2) = 6.14, [P=0.05]).

Progression or Death

The random-effects model included 2,965 patients treated with Daratumumab and 2,800 patients in the control group. The pooled RD was -0.14 (95% CI: -0.16 to -0.12, [P<0.01]), indicating a significant reduction in progression or death with Daratumumab (Figure- 6 ). Subgroup analysis showed varying effects: ND/ESCT group had an RD of -0.11 (95% CI: -0.17 to -0.04) with moderate heterogeneity (I²=46%, [P=0.16]), ND/ISCT demonstrated an RD of -0.10 (95% CI: -0.15 to -0.06) with similar heterogeneity (I²=54%, [P=0.09]), and RRMM patients exhibited a larger RD of -0.17 (95% CI: -0.21 to -0.13) with high heterogeneity (I²=87%, [P<0.01]). Overall heterogeneity was substantial (I²=78%, τ²=0.0095, [P<0.01]), although subgroup differences were not statistically significant (χ² (df=2) = 3.90, [P=0.14]).

The combined funnel plots reveal varying degrees of symmetry, which provides insight into potential publication bias and heterogeneity among studies. Figure- 7 .a, representing risk difference of MRD, shows some asymmetry and scatter in smaller studies, suggesting possible publication bias and variability. Figure- 7 .b, is more symmetrical, implying less bias, though small studies show a wider spread.

Discussion

The aim of this meta-analysis was to evaluate the efficacy of Daratumumab compared to control treatments in multiple myeloma patients across different subgroups, including relapsed/refractory multiple myeloma, newly diagnosed patients eligible for stem cell transplant, and those ineligible for transplant. Key findings demonstrate that Daratumumab significantly improved clinical outcomes, with minimal residual disease negativity rates increased by approximately 20% compared to controls. The overall response rate was also substantially higher, with a pooled odds ratio of 2.58, indicating a nearly 2.6-fold increase in response likelihood with Daratumumab. Additionally, Daratumumab was associated with a 14% reduction in the absolute risk of progression or death (RD: -0.14), with hazard ratios consistently lower across subgroups, suggesting significant survival benefits. Despite some heterogeneity (I² values ranging from 31% to 87%) and potential publication bias observed in smaller studies, the results consistently favored Daratumumab.

Our meta-analysis findings align with several previous studies that have evaluated the efficacy of Daratumumab in multiple myeloma treatment. A 2018 meta-analysis by Abu Zar et al. reported an overall response rate of 69% among relapsed/refractory multiple myeloma patients treated with Daratumumab-based regimens, with very good partial response or better (≥VGPR) in 40% of cases. In comparison, our meta-analysis showed a pooled ORR of 2.58, indicating a significant improvement across all subgroups, including RRMM, ND/ESCT, and ND/ISCT [ 49 ]. Another systematic review and meta-analysis by Giri et al. focused on high-risk cytogenetic profiles among multiple myeloma patients, reporting that adding Daratumumab to standard treatments improved progression-free survival by 15 months compared to control groups (HR: 0.37; 95% CI: 0.27-0.52). In our study, we observed a similar trend, with an overall pooled hazard ratio (HR) of 0.50 (95% CI: 0.46-0.55) for progression or death, reflecting a consistent survival benefit with Daratumumab, even among newly diagnosed and high-risk patient populations [ 50 ]. Additionally, Fu et al. (2022) focused on patients with renal impairment, finding that Daratumumab improved PFS by approximately 12 months compared to control (HR: 0.60; 95% CI: 0.45-0.75). Our results similarly demonstrated a significant reduction in the risk of progression or death with an RD of -0.14 across all patients, including those with renal insufficiency. Another meta-analysis study found that adding Daratumumab to standard therapies improved progression-free survival and overall survival in both relapsed/refractory multiple myeloma and newly diagnosed patients. This effect may be attributed to Daratumumab’s modulation of the tumor microenvironment. By depleting immunosuppressive CD38+ regulatory T cells and myeloid-derived suppressor cells, Daratumumab not only targets tumor cells but also reduces immune suppression, allowing for a more effective anti-tumor immune response [ 51 ][ 52 ].

While most trials included in our analysis reported follow-up of up to 48 months, understanding Daratumumab’s performance over longer periods is essential. Late-onset adverse effects—such as cumulative immunosuppression, infection risk, or secondary malignancies—may not manifest until years after treatment initiation. Future long-term extension studies and real-world registries should systematically capture these outcomes to ensure a truly comprehensive assessment of Daratumumab’s benefit-risk profile.

Furthermore, studies focusing on high-risk cytogenetic subgroups, such as those with 17p deletion or t (4;14) translocations, indicate that Daratumumab may provide unique advantages in this challenging population and observed a marked improvement in PFS among high-risk multiple myeloma patients treated with Daratumumab. The sustained efficacy of Daratumumab in high-risk patients may stem from its robust immune-mediated mechanisms, which are less dependent on the genetic vulnerabilities of the tumor, thus offering an effective option for patients with resistant disease profiles

Many trials excluded patients with comorbidities, advanced age, or poor performance status, limiting applicability to the broader multiple myeloma population seen in clinical practice. To enhance external validity, future research could employ adaptive trial designs or pragmatic cohort studies that enroll patients across a wider spectrum of age, organ function, and frailty. Embedding translational substudies in these trials—such as biomarker assessments in elderly or comorbid patients—would further illuminate Daratumumab’s real-world effectiveness and safety in those typically underrepresented.

We observed considerable variation in how adverse events were defined, graded, and reported, complicating cross-study comparisons and potentially biasing safety conclusions. Adopting uniform frameworks—such as the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for toxicity grading and the International Conference on Harmonisation (ICH) guidelines for immunogenicity—would improve consistency. Future meta-analyses could then perform more reliable pooled safety evaluations, thereby guiding clinicians with clearer, comparable safety profiles for Daratumumab.

There are several limitations in the existing literature that need addressing such as Daratumumab's long-term impact, particularly regarding sustained minimal residual disease negativity and relapse rates after five or more years. Future studies should extend follow-up durations to capture more comprehensive survival data and examine how long MRD negativity persists, especially given multiple myeloma’s tendency to relapse even after achieving deep responses. Another limitation can be observed in the study by Dimopoulos et al. [ 21 ][ 53 ][ 54 ], which evaluated Daratumumab in combination with standard therapies but did not include patients with significant comorbidities or high frailty scores. This exclusion limits the generalizability of the results, where patients often have multiple health issues and may not be candidates for aggressive therapies. To improve applicability, future studies should incorporate broader eligibility criteria, including patients with renal impairment, cardiovascular issues, or advanced age. Such inclusivity would allow for a better understanding of Daratumumab's efficacy and tolerability in typical clinical settings, particularly for patients who might benefit from less intensive treatment regimens. In addition, several studies evaluated the infection risk associated with Daratumumab but noted a lack of standardized criteria for defining and reporting adverse events [ 18 ][ 41 ][ 55 ]. Variability in the classification and severity grading of infections makes it challenging to compare safety data across different studies, which can lead to inconsistent conclusions. Future studies would benefit from adopting standardized adverse event criteria, such as the Common Terminology Criteria for Adverse Events (CTCAE) [ 56 ], to ensure uniform reporting. This standardization would improve the accuracy of pooled safety analyses and help clinicians better manage and anticipate potential risks associated with Daratumumab, especially in combination regimens.

A potential publication bias in favor of Daratumumab can be observed. The positive outcomes reported in many studies may be influenced by selective reporting, where studies with less favorable results are underrepresented. Our funnel plot analysis also suggests some asymmetry, indicating possible publication bias.

This study includes multiple subgroups of multiple myeloma patients, this subgroup-specific analysis offers a nuanced view of Daratumumab's efficacy across diverse patient populations, which enhances the clinical applicability of the findings. However, our study was faced with certain limitations. Despite efforts to assess and adjust for publication bias, the funnel plot analysis indicated some asymmetry, suggesting that smaller studies with less favorable outcomes may be underreported. This potential bias may slightly inflate the observed benefits of Daratumumab. Significant heterogeneity was observed in certain outcomes, particularly in progression or death. This variability may be due to differences in study design, patient selection criteria, and treatment regimens across studies, which could impact the consistency of the pooled results. Many of the included studies had relatively short follow-up periods, restricting insights into Daratumumab's long-term efficacy, sustained MRD negativity, and late-onset adverse effects. Some included studies lacked data on patients with significant comorbidities, such as advanced age or renal impairment, limiting the generalizability of findings to all multiple myeloma patients. Future studies should incorporate these underrepresented populations to improve the external validity of the results.

Conclusion

This meta-analysis provides comprehensive evidence supporting the efficacy of Daratumumab in treating multiple myeloma across diverse patient subgroups. By pooling data from multiple studies, this analysis demonstrates that Daratumumab significantly improves key clinical outcomes. The results indicate a substantial reduction in disease progression risk and a higher likelihood of achieving MRD negativity, which are pivotal in managing multiple myeloma, a disease marked by its recurrent nature. The findings also highlight Daratumumab’s capacity to enhance survival outcomes when used alongside standard regimens, reflecting its mechanism of action targeting CD38 on myeloma cells. Despite these positive outcomes, the study also underscores important considerations. While Daratumumab demonstrates a favorable benefit-risk profile, some adverse effects, particularly infections, are noted across studies. These require vigilant monitoring and supportive care to optimize treatment outcomes. Long-term data on survival and safety outcomes would also be valuable in providing a more complete assessment of Daratumumab's effectiveness over time.

Conflict of Interest

The authors have no conflicts of interest to declare.

References

Abdallah AO et al Clinical efficacy of retreatment of daratumumabbased therapy (D2) in daratumumabrefractory multiple myeloma Eur J Haematol 2023 110 6 626632 626632 10.1111/ejh.13942 36752328

Abe Y et al Efficacy and Safety of Ixazomib Plus Lenalidomide and Dexamethasone Following Injectable PIBased Therapy in Relapsed/Refractory Multiple Myeloma Ann Hematol 2023 102 9 24932504 24932504 10.1007/s00277-023-05212-7 PMC10444638 37341778

Ailawadhi S et al Ibrutinib, lenalidomide and dexamethasone in patients with relapsed and/or refractory multiple myeloma: Phase I trial results Hematol Oncol 2022 40 4 695703 695703 10.1002/hon.3012 35488778

An G et al Subcutaneous daratumumab in Chinese patients with relapsed or refractory multiple myeloma: an openlabel, multicenter, phase 1 study (MMY1010) Blood Sci 2024 6 3 e00193 e00193 10.1097/BS9.0000000000000193 PMC11146469 38832105

Antonioli E et al Carfilzomib, lenalidomide, and dexamethasone in relapsed refractory multiple myeloma: a prospective reallife experience of the Regional Tuscan Myeloma Network Front Oncol 2023 13 1162990 1162990 37182182 10.3389/fonc.2023.1162990 PMC10166989

Auner HW et al Ixazomib with cyclophosphamide and dexamethasone in relapsed or refractory myeloma: MUKeight phase II randomised controlled trial results Blood Cancer J 2022 12 4 52 52 10.1038/s41408-022-00626-4 PMC8972903 35365598

Fazio F et al Daratumumab combined with dexamethasone and lenalidomide or bortezomib in relapsed/refractory multiple myeloma (RRMM) patients: Report from the multiple myeloma GIMEMA Lazio group EJHaem 2022 3 1 121128 121128 10.1002/jha2.359 PMC9175681 35846211

Fu W et al Daratumumab, bortezomib, melphalan, and prednisone versus bortezomib, melphalan, and prednisone alone in transplantineligible Asian patients with newly diagnosed multiple myeloma: final analysis of the phase 3 OCTANS Study Ann Hematol 2025 104 1 51525 51525 10.1007/s00277-024-05958-8 PMC11868237 39227450

Fu W et al Daratumumab, Bortezomib, and Dexamethasone versus Bortezomib and Dexamethasone in Chinese Patients With Relapsed or Refractory Multiple Myeloma: Updated Analysis of LEPUS Clin Lymphoma Myeloma Leuk 2023 23 1 e51e58 e51e58 10.1016/j.clml.2022.10.007 36402700

Mollee P et al Daratumumab, cyclophosphamide, bortezomib, and dexamethasone for transplantineligible myeloma: AMaRC 0316 Blood Adv 2024 8 14 37213730 37213730 10.1182/bloodadvances.2023012539 PMC11296246 38739707

Morabito F et al Adjusted comparison between elotuzumab and carfilzomib in combination with lenalidomide and dexamethasone as salvage therapy for multiple myeloma patients Eur J Haematol 2022 108 3 178189 178189 10.1111/ejh.13723 34716957

Moreau P et al Daratumumab, carfilzomib, and dexamethasone in relapsed or refractory myeloma: final analysis of PLEIADES and EQUULEUS Blood Cancer J 2023 13 1 33 33 10.1038/s41408-023-00805-x PMC9989580 36882409

ReinosoSegura M et al Phase II Trial of Allogeneic Transplantation Plus Novel Drugs in Multiple Myeloma: Effect of Intensifying ReducedIntensity Conditioning with Bortezomib and Adding Maintenance Treatment Transplant Cell Ther 2022 28 5 258.e1258.e8 258.e1258.e8 10.1016/j.jtct.2022.01.026 35131486

Richardson PG et al Pomalidomide, bortezomib, and dexamethasone at first relapse in lenalidomidepretreated myeloma: A subanalysis of OPTIMISMM by clinical characteristics Eur J Haematol 2022 108 1 7383 7383 10.1111/ejh.13706 PMC9293199 34496096

Richter J et al Matchingadjusted indirect comparison of isatuximab plus carfilzomib and dexamethasone with daratumumab plus lenalidomide and dexamethasone in relapsed multiple myeloma Cancer Med 2023 12 7 80058017 80058017 10.1002/cam4.5584 PMC10134287 36726287

Usmani SZ et al Final analysis of the phase III noninferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma Haematologica 2022 107 10 24082417 24082417 10.3324/haematol.2021.279459 PMC9521240 35354247

Usmani SZ et al Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, openlabel, phase 3 study Lancet Oncol 2022 23 1 6576 6576 10.1016/S1470-2045(21)00579-9 34871550

Usmani SZ et al Final analysis of carfilzomib, dexamethasone, and daratumumab vs carfilzomib and dexamethasone in the CANDOR study Blood Adv 2023 7 14 37393748 37393748 10.1182/bloodadvances.2023010026 PMC10368773 37163358

Page MJ et al The PRISMA 2020 statement: an updated guideline for reporting systematic reviews bmj 2021 372 n71 n71 33782057 10.1136/bmj.n71 PMC8005924

Dimopoulos MA et al Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma New England Journal of Medicine 2016 375 14 13191331 13191331 10.1056/NEJMoa1607751 27705267

Mateos MV et al Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma New England Journal of Medicine 2018 378 6 518528 518528 10.1056/NEJMoa1714678 29231133

Facon T et al Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma N Engl J Med 2019 380 22 21042115 21042115 10.1056/NEJMoa1817249 PMC10045721 31141632

Moreau P et al Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stemcell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, openlabel, phase 3 study The Lancet 2019 394 10192 2938 2938 10.1016/S0140-6736(19)31240-1 31171419

Bahlis NJ et al Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended followup of POLLUX, a randomized, openlabel, phase 3 study Leukemia 2020 34 7 18751884 18751884 10.1038/s41375-020-0711-6 PMC7326710 32001798

Dimopoulos M et al Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, openlabel, phase 3 study The Lancet 2020 396 10245 186197 186197 10.1016/S0140-6736(20)30734-0 32682484

Durie BGM et al Daratumumablenalidomidedexamethasone vs standardofcare regimens: Efficacy in transplantineligible untreated myeloma Am J Hematol 2020 95 12 14861494 14861494 10.1002/ajh.25963 PMC7754114 32804408

Mateos MV et al Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, openlabel, phase 3 trial The Lancet 2020 395 10218 132141 132141 10.1016/S0140-6736(19)32956-3 31836199

Mateos MV et al Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Patients With Previously Treated Multiple Myeloma: Threeyear Followup of CASTOR Clinical Lymphoma, Myeloma and Leukemia 2020 20 8 509518 509518 10.1016/j.clml.2019.09.623 32482541

Voorhees PM et al Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplanteligible newly diagnosed multiple myeloma: the GRIFFIN trial Blood, The Journal of the American Society of Hematology 2020 136 8 936945 936945 10.1182/blood.2020005288 PMC7441167 32325490

Dimopoulos MA et al Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an openlabel, randomised, phase 3 trial The Lancet Oncology 2021 22 6 801812 801812 10.1016/S1470-2045(21)00128-5 34087126

Facon T et al Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, openlabel, phase 3 trial Lancet Oncol 2021 22 11 15821596 15821596 10.1016/S1470-2045(21)00466-6 34655533

Lu J et al Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Chinese Patients with Relapsed or Refractory Multiple Myeloma: Phase 3 LEPUS (MMY3009) Study Clinical Lymphoma, Myeloma and Leukemia 2021 21 9 e699e709 e699e709 10.1016/j.clml.2021.04.012 34108127

Facon T et al Daratumumab plus lenalidomide and dexamethasone in transplantineligible newly diagnosed multiple myeloma: frailty subgroup analysis of MAIA Leukemia 2022 36 4 10661077 10661077 10.1038/s41375-021-01488-8 PMC8979809 34974527

He J et al Indirect Treatment Comparison of Daratumumab, Pomalidomide, and Dexamethasone Versus Standard of Care in Patients with DifficulttoTreat Relapsed/Refractory Multiple Myeloma Adv Ther 2022 39 9 42304249 42304249 10.1007/s12325-022-02226-x PMC9402768 35876974

Jakubowiak AJ et al Daratumumab Improves Depth of Response and Progressionfree Survival in Transplantineligible, Highrisk, Newly Diagnosed Multiple Myeloma Oncologist 2022 27 7 e589e596 e589e596 10.1093/oncolo/oyac067 PMC9256027 35462406

Derman BA et al Phase 1/2 study of carfilzomib, pomalidomide, and dexamethasone with and without daratumumab in relapsed multiple myeloma Blood Adv 2023 7 19 57035712 57035712 10.1182/bloodadvances.2022008866 PMC10539870 36763537

Dimopoulos MA et al Overall Survival With Daratumumab, Lenalidomide, and Dexamethasone in Previously Treated Multiple Myeloma (POLLUX): A Randomized, OpenLabel, Phase III Trial J Clin Oncol 2023 41 8 15901599 15901599 10.1200/JCO.22.00940 PMC10022849 36599114

Sonneveld P et al Overall Survival With Daratumumab, Bortezomib, and Dexamethasone in Previously Treated Multiple Myeloma (CASTOR): A Randomized, OpenLabel, Phase III Trial J Clin Oncol 2023 41 8 16001609 16001609 10.1200/JCO.21.02734 PMC10022857 36413710

Stork M et al Daratumumab with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma patients real world evidence analysis Ann Hematol 2023 102 6 15011511 15011511 10.1007/s00277-023-05188-4 PMC10182121 37088816

Chari A et al Daratumumab in transplanteligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN Blood Cancer J 2024 14 1 107 107 10.1038/s41408-024-01088-6 PMC11231363 38977707

Gordan LN et al ProgressionFree Survival of Daratumumab Versus Bortezomib Triplet Combination With Lenalidomide and Dexamethasone in Transplant Ineligible Patients With Newly Diagnosed Multiple Myeloma: TAURUS Chart Review Study Clin Lymphoma Myeloma Leuk 2024 24 1 5563 5563 10.1016/j.clml.2023.09.003 37838502

Han X et al Clinical outcomes of pomalidomidebased and daratumumabbased therapies in patients with relapsed/refractory multiple myeloma: A realworld cohort study in China Cancer Med 2024 13 9 e7232 e7232 10.1002/cam4.7232 PMC11066492 38698679

Joseph NS et al Quadruplet therapy for newly diagnosed myeloma: comparative analysis of sequential cohorts with triplet therapy lenalidomide, bortezomib and dexamethasone (RVd) versus daratumamab with RVD (DRVd) in transplanteligible patients Blood Cancer J 2024 14 1 159 159 10.1038/s41408-024-01120-9 PMC11399152 39271684

Moreau P et al Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplanteligible newly diagnosed multiple myeloma: longterm followup of the CASSIOPEIA randomised controlled phase 3 trial Lancet Oncol 2024 25 8 10031014 10031014 10.1016/S1470-2045(24)00282-1 PMC12375812 38889735

Ocio EM et al ANCHOR: melflufen plus dexamethasone and daratumumab or bortezomib in relapsed/refractory multiple myeloma: final results of a phase I/IIa study Haematologica 2024 109 3 867876 867876 10.3324/haematol.2023.283490 PMC10905089 37646657

Pour L et al Efficacy and safety of melflufen plus daratumumab and dexamethasone in relapsed/refractory multiple myeloma: results from the randomized, openlabel, phase III LIGHTHOUSE study Haematologica 2024 109 3 895905 895905 10.3324/haematol.2023.283509 PMC10905085 37646660

Spencer A et al Daratumumab for patients with myeloma with early or late relapse after initial therapy: subgroup analysis of CASTOR and POLLUX Blood Adv 2024 8 2 388398 388398 10.1182/bloodadvances.2023010579 PMC10820288 38048391

Sonneveld P FourDrug Therapy for Multiple Myeloma Reply N Engl J Med 2024 390 15 14401441 14401441 10.1056/NEJMc2402133 38631010

Abu Zar et al Efficacy and Safety of Daratumumab Based Regimens for Multiple Myeloma: A Systematic Review and MetaAnalysis Blood 2018 132 Supplement 1 32923292 32923292

Giri S et al Evaluation of Daratumumab for the Treatment of Multiple Myeloma in Patients With Highrisk Cytogenetic Factors: A Systematic Review and Metaanalysis JAMA Oncol 2020 6 11 17591765 17591765 10.1001/jamaoncol.2020.4338 PMC7516804 32970151

Tang W et al Daratumumabbased immunotherapy vs lenalidomide, bortezomib and dexamethasone in transplantineligible newly diagnosed multiple myeloma: a systemic review Front Oncol 2024 14 1286029 1286029 38333688 10.3389/fonc.2024.1286029 PMC10850248

Tauseef A et al Role of daratumumab in relapsed or refractory multiple myeloma patient: A metaanalysis and literature to review J Family Med Prim Care 2022 11 6 26482655 26482655 10.4103/jfmpc.jfmpc_1987_21 PMC9480675 36119264

Dimopoulos MA et al Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended 4year followup and analysis of relative progressionfree survival from the randomized ELOQUENT2 trial Cancer 2018 124 20 40324043 40324043 10.1002/cncr.31680 30204239

Moreau P et al Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study The Lancet Oncology 2018 19 7 953964 953964 10.1016/S1470-2045(18)30354-1 29866475

Voorhees P et al Alliance A061202: ixazomib, pomalidomide, and dexamethasone for patients with lenalidomiderefractory MM in first relapse Blood Adv 2024 8 19 50395050 50395050 10.1182/bloodadvances.2024013623 PMC11465741 39058954

Goldsmith SR Slade MJ Fiala M Harding M Crees ZD Schroeder MA StockerlGoldstein K Vij R A phase Ib trial of isatuximab, bendamustine, and prednisone in relapsed/refractory multiple myeloma Annals of Hematology 2024 103 11 455765 455765 10.1007/s00277-024-05975-7 39227452