Abstract
Background
Multiple myeloma (MM) is the second most common hematologic malignancy worldwide. Recent therapeutic innovations, including the addition of daratumumab to standard regimens, have shown promising improvements in patient outcomes.
Objectives
This study aims to compare the efficacy and safety of daratumumab-based quadruplet therapy regimens with standard triplet therapy regimens in newly diagnosed multiple myeloma (NDMM) patients.
Design
Systematic review and meta-analysis of randomized controlled trials.
Data sources and Methods
A comprehensive literature search was conducted on PubMed, Cochrane Library, Embase, and ClinicalTrials.gov from inception to April 2026. Primary outcomes were Progression-free survival (PFS) and Minimal residual disease (MRD) negativity. Subgroup analysis based on cytogenetic risk was performed. The statistical assessment was done using The Review Manager (RevMan, Version 5.4).
Results
Our meta-analysis included 7 RCTs, comprising 3 studies in transplant-eligible multiple myeloma (TE-MM) and 4 in transplant-ineligible multiple myeloma (TIE-MM) patients, containing 3,443 patients (1,759 in the daratumumab group and 1684 in the non-daratumumab group). The median age across studies ranged from approximately 59 to 76 years. Daratumumab-based therapy demonstrated significantly higher PFS (HR 0.50, 95%CI: 0.43- 0.58, p < 0.00001). The analysis showed statistically significant high MRD negativity with daratumumab based quadruplet therapy compared to non-Dara triplet arm (RR 1.99, 95%CI 1.59-2.50, P<0.00001). Subgroup analysis based on cytogenetic risk demonstrated significant improved PFS in standard-risk (HR 0.45) as well as high-risk (HR 0.67), whereas MRD negativity increased significantly only in standard-risk (RR 1.76) but not high-risk (RR 1.23). Daratumumab-based quadruplet therapy was associated with increased neutropenia (56.2% vs 40.3%), thrombocytopenia (40.7% vs 32.5%), and infections (33.1% vs 23.3%).
Conclusion
The meta-analysis shows higher efficacy yet higher adverse events in Daratumumab-based quadruplet therapy for NDMM patients (TE, and TIE).
Keywords: daratumumab, newly diagnosed multiple myeloma, progression-free survival
Plain language summary
Multiple myeloma is a blood cancer that begins in plasma cells in the bone marrow. Although treatment has improved, many patients still relapse or have disease progression. Standard treatment commonly used three medicines, known as triplet therapy. More recently, daratumumab, a targeted antibody treatment, has been added as a fourth medicine to create quadruplet therapy. This systematic review and meta-analysis compared daratumumab-based quadruplet therapy with standard non-daratumumab triplet therapy in newly diagnosed multiple myeloma. We searched PubMed, Cochrane Library, Embase, and ClinicalTrials.gov from inception to April 2026. Seven randomized controlled trials were included, with 3,443 patients in total, including both transplant-eligible and transplant-ineligible patients. Overall, daratumumab-based quadruplet therapy showed better treatment efficacy than standard triplet therapy. Patients receiving daratumumab had improved progression-free survival, meaning they lived longer without their disease worsening. They were also more likely to achieve minimal residual disease negativity, meaning very sensitive tests could no longer detect myeloma cells after treatment. In subgroup analysis, daratumumab-based therapy improved progression-free survival in both standard-risk and high-risk cytogenetic groups. However, improvement in minimal residual disease negativity was significant only in standard-risk patients and not in high-risk patients. This suggests that high-risk patients may still need further treatment optimization. Daratumumab-based quadruplet therapy was associated with more side effects, including neutropenia, thrombocytopenia, and infections. In conclusion, adding daratumumab to standard frontline treatment improves outcomes in newly diagnosed multiple myeloma, but careful monitoring for blood count abnormalities and infections is needed.
Introduction
Multiple myeloma (MM) is a plasma cell malignancy, distinguished by the clonal proliferation of plasma cells. 1 MM is the second most common hematologic malignancy worldwide and is associated with high mortality. 2 Despite significant advancement in patient survival over the past decades, MM treatment remains complex with a survival ranging from a few months to over 10 years. 3
Daratumumab is a fully humanized IgGκ monoclonal antibody targeting CD38 on MM cells. It received its first FDA approval on June 27, 2019, for use in newly diagnosed multiple myeloma patient’s ineligible for autologous stem cell transplant (ASCT), in combination with lenalidomide and dexamethasone. 4 Subsequently, on September 26, 2019, daratumumab was also approved for use in transplant-eligible patients, in combination with bortezomib, thalidomide, and dexamethasone. 5 Thus, daratumumab is now FDA-approved for frontline therapy in both transplant-eligible and transplant-ineligible NDMM populations.
Recently The NCCN Guidelines Version 5.2026 recommended four-drug regimens, including anti-CD38 monoclonal antibody–based quadruplets, as preferred primary therapy options for eligible patients with newly diagnosed multiple myeloma. 6 Currently, quadruplet therapy regimens comprising an anti-CD 38 monoclonal antibody like daratumumab and Isatuximab are preferred, leading to a higher Minimal Residual Disease (MRD) negativity and deeper responses, translating into longer Progression-Free Survival (PFS). 7
It is often used as a combination with standard induction therapy in various trials such as GRIFFIN, CASSIOPEIA, ALCYONE, and MAIA 8 , The CASSIOPEIA trial showed that adding daratumumab to VTD significantly improved MRD negativity in transplant-eligible (TE) patients. In the ALCYONE trial, daratumumab combined with VMP led to superior progression-free survival (PFS) and overall survival (OS) in transplant-ineligible patients (TIE), though with more infections. These trials showed efficacy of quadruplet therapies in MM, but in majority of trials the efficacy was restricted to standard cytogenetic risk group and was not statistically significant in high cytogenetic risk group. There are certain studies showing efficacy even in high cytogenetic risk groups, such as Master trial showing that daratumumab based quadruplet therapy produced deep remission in high cytogenetic risk group, but still even this study mentioned worse performance by patient with ultra-high risk.9,10
Previous meta-analyses have evaluated daratumumab-based induction therapy or the addition of daratumumab to MM backbone regimens; however, many were limited by the number of available randomized trials, broader inclusion criteria, or lack of specific focus on daratumumab-based quadruplet therapy compared with non-daratumumab triplet regimens in NDMM. In addition, the certainty of evidence for efficacy and safety outcomes, particularly across cytogenetic-risk subgroups, has not been fully clarified. With the availability of newer randomized controlled trials, an updated and focused synthesis is needed.
Therefore, this systematic review and meta-analysis of randomized controlled trials aimed to compare the efficacy and safety of daratumumab-based quadruplet therapy versus non-daratumumab-based triplet therapy in patients with newly diagnosed multiple myeloma. We further assessed whether treatment benefit differed according to cytogenetic-risk status and evaluated the certainty of evidence using the GRADE approach to support clinical decision-making.
Methods
Study Design and Protocol Registration
This systematic review and meta-analysis adhere to the guidelines established by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 11 , and it is registered in PROSPERO (CRD42024584896).
Literature search strategy
A systematic literature search was conducted on PubMed, Embase, ClinicalTrials.gov, and Cochrane from inception to April 2026, using Medical Subject Headings (MeSH) and keywords for “Multiple Myeloma” and “daratumumab”. Bibliographies of all the included articles were also searched for relevant articles. The comprehensive search string is accessible in full and is available in a supplementary Table 1.
Study selection and eligibility criteria
We imported all the references retrieved by our search into Endnote v20 and the duplicates were removed. Two authors (MHK and AH) independently screened all the studies’ titles and abstracts and removed those that did not fulfill our inclusion criteria. The remaining articles were evaluated against the eligibility criteria by reviewing their full texts. Disagreements and conflicts were discussed with a third author (AT) and resolved. The eligibility criteria were: 1. Population: Patients with newly diagnosed multiple myeloma (NDMM), including both transplant-eligible (TE) and transplant-ineligible (TIE) populations. 2. Intervention: daratumumab-based quadruplet therapy regimens for induction 3. Comparator: non-daratumumab-based triplet therapy regimen for induction 4. Study Designs: randomized control trials.
Data extraction and outcomes
Data were extracted independently by two authors (MO and AA) into a pre-defined data collection form on Microsoft Excel. In case of any discrepancies, a third author (SK) was consulted. The data extracted from the included studies comprised of study characteristics (first author, publication year, study setting, study design, and sample size), patient characteristics (age, sex), treatment characteristics (Regimen, maintenance therapy, dose of daratumumab in cycle 1, route of administration) and outcomes (stringent complete response (sCR), progression-free survival (PFS), complete response (CR), complete response or better (≥ CR), overall response (ORR), MRD negative status regardless of response, MRD negativity with complete response or better, VGPR, VGPR or better, progressive disease, stable disease. Safety profile includes hematological Adverse events or toxicity like neutropenia, thrombocytopenia, anemia, and lymphopenia whereas non-hematological adverse events or toxicity include diarrhea, pneumonia, upper respiratory tract infection, constipation, peripheral sensory neuropathy, fatigue, any infusion-related reaction, pyrexia, peripheral edema, nausea, cough, asthenia, back pain, and second primary cancer. MRD negativity and progression-free survival were the two primary outcomes.
Quality Assessment
Two independent authors (IA and MBH) evaluated the risk of bias in the studies that were included, utilizing the Cochrane “risk of bias” tool (RoB 2.0) for RCTs 12 . Studies were classified as having a low bias, some concerns, or a high risk of bias based on the assessment of the randomization process, deviation from intended intervention, missing outcome data, outcome measurement, and reporting bias. We discussed and resolved any discrepancies in the bias assessment with another author (ZA). GARDE assessment was also used to look for the quality of evidence.
Data Synthesis and Statistical Analysis
The data analysis was conducted by using Review Manager (RevMan, Version 5.4; The Cochrane Collaboration, Copenhagen, Denmark) software. The risk ratios (RR) with 95% confidence intervals were determined for qualitative data. The Mantel Haenszel method with random effects model was employed to aggregate the RRs. The hazard ratios (HR) were aggregated for variables involving time like PFS. The chi-square Cochrane Q test was utilized to identify any notable variation in heterogeneity among the various trials and between subgroups. The I2 statistic was used to assess the heterogeneity between the included studies. Cochrane Handbook for Systematic Reviews of Interventions, section 10.10 was used to interpret the I2 values. 13 Publication bias was assessed based on funnel plots visualization.
Subgroup analyses: Subgroup analyses of all efficacy outcomes were conducted based on the transplant eligibility: (TEMM vs TIEMM), and cytogenetic risk (standard vs high risk).
Results
Search results
Initially, the literature search retrieved 3,109 articles. 353 duplicates were then removed, leaving 2,756 unique articles. After screening the titles and abstracts, 2,662 articles were excluded, leaving 94 studies for full-text screening against the eligibility criteria. Ultimately, 7 RCTs were included in this meta-analysis, included trials encompassed both transplant-eligible (TE) and transplant-ineligible (TIE) populations.6,14–19 The CASSIOPEIA trial (Phase III) evaluated daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTD) in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients, demonstrating improved depth of response. The GRIFFIN trial (Phase II) assessed daratumumab with lenalidomide, bortezomib, and dexamethasone (D-RVD) in a similar transplant-eligible NDMM population, showing deeper responses and MRD negativity. PERSEUS (Phase III) further confirmed the benefit of D-RVD with subcutaneous daratumumab in transplant-eligible NDMM. ALCYONE (Phase III) focused on transplant-ineligible NDMM, showing that daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) significantly prolonged PFS. The AMaRC 03-16 trial (Phase II) investigated daratumumab with VMP in elderly or frail transplant-ineligible NDMM patients, supporting its feasibility and efficacy. Lastly, OCTANS (Phase III) evaluated daratumumab with VMP in transplant-ineligible NDMM. The CEPHEUS trial (Phase III) evaluated daratumumab plus bortezomib, lenalidomide, and dexamethasone (D-VRd) in transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma (NDMM) patients, demonstrated higher rates of MRD negativity with DVRd, compared with VRd alone. Details of the screening process are presented in Figure 1.
Figure 1.
Prisma flow chart of included studies.
Study characteristics
In this meta-analysis, seven RCTs were included, conducted across Europe, the United States, Australia, Asia, and multinational settings spanning North and South America, Europe, and the Asia–Pacific region. The publication dates ranged from 2017 to 2025. A total 3,443 patients (1,759 in the daratumumab group and 1684 in the non-daratumumab group) were involved in these studies. The median age across studies ranged from approximately 59 to 76 years. Across all included studies, 55.4% of participants were male overall, with 54.9% in the daratumumab arm and 55.9% in the non-daratumumab arm. The baseline characteristics for the included studies are summarized in Tables 1 and 2.
Table 1.
Baseline characteristics of included studies (first 4 RCTs).
| Study characteristic | ||||||
|---|---|---|---|---|---|---|
| Study ID | Moreau 2019 | Voorhees 2020 | Sonneveld P 2024 | Mateos 2017 | ||
| Trial Name | CASSIOPEIA | GRIFFIN | PERSEUS | ALCYONE | ||
| Country | Europe | USA | Europe | North and South America, Europe, Asia–Pacific region | ||
| Sample size: Total (A vs B) | 1085 (543 vs 542) | 207 (104 vs 103) | 709 (355 vs 354) | 706 (350 vs 356) | ||
| Median Age, in years (Range) A vs B | 59·0 (22–65) vs 58·0 (26–65) | 59 (29-70) vs 61 (40-70) | 61.0 (32–70) vs 59.0 (31–70) | 71.0 (40 - 93) vs 71.0 (50 - 91) | ||
| Male (%) A vs B | 316 (58·2) vs 319 (58·9) | 58 (55.8) vs 60 (58.3) | 211 (59.4) vs 205 (57.9) | 160 (45.7) vs 167 (46.91) | ||
| TEMM/TIEMM | TEMM | TEMM | TEMM | TIEMM | ||
| Regimens (A vs B) | D-VTD vs VTD | D-RVd vs RVd | D-VRD vs VRD | D-VMP vs VMP | ||
| Dose of daratumumab in cycle 01 (mg) | 16mg/kg | 16mg/kg | 1800 mg | 16mg/kg | ||
| Route of daratumumab: (SC, IV) | IV | IV | SC | IV | ||
| ECOG Performance Score: 0, 1, 2. | 0 | D standard n (%) | 265 (49) | 39 (38.6) | 221 (62.3) | 78(22.3) |
| Standard n (%) | 257 (47) | 40 (39.2) | 230 (65.0) | 99 (27.8) | ||
| 1 | D standard n (%) | 225 (41) | 51 (50.5) | 114 (32.1) | 182 (52.0) | |
| Standard n (%) | 230 (42) | 52 (51.0) | 108 (30.5) | 173 (48.6) | ||
| ≥2 | D standard n (%) | 53 (10) | 11 (10.9) | 20 (5.6) | 90 (25.7) | |
| Standard n (%) | 55 (10) | 10 (9.8) | 16 (4.5) | 84 (23.6) | ||
| Not Known | D standard n (%) | NR | NR | NR | NR | |
| Standard n (%) | NR | NR | NR | NR | ||
| Type of measurable disease | IgG | D standard n (%) | 331 (61) | 55 (52.9) | 204 (57.5) | 143 (40.8) |
| | Standard n (%) | 314 (58) | 52 (50.49) | 185 (52.3) | 140 (39.3) | |
| Non-IgG | D standard n (%) | 212 (39) | 49 (47.1) | 151 (42.5) | 207 (59.1) | |
| Standard n (%) | 228 (42) | 51 (49.51) | 169 (47.7) | 216 (60.67) | ||
| ISS Disease stage | I | D standard n (%) | 204 (38) | 49 (47.1) | 186 (52.4) | 69 (19.7) |
| Standard n (%) | 228 (42) | 50 (48.5) | 178 (50.4) | 67 (18.8) | ||
| II | D standard n (%) | 255 (47) | 40 (38.5) | 114 (32.1) | 139 (39.7) | |
| Standard n (%) | 233 (43) | 37 (35.9) | 125 (35.4) | 160 (44.9) | ||
| III | D standard n (%) | 84 (15) | 14 (13.5) | 55 (15.5) | 142 (40.6) | |
| Standard n (%) | 81 (15) | 14 (13.6) | 50 (14.2) | 129 (36.2) | ||
| Not Known | D standard n (%) | NR | 1 (1.0) | NR | NR | |
| Standard n (%) | NR | 2 (1.9) | NR | NR | ||
| Cytogenetics classification | Standard | D standard n (%) | 460 (84.9) | 82 (83.7) | 264 (74.4) | 261 (83.1) |
| Standard n (%) | 454 (84.1) | 83 (85.6) | 266 (75.1) | 257 (85.1) | ||
| High | D standard n (%) | 82 (15.1) | 16 (16.3) | 76 (21.4) | 53 (16.9) | |
| Standard n (%) | 86 (15.9) | 14 (14.4) | 78 (22) | 45 ( (14.9) | ||
| Indeterminate | D standard n (%) | NR | NR | 15 (4.2) | NR | |
| Standard n (%) | NR | NR | 10 (2.9) | NR | ||
| Baseline creatinine clearance (ml/min) | D standard n (%) | >90: 29 (5.3) | >50: 95 (91.3) | NR | >60: 56 (16) | |
| <90: 16 (3) | <50: 9 (8.7) | NR | <60: 32 (9.1) | |||
| Standard n (%) | >90: 47 (8.7) | >50: 94 (91.3) | NR | >60: 80 (22.4) | ||
| <90: 44 (8.1) | <50: 9 (8.7) | NR | <60: 63 (17.7) | |||
| Death | D standard n (%) | 14 (2.57) | 1 (1.01) | 34 (9.57) | 14 (4.0) | |
| Standard n (%) | 32 (5.9) | 0 (0) | 44 (12.4) | 16 (4.4) | ||
| Median Time since initial diagnosis of MM, (months, range) | D standard | 0·92 (0·2–9·4) | 0.7 (0-12) | 1.2 (0.0–46.5) | 0.8 (0.1 - 11.4) | |
| Standard | 0·92 (0·2–22·9) | 0.9 (0-61) | 1.1 (0.1–184.6) | 0.8 (0.1 - 25.3) | ||
Table 2.
Baseline characteristics of included studies (last 3 RCTs).
| Study characteristic | |||||
|---|---|---|---|---|---|
| Study ID | Molle 2024 | Weijun Fu 2023 | Usmani 2025 | ||
| Trial Name | AMaRC 03-16 | OCTANS | CEPHEUS | ||
| Country | Australia | Asia | North America, Europe | ||
| Sample size: Total (A vs B) | 121 (64 vs 57) | 220(146 vs 74) | 395 (197 vs 198) | ||
| Median Age, in years (Range) A vs B | 75.9 (64 – 91) vs 75.4 (62 – 89) | 69.0 (58-81) vs 69.0 (57-84) | 70 (42–79) vs 70 (31–80) | ||
| Male (%) A vs B | 49(76.6) vs 34(59.7) | 85(58.2) vs 46(62.1) | 87 (44.2) vs 111 (56.1) | ||
| TEMM/TIEMM | TIEMM | TIEMM | TIEMM | ||
| Regimens (A vs B) | VCDD vs VCD | D-VMP vs VMP | D-VRD vs VRD | ||
| Dose of daratumumab in cycle 01 (mg) | 16mg/kg | 16mg/kg | 1800 mg | ||
| Route of daratumumab: (SC, IV) | IV | IV | SC | ||
| ECOG Performance Score: 0, 1, 2. | 0 | D standard n (%) | 26 (40.6) | 50 (34.2) | 71 (36) |
| Standard n (%) | 26 (45.6) | 21 (28.4) | 84 (42.4) | ||
| 1 | D standard n (%) | 24 (37.5) | 71 (48.6) | 103 (52.3) | |
| Standard n (%) | 20 (35.1) | 40 (54.1) | 100 (50.5) | ||
| ≥2 | D standard n (%) | 13 (20.4) | 25 (17.1) | 23 (11.7) | |
| Standard n (%) | 10 (17.5) | 13 (17.6) | 14 (7.1) | ||
| Not Known | D standard n (%) | 1 (1.6) | NR | NR | |
| Standard n (%) | 1 (1.8) | NR | NR | ||
| Type of measurable disease | IgG | D standard n (%) | NR | 56 (38.4) | 89 (45.2) |
| | Standard n (%) | NR | 29 (39.2) | 76 (38.4) | |
| Non-IgG | D standard n (%) | NR | 90 (61.6) | 27 (13.7) | |
| Standard n (%) | NR | 45 (60.8) | 31 (15.7) | ||
| ISS Disease stage | I | D standard n (%) | 8 (12.5) | 37 (25.3) | 68 (34.5) |
| Standard n (%) | 6 (10.5) | 19 (25.7) | 68 (34.3) | ||
| II | D standard n (%) | 41 (64.1) | 37 (25.3) | 73 (37.1) | |
| Standard n (%) | 44 (77.2) | 32 (43.2) | 75 (37.9) | ||
| III | D standard n (%) | 9 (14.1) | 41 (28.1) | 56 (28.4) | |
| Standard n (%) | 3 (5.3) | 23 (31.1) | 55 (27.8) | ||
| Not Known | D standard n (%) | 6 (9.4) | NR | NR | |
| Standard n (%) | 4 (7.0) | NR | NR | ||
| Cytogenetics classification | Standard | D standard n (%) | 42 (65.6) | 117 (80.7) | 149 (75.6) |
| Standard n (%) | 43 (75.4) | 54 (73) | 149 (75.2) | ||
| High | D standard n (%) | 12 (18.8) | 28 (19.3) | 25 (12.6) | |
| Standard n (%) | 7 (12.3) | 20 (33) | 27 (13.6) | ||
| Indeterminate | D standard n (%) | 10 (15.6) | NR | NR | |
| Standard n (%) | 7 (12.3) | NR | NR | ||
| Baseline creatinine clearance (ml/min) | D standard n (%) | >60: 54 (84.4) | >60: 83 (56.8) | NR | |
| <60: 10 (15.6) | <60: 63 (43.1) | NR | |||
| Standard n (%) | >60: 43 (75.4) | >60: 41 (55.4) | NR | ||
| <60: 14 (24.6) | <60: 33 (44.6) | NR | |||
| Death | D standard n (%) | 5 (7.8) | 6 (4.1) | NR | |
| Standard n (%) | 1 (1.7) | 4 (5.4) | NR | ||
| Median Time since initial diagnosis of MM, (months, range) | D standard | NR | 0.66 (0.1-14.6) | 1.2 (0.4–5.8) | |
| Standard | NR | 0.61 (0.1-2.1) | 1.3 (0.3–8.0) | ||
TEMM = Transplant Eligible Multiple Myeloma, TIEMM = Transplant Ineligible Multiple Myeloma, D-VTD = Daratumumab + Bortezomib+ Thalidomide + Dexamethasone, VTD = Bortezomib+ Thalidomide + Dexamethasone, D-RVd = Daratumumab + Lenalidomide+ Bortezomib +Dexamethasone, RVd = Lenalidomide + Bortezomib + dexamethasone, D-VMP = Daratumumab + Bortezomib + Melphalan + Prednisone.
VMP = Bortezomib + Melphalan + Prednisone; VCDD= Daratumumab + Bortezomib + Cyclophosphamide + Dexamethasone, VCD = Bortezomib + Cyclophosphamide + Dexamethasone; IV = Intravenous; SC = Subcutaneous; ECOG = Eastern Cooperative Oncology Group; ISS = International Staging System; MM = Multiple Myeloma; NR = Not Reported.
Bias assessment
The Cochrane ROB 2.0 was used to evaluate the risk of bias in the studies that were included. Some bias concerns were observed in two of the included studies. These concerns were related to deviation from the intended intervention, outcome measurement, and reported result selection. The other four studies were judged to be at a low risk of bias. The summary graph for the quality assessment is in Supplementary Figure 1. Using the GRADE approach, the certainty of evidence ranged from high to moderate for most primary outcomes, while some secondary outcomes were graded as low certainty due to heterogeneity and imprecision (Table 3).
Table 3.
GRADE assessment.
| Patient or population: NDMM | |||||
|---|---|---|---|---|---|
| Intervention: Dara | |||||
| Comparison: Non-dara | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | |
| Risk with non-DARA | Risk with DARA | ||||
| MRD Overall | 302 per 1,000 | 517 per 1,000(478 to 559) | RR 1.71 (1.58 to 1.85) | 3443 (7 RCTs) | ⨁⨁⨁◯ Moderate a |
| OS | 200 per 1,000 | 145 per 1,000 (114 to 186) | HR 0.70 (0.54 to 0.92) | 2000 (6 RCTs) | ⨁⨁⨁⨁ High |
| CR | 142 per 1,000 | 159 per 1,000 (136 to 187) | RR 1.12 (0.96 to 1.32) | 3432 (7 RCTs) | ⨁⨁◯◯ Lowa,b |
| VGPR | 333 per 1,000 | 273 per 1,000 (200 to 372) | RR 0.82 (0.60 to 1.12) | 3311 (6 RCTs) | ⨁⨁◯◯ Lowa,b |
| PFS | 0 per 1,000 | --per 1,000 (-- to --) | HR 0.50 (0.43 to 0.58) | 3443 (7 RCTs) | ⨁⨁⨁⨁ High |
| OR | 864 per 1,000 | 933 per 1,000 (916 to 959) | RR 1.08 (1.06 to 1.11) | 3432 (7 RCTs) | ⨁⨁⨁◯ Moderate a |
| sCR | 249 per 1,000 | 394 per 1,000 (339 to 461) | RR 1.58 (1.36 to 1.85) | 3432 (7 RCTs) | ⨁⨁⨁⨁ High |
| CR or better | 402 per 1,000 | 575 per 1,000 (499 to 664) | RR 1.43 (1.24 to 1.65) | 3311 (6 RCTs) | ⨁⨁⨁◯ Moderate a |
| VGPR or better | 719 per 1,000 | 878 per 1,000 (784 to 971) | RR 1.22 (1.09 to 1.35) | 3432 (7 RCTs) | ⨁⨁⨁◯ Moderate a |
CI: confidence interval; HR: hazard ratio; RR: risk ratio.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
Explanations.
aHigh I2 more than 50%.
b95% crossess 0.
Meta-analysis of primary efficacy-related outcomes
1: Progression free survival (PFS)
Seven studies, involving a total of 3,443 patients (1759 DARA vs 1684 non-DARA), showed a significantly high progression-free survival (PFS) for the DARA group compared to the non-DARA group (HR 0.50, 95%CI: 0.43- 0.58, p < 0.00001, I2= 0%) (Figure 2).
Figure 2.
Forest plot of progression-free survival (PFS).
The funnel plot demonstrated a symmetric distribution of studies around the pooled effect estimate, suggesting no significant evidence of publication bias (Supplementary Figure 8a).
Subgroup analysis
1) Subgroup analysis based on cytogenetic risk showed statistically significant high PFS both for standard cytogenetic risk (HR 0.45, 95%CI 0.38-0.55, P<0.00001), as well as high cytogenetic risk (HR 0.67, 95%CI: 0.51-0.89, P= 0.006) (Supplemental Figure 9a).
2) Subgroup analysis based on transplant eligibility showed statistically significant benefits for both TE and TIE subgroup. TEMM (HR 0.44, 95%CI 0.35-0.56; P < 0.00001) and TIE-MM (HR 0.54, 95%CI 0.45-0.65; P < 0.00001) (Supplemental Figure 9b).
2: MRD negativity
This outcome was reported by 7 RCTs with 3443 patients (1759 Dara vs 1684 non-Dara). The analysis showed statistically significant MRD negativity with daratumumab based quadruplet therapy compared to non-Dara triplet arm (RR 1.99, 95%CI 1.59-2.50, P<0.00001) (Figure 3).
Figure 3.
Forest Plot of MRD negativity.
The funnel plot displayed a symmetric distribution of studies around the pooled effect estimate, indicating no significant evidence of publication bias (Supplementary Figure 8b).
Subgroup analysis
1) Subgroup analysis based on cytogenetic risk showed that there was significantly high MRD negativity in standard risk group (RR 1.76, 95%CI 1.42-2.18, P<0.00001), compared to non-significant increase MRD negativity in the high-risk group (RR 1.23, 95%CI 0.87-1.73, P=0.24) (Supplementary Figure 9c).
2) Subgroup analysis based on transplant eligibility showed that MRD negativity was significantly high in both TE (RR 1.62, 95%CI: 1.37-1.92, P <0.00001), and TIEMM (RR 2.79, 95% CI: 1.58-4.93, P =0.0004) (Supplemental Figure 9d).
Secondary efficacy related outcomes
1: Stringent complete response (sCR)
A total of seven studies encompassed a total of 3,443 patients (1754 DARA vs 1678 non-DARA). The findings demonstrated a statistically significant higher sCR rate in the DARA group compared with the non-DARA group. (RR 1.58, 95%CI: 1.36-1.85, p < 0.00001, I2 = 47%) (Figure 4).
Figure 4.
Forest Plot of sCR.
The funnel plot showed a symmetric distribution of studies around the pooled effect estimate, indicating no apparent publication bias (Supplementary Figure 8c).
Subgroup analysis of sCR
1) Subgroup analysis was conducted based on cytogenetic risk. The results showed that high cytogenetic risk has comparable sCR across both arm (RR 0.82, p=0.45), compared to the standard cytogenetic risk group, which shows a significant increase in sCR (RR 1.52, p<0.0001) (Supplemental Figure 9e).
2) Subgroup analysis based on transplant eligibility showed statistically significant higher sCR for both TE and TIE subgroup. TE-MM (RR 1.50 CI 1.34-1.67; P < 0.00001, i2= 0%) and TIE-MM (RR 2.18, 95%CI 1.26-3.77; P= 0.005, i2= 72%) (Supplemental Figure 9f).
2: Overall survival
This outcome was reported by 7 RCTs. Daratumumab based quadruplet therapy was associated with a significantly improved overall survival compared with non-daratumumab-based triplet therapy (HR 0.71, 95%CI 0.55-0.90, P= 0.005) (Supplementary Figure 2).
The funnel plot demonstrated a symmetric distribution of studies around the pooled effect estimate, suggesting no significant evidence of publication bias (Supplementary Figure 8d).
3: Complete response or better
This outcome was reported by 6 studies 3311 (1690 Dara vs 1621 non-DARA). The analysis showed statistically significant complete response or better in Daratumumab based quadruplet therapy versus non-Dara based triplet therapy (RR1.43, 95%CI 1.24-1.65, P<0.00001) (Supplemental Figure 3).
The funnel plot demonstrated a symmetric distribution of studies around the pooled effect estimate, suggesting no significant evidence of publication bias (Supplementary Figure 8e).
Subgroup analysis based on transplant eligibility showed higher CR or better in both TE (RR 1.32, 95%CI 1.15-1.51, P <0.00001), and TIE (RR 1.66, 95%CI 1.20-2.31) (Supplementary Figure 9g).
4: VGPR or better
This outcome was reported by 7 studies 3432 patients (1754 DARA vs 1678 non-DARA). The analysis showed statistically significant higher VGPR or better in Dara based quadruplet therapy vs non-Dara triplet therapy (RR 1.22, 95%CI 1.09-1.35, P=0.000) (Supplemental Figure 4).
The funnel plot demonstrated symmetry around the pooled effect estimate, providing no evidence of significant publication bias (Supplementary Figure 8f).
5: Overall response
This outcome being reported by 7 studies in 3432 patients (1754 Dara vs 1678 non-Dara). The forest plot showed that OR is significantly higher in quadruplet therapy compared to non-Dara based triplet therapy (RR 1.09, 95%CI 1.03-1.15, P=0.002) (Supplemental Figure 5).
The funnel plot showed a symmetrical distribution of studies around the pooled effect estimate, indicating no evidence of publication bias (Supplementary Figure 8g).
6: Complete response
This outcome was extracted from 7 studies with 3432 patients (1754 Dara vs 1678 non-Dara). The analysis revealed no significant difference in complete response between Dara based quadruplet therapy and non-Dara based triplet therapy (RR 1.16, 95%CI: 0.85-1.59, P= 0.35) (Supplemental Figure 6).
The funnel plot demonstrated a symmetric distribution of studies around the pooled effect estimate, suggesting no significant evidence of publication bias (Supplementary Figure 8h).
7: VGPR
This outcome was reported by 6 studies including 3311 patients (1690 Dara vs 1621 non-Dara). The forest plot showed comparable VGPR between two arms (RR 0.82, 95%CI: 0.60-1.12, p= 0.20) (Supplemental Figure 7).
The funnel plot demonstrated a symmetric distribution of studies around the pooled effect estimate, suggesting no significant evidence of publication bias (Supplementary Figure 8I).
Adverse effects
a) hematological
Hematological adverse events were more frequent with daratumumab-based regimens. Neutropenia showed the most pronounced increase, both for any grade (56.2% vs 40.3%) and grade ≥3 events (41.2% vs 31.7%). Similarly, thrombocytopenia was higher in the daratumumab arm (40.7% vs 32.5% for any grade; 25.1% vs 19.5% for grade ≥3). Lymphopenia also occurred more commonly with daratumumab, particularly for severe events (18.6% vs 12.1%). In contrast, anemia rates were comparable between groups for both any grade and grade ≥3 events, suggesting no significant additional risk attributable to daratumumab (Table 4).
Table 4.
Hematological and non-hematological adverse events.
| Events | Any grade | Grade 3 or more | ||
|---|---|---|---|---|
| Dara n (%) | Non-DARA n (%) | Dara n (%) | Non-DARA n (%) | |
| Hematological Adverse Events | ||||
| Neutropenia | 842 (56.2%) | 647 (40.3%) | 689 (41.2%) | 509 (31.7%) |
| Thrombocytopenia | 707 (40.7%) | 541 (32.5%) | 419 (25.1%) | 313 (19.5%) |
| Anemia | 385 (32.1%) | 360 (32.0%) | 146 (12.8%) | 140 (13.1%) |
| Lymphopenia | 230 (22.1%) | 163 (16.9%) | 182 (18.6%) | 110 (12.1%) |
| Non-Hematological Adverse Events | ||||
| Upper Respiratory Infection | 398 (33.1%) | 262 (23.3%) | 22 (1.8%) | 15 (1.3%) |
| Constipation | 578 (41.5%) | 531 (40.5%) | 21 (1.5%) | 13 (1.0%) |
| Peripheral sensory neuropathy | 787 (45.0%) | 845 (49.7%) | 93 (5.7%) | 102 (6.3%) |
| Fatigue | 228 (26.6%) | 227 (26.4%) | 34 (4.0%) | 40 (4.7%) |
| Infusion-related reaction | 312 (33.0%) | Not applicable | 32 (3.4%) | Not applicable |
| Pyrexia | 413 (31.5%) | 309 (25.2%) | 27 (2.1%) | 25 (2.1%) |
| Peripheral edema | 365 (28.0%) | 342 (27.4%) | 13 (1.0%) | 11 (0.9%) |
| Nausea | 347 (26.4%) | 301 (24.3%) | 25 (1.9%) | 19 (1.5%) |
| Cough | 192 (22.3%) | 118 (15.3%) | 2 (0.3%) | 2 (0.3%) |
| Asthenia | 316 (30.8%) | 284 (29.3%) | 26 (2.5%) | 20 (2.1%) |
| Back pain | 173 (26.1%) | 143 (22.3%) | 9 (1.4%) | 11 (1.7%) |
| Second primary cancer | 62 (5.7%) | 55 (5.2%) | 0 (0.0%) | 0 (0.0%) |
b) non-hematological adverse events
Among non-hematological adverse events, infection-related outcomes were notably increased with daratumumab, including upper respiratory tract infections (33.1% vs 23.3%) and pyrexia (31.5% vs 25.2%), along with a higher incidence of cough. Infusion-related reactions were observed exclusively in the daratumumab arm, as expected (these reactions were particularly in RCTs where intravenous form of daratumumab was used, and was significantly less in studies where subcutaneous route was used). Gastrointestinal and general symptoms such as constipation, nausea, fatigue, asthenia, and peripheral edema were largely comparable between groups. Peripheral sensory neuropathy appeared slightly lower with daratumumab, likely reflecting differences in backbone regimens. Rates of serious events (grade ≥3) remained low across most non-hematological outcomes, with minimal differences between treatment arms (Table 4).
Discussion
This meta-analysis indicates that daratumumab (DARA) -based quadruplet regimens significantly improve progression-free survival (PFS) (HR 0.50) and the rate of stringent complete response (sCR) (RR 1.58) in patients with multiple myeloma (MM), regardless of transplant eligibility. Minimal residual disease (MRD) negativity was also markedly higher with these regimens (RR 1.99). Additional efficacy benefits were observed for overall survival (HR 0.71), overall response rate (RR 1.09), and VGPR or better (RR 1.22). However, these improvements in clinical outcomes were associated with an increased risk of treatment-emergent adverse events, particularly neutropenia, thrombocytopenia, and infection-related complications.
The mechanism underlying the therapeutic effects of daratumumab (DARA) involves targeting CD38 expressed on myeloma cells, thereby inducing apoptosis through complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP).20–23 In addition, DARA modulates the immune microenvironment by depleting regulatory T cells and myeloid-derived suppressor cells. 24 Both intravenous and subcutaneous formulations of DARA are approved for the treatment of MM.25–27
Regarding progression-free survival, our pooled analysis showed a marked improvement with daratumumab-based quadruplet therapy (HR 0.50), in line with recent meta-analyses.10,28,29 Subgroup analyses based on cytogenetic risk demonstrated that this benefit extended to both standard-risk (HR 0.45) and high-risk (HR 0.67) patients, although it was less pronounced in the latter group. These findings suggest that while quadruplet therapy enhances disease control across different risk categories, it does not fully overcome the unfavorable prognosis associated with high-risk cytogenetic features. This observation is consistent with data from recent trials, including PERSEUS and CEPHEUS, where high-risk patients experienced clinical benefit but continued to have comparatively poorer outcomes than standard-risk individuals.17,19
Minimal residual disease (MRD) negativity was significantly enhanced with daratumumab-based quadruplet therapy (RR 1.99), supporting its effectiveness in achieving deeper treatment responses. However, subgroup analysis revealed variability according to cytogenetic risk. MRD negativity was significantly improved among standard-risk patients (RR 1.76), whereas the increase did not reach statistical significance in high-risk patients (RR 1.23). This finding highlights a key limitation of existing therapeutic approaches, as patients with high-risk cytogenetic features appear less likely to attain sustained MRD negativity. Furthermore, emerging data indicate that MRD negativity may not yield equivalent prognostic value in high-risk populations compared with standard-risk groups, potentially reflecting more aggressive disease biology and greater clonal heterogeneity.30,31 Collectively, these results highlight the necessity for risk-adapted treatment strategies and the development of novel therapeutic options for this subgroup.
Our analysis demonstrated a significant improvement in stringent complete response (sCR) with daratumumab-based quadruplet therapy (RR 1.58), consistent with prior meta-analyses and recent studies evaluating intensified induction regimens.5,9,10 Subgroup analysis further indicated that this benefit was predominantly observed in standard-risk patients (RR 1.52), while no statistically significant improvement was seen in the high-risk subgroup. This pattern highlights the persistent challenge of achieving deep responses in biologically aggressive disease. Collectively, these findings emphasize the importance of individualized treatment strategies, suggesting that patients with high-risk features may require additional therapeutic intensification or the incorporation of novel agents beyond current quadruplet regimens.32,33
The observed improvement in overall survival (HR 0.71) further supports the clinical benefit of daratumumab-based quadruplet therapy. Although earlier studies were constrained by immature survival data, more recent trials and updated analyses have begun to demonstrate a clear survival advantage associated with daratumumab-containing regimens.19,28 This outcome likely reflects the cumulative effect of achieving deeper responses and enhanced disease control, thereby supporting the incorporation of quadruplet therapy as a frontline standard of care in eligible patients. These findings are also consistent with the latest European Hematology Association–European Myeloma Network (EHA–EMN) recommendations, which place anti-CD38 monoclonal antibody–based quadruplet regimens among the preferred initial treatment options for newly diagnosed multiple myeloma. Our results provide pooled randomized evidence supporting these recommendations, while also showing that the magnitude of benefit may remain lower in patients with high-risk cytogenetic features. 34
Secondary efficacy outcomes also favored daratumumab-based quadruplet therapy, demonstrating significant improvements in complete response or better (RR 1.43), very good partial response (VGPR) or better (RR 1.22), and overall response rate (RR 1.09), in line with findings from previous studies.35–37 However, individual endpoints such as complete response and VGPR alone did not reach statistical significance, suggesting that the primary benefit of this approach lies in achieving deeper and more sustained responses rather than simply increasing initial response rates.
The safety analysis indicated an increased incidence of hematological toxicities, particularly neutropenia and thrombocytopenia, as well as a higher rate of infection-related adverse events, including upper respiratory tract infections and pneumonia. These findings are consistent with prior meta-analyses.37,38 Nevertheless, most non-hematological adverse events were comparable between treatment groups, and the occurrence of serious toxicities remained relatively low, supporting an overall manageable safety profile. Importantly, the increased frequency of certain adverse events did not result in higher rates of treatment discontinuation, indicating that these toxicities are largely manageable and exert minimal impact on overall treatment outcomes.
Overall, these findings favor daratumumab-based quadruplet therapy as a frontline treatment approach in newly diagnosed multiple myeloma, particularly among patients with standard-risk disease. In contrast, the more limited benefit seen in high-risk cytogenetic subgroups points to a continuing gap in treatment efficacy, highlighting the need for tailored therapeutic strategies and the development of novel approaches for this population.
Although this analysis specifically focused on daratumumab-based quadruplet regimens, the findings should be interpreted in the broader context of anti-CD38–directed therapies. Isatuximab-based combinations have shown comparable efficacy, with significant progression-free survival benefits reported in ICARIA-MM (HR 0.60, 95% CI 0.44–0.81) and IKEMA (HR 0.53, 95% CI 0.32–0.89), suggesting a possible class effect.39,40 Likewise, our recent meta-analysis (Osama et al.) confirmed improved survival and response outcomes associated with anti-CD38–based therapies. 41 Moreover, daratumumab-based regimens incorporating carfilzomib (Dara-KRd) have achieved high rates of MRD negativity (>60%) and have been associated with durable responses. 42
Limitations
This meta-analysis has several limitations. First, it included only randomized controlled trials, excluding cohort studies that may provide additional insights and reflect real-world evidence. In addition, the analysis did not account for the impact of maintenance therapy or variations in regimens combined with daratumumab. Reporting of disease staging was also inconsistent, with only one study providing Revised International Staging System (R-ISS) data, while others reported the International Staging System (ISS) alone, and none included SLiM-CRAB criteria. Consequently, subgroup analyses based on these classifications could not be performed. Addressing these limitations in future studies may offer a more comprehensive understanding of the impact of daratumumab in patients with multiple myeloma.
Clinical implications
This meta-analysis demonstrates that daratumumab-based quadruplet therapy is associated with improved survival, enhanced response rates, and higher rates of MRD negativity in newly diagnosed multiple myeloma. From a clinical standpoint, these results support its adoption as a first-line induction approach in eligible patients. Moving forward, these findings may inform more personalized treatment strategies, shape decisions regarding sequencing and maintenance, and further position daratumumab-based quadruplet regimens as a key standard for optimizing long-term outcomes in multiple myeloma.
Conclusion
In conclusion, daratumumab-based regimens significantly improve key efficacy outcomes, including progression-free survival (PFS), and MRD negativity in patients with multiple myeloma, particularly among those with standard-risk disease and earlier-stage presentation. Our analysis, restricted to randomized controlled trials, also identified an increased risk of certain infections associated with these regimens, highlighting the importance of vigilant monitoring and prophylaxis for their prevention. These findings support the need for individualized treatment approaches, taking into account patient-specific factors such as cytogenetic risk, and disease characteristics to optimize clinical outcomes.
Supplemental material
Supplemental material for Efficacy and safety of daratumumab-based quadruplet therapy vs non-daratumumab-based triplet therapy in newly diagnosed multiple myeloma patients: A GRADE assessed systematic review and meta-analysis of randomized controlled trials by Muhammad Osama, Muhammad Haris Khan, Ammara Tahir, Amna Hussain, Ahmad Iftikhar, Aizaz Ali, Safeena Khan, Malak Bilal Hassan, Intikhab Alam, Zeeshan Khan, Abdullah Afridi, Mohammad Ebad Ur Rehman, Amna Gul, Pawan Kumar Thada in Therapeutic Advances in Hematology
Acknowledgements
The abstract for this meta-analysis has already been published in the “Blood” journal of ASH.
Author contributions: Muhammad Osama Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft. Muhammad Haris Khan, Ahmad Iftikhar, and Ammara Tahir were involved in screening studies, data extraction, formal analysis, and quality assessment. Amna Hussain, Ahmad Iftikhar, Safeena Khan, and Aizaz Ali assisted in the data curation, formal analysis, and investigation, and critically revised the manuscript for important intellectual content. Malak Bilal Hassan, Ahmad Iftikhar, Zeeshan Khan, and Intikhab Alam evaluated the risk of bias and ensured adherence to PRISMA guidelines. Mohammad Ebad Ur Rehman, Amna Gul and Abdullah Afridi contributed to subgroup analyses and graphical presentations. reviewed the methodology and provided significant input on the results interpretation. Pawan Kumar Thada, as the corresponding author, performed formal analysis, manuscript writing, provided overall guidance, reviewed the manuscript rigorously, and ensured its readiness for submission.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Trial registration: This meta-analysis is registered in PROSPERO (CRD42024584896).
Supplemental material: Supplemental material for this article is available online.
ORCID iDs
Muhammad Osama https://orcid.org/0000-0003-0197-4264
Zeeshan Khan https://orcid.org/0009-0006-4563-7760
Ethical considerations
The study did not require ethical approval, and the authors have nothing to report. (Already available data used).
Data Availability Statement
The datasets obtained and analyzed in the current study are available from the corresponding author upon reasonable request.*
References
- 1.Kyle RA, Rajkumar SV. Multiple myeloma. Blood 2008; 111(6): 2962–2972. 10.1182/blood-2007-10-078022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Rajkumar SV. Multiple myeloma: 2018 update on diagnosis, risk stratification, and management. Am J Hematol 2018; 93(8): 981–1114. 10.1002/ajh.25117. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Liu X, Wu F, Ye W, Deng J, Zhang M, Zhang C, et al. Prognostic value of circulating plasma cells detected by flow cytometry in newly diagnosed multiple myeloma patients: a systematic review and meta-analysis. BMJ Open 2024; 14(1): e071548. 10.1136/bmjopen-2022-071548. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.U.S. Food and Drug Administration . FDA approves daratumumab for newly diagnosed multiple myeloma ineligible for autologous stem cell transplant. Silver Spring (MD). FDA, 2019. Available from. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-multiple-myeloma-ineligible-autologous-stem-cell-transplant. [Google Scholar]
- 5.U.S. Food and Drug Administration . FDA approves daratumumab for transplant-eligible newly diagnosed multiple myeloma. Silver Spring (MD). FDA, 2019. Available from. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-transplant-eligible-multiple-myelomaU.S.FoodandDrugAdministration. [Google Scholar]
- 6.Kumar SK, Callander NS, Adekola K, et al. Multiple Myeloma, Version 5.2026, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2026; 24(1): e260001. 10.6004/jnccn.2026.0001. [DOI] [PubMed] [Google Scholar]
- 7.Voorhees PM, Kaufman JL, Laubach J, Sborov DW, Reeves B, Rodriguez C, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood 2020; 136(8): 936–945. 10.1182/blood.2020005288. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Ding J, Gong S. Quadruplet regimen for newly diagnosed multiple myeloma is effective in the standard-risk subgroup but not in the high-risk subgroup. Front Pharmacol 2024; 15: 1398879. 10.3389/fphar.2024.1398879. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Callander N., Silbermann R., Kaufman JL, et al. Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk. Blood Cancer Journal 2024; 14: 69. 10.1038/s41408-024-01030-w [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Touzeau C, Perrot A, Hulin C, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with tandem transplant for high-risk newly diagnosed myeloma. Blood 2024; 143(20): 2029–2036, PMID: 38394666; PMCID: PMC12782976. 10.1182/blood.2023023597. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj 2021; 372: n71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. Bmj 2011; 343: d5928. 10.1136/bmj.d5928. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Higgins JPT TJ, Chandler J, Cumpston M, Li T, Page MJ, Welch VA. (eds). Cochrane Handbook for Systematic Reviews of Interventions. Cochrane, 2024. 2024. version 6.5(updated August 2024)[Available from. https://www.training.cochrane.org/handbook [Google Scholar]
- 14.Mollee P, Reynolds J, Janowski W, Quach H, Campbell P, Gibbs S, et al. Daratumumab, cyclophosphamide, bortezomib, and dexamethasone for transplant-ineligible myeloma: AMaRC 03-16. Blood Adv 2024; 8(14): 3721–3730. 10.1182/bloodadvances.2023012539. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Fu W, Bang SM, Huang H, Kim K, Li W, An G, et al. Bortezomib, Melphalan, and Prednisone With or Without Daratumumab in Transplant-ineligible Asian Patients With Newly Diagnosed Multiple Myeloma: The Phase 3 OCTANS Study. Clin Lymphoma Myeloma Leuk 2023; 23(6): 446. 10.1016/j.clml.2023.02.009. [DOI] [PubMed] [Google Scholar]
- 16.Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med 2018; 378(6): 518–528. 10.1056/NEJMoa1714678. [DOI] [PubMed] [Google Scholar]
- 17.Sonneveld P, Dimopoulos MA, Boccadoro M, Quach H, Ho PJ, Beksac M, et al. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2024; 390(4): 301–313. 10.1056/nejmoa2312054. [DOI] [PubMed] [Google Scholar]
- 18.Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet 2019; 394(10192): 29–38. 10.1016/S0140-6736(19)31240-1. [DOI] [PubMed] [Google Scholar]
- 19.Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nat Med 2025; 31(4): 1195–1202, PMID: 39910273; PMCID: PMC12003169. 10.1038/s41591-024-03485-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Atanackovic D, Steinbach M, Radhakrishnan SV, Luetkens T. Immunotherapies targeting CD38 in Multiple Myeloma. Oncoimmunology 2016; 5(11): e1217374. 10.1080/2162402X.2016.1217374. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Goldsmith SR, Foley N, Schroeder MA. Daratumumab for the treatment of multiple myeloma. Drugs Today (Barc) 2021; 57(10): 591–605. [DOI] [PubMed] [Google Scholar]
- 22.Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med 2015; 373(13): 1207–1219. 10.1056/NEJMoa1506348. [DOI] [PubMed] [Google Scholar]
- 23.Sanchez L, Wang Y, Siegel DS, Wang ML. Daratumumab: a first-in-class CD38 monoclonal antibody for the treatment of multiple myeloma. J Hematol Oncol 2016; 9(1): 51. 10.1186/s13045-016-0283-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood 2016; 128(3): 384–394. 10.1182/blood-2015-12-687749. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Usmani SZ, Nahi H, Legiec W, Grosicki S, Vorobyev V, Spicka I, et al. Final analysis of the phase III non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma. Haematologica 2022; 107(10): 2408–2417. 10.3324/haematol.2021.279459. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Facon T, San-Miguel J, Dimopoulos MA, Mateos MV, Cavo M, van Beekhuizen S, et al. Treatment Regimens for Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma: A Systematic Literature Review and Network Meta-analysis. Adv Ther 2022; 39(5): 1976–1992. 10.1007/s12325-022-02083-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus Lenalidomide and Dexamethasone for Newly Diagnosed Multiple Myeloma. N Engl J Med 2019; 380(22): 2104–2115. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Souto Filho JTD, Cantadori LO, Crusoe EdQ, et al. Daratumumab-based quadruplet versus triplet induction regimens in transplant-eligible newly diagnosed multiple myeloma: a systematic review and meta-analysis. Blood Cancer J 2025; 15(1): 37. 10.1038/s41408-025-01253-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Paul B, Anwer F, Raza S, Mammadzadeh A, et al. Comparative Meta-Analysis of Triplet vs. Quadruplet Induction Regimens in Newly Diagnosed, Treatment Naïve, Multiple Myeloma. Cancers (Basel) 2024; 16(17): 2938. 10.3390/cancers16172938. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Perrot A, Lauwers-Cances V, Corre J, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood 2018; 132(23): 2456–2464. 10.1182/blood-2018-06-858613, Epub 2018 Sep 24. PMID: 30249784; PMCID: PMC6284215. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Mao J., Xue L., Wang H., Zhou H., Zhu Y., Jia T., Cai Z., Zhao L., Zhao L., Wang Y., Wang J. Cytogenetic risk stratification combined with minimal residual disease status influences the therapeutic outcome and prognosis of multiple myelomas. Scientific Reports 2025; 15: 12545. 10.1038/s41598-025-97125-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Abu Zar M, Kamal A, Khan AY, Malik SU, Malik MN, Rafae A, et al. Efficacy and Safety of Daratumumab Based Regimens for Multiple Myeloma: A Systematic Review and Meta-Analysis. Blood 2018; 132(Supplement 1): 3292. 10.1182/blood-2018-99-110580. [DOI] [Google Scholar]
- 33.Theprungsirikul P, Liu Y, Neparidze N. Real-World Utilization of Daratumumab in Front-Line Treatment of Newly Diagnosed Multiple Myeloma: A Retrospective Observational Study. Blood 2023; 142(Supplement 1): 7364. 10.1182/blood-2023-186985. [DOI] [Google Scholar]
- 34.Dimopoulos MA, Moreau P, Terpos E, et al. EHA Guidelines Committee. Electronic address: guidelines@ehaweb.org; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol 2021; 32(3): 309–322. 10.1016/j.annonc.2020.11.014, Epub 2021 Feb 3. Erratum in: Ann Oncol. 2022 Jan. [DOI] [PubMed] [Google Scholar]
- 35.Jakubowiak AJ, Kumar S, Medhekar R, Pei H, Lefebvre P, Kaila S, et al. Daratumumab Improves Depth of Response and Progression-free Survival in Transplant-ineligible, High-risk, Newly Diagnosed Multiple Myeloma. Oncologist 2022; 27(7): e589–e596. 10.1093/oncolo/oyac067. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Tang W, Zhang L, Zheng Y, Pan L, Niu T. Daratumumab-based immunotherapy vs. lenalidomide, bortezomib and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: a systemic review. Front Oncol 2024; 14: 1286029. 10.3389/fonc.2024.1286029. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Wang Y, Li Y, Chai Y. Efficacy and safety of daratumumab in the treatment of multiple myeloma: a systematic review and meta-analysis. J Int Med Res 2021; 49(8): 3000605211038135, PMID: 34433331; PMCID: PMC8404651. 10.1177/03000605211038135. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Wang P, Jin SY. Meta-analysis of the efficacy and safety of daratumumab in the treatment of multiple myeloma. World J Clin Cases 2023; 11(29): 7091–7100. 10.12998/wjcc.v11.i29.7091. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Attal M, Richardson PG, Rajkumar SV, ICARIA-MM study group , et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet 2019; 394(10214): 2096–2107. 10.1016/S0140-6736(19)32556-5. [DOI] [PubMed] [Google Scholar]
- 40.Moreau P, Dimopoulos MA, Mikhael J, et al. IKEMA study group. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet 2021; 397(10292): 2361–2371. DOI: 10.1016/S0140-6736(21)00592-4, Epub 2021 Jun 4. PMID: 34097854. [DOI] [PubMed] [Google Scholar]
- 41.Osama M, Khan MH, Khan S, Hussain A, et al. Efficacy and safety of anti-CD38 monoclonal antibodies-based therapy versus standard therapy in newly diagnosed multiple myeloma patients: a systematic review and meta-analysis. Ther Adv Hematol 2025; 16: 20406207251314289, PMID: 39872010; PMCID: PMC11770704. 10.1177/20406207251314289. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Costa LJ, Chhabra S, Godby KN, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) in newly diagnosed multiple myeloma. J Clin Oncol 2021; 39(25): 2750–2760. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental material for Efficacy and safety of daratumumab-based quadruplet therapy vs non-daratumumab-based triplet therapy in newly diagnosed multiple myeloma patients: A GRADE assessed systematic review and meta-analysis of randomized controlled trials by Muhammad Osama, Muhammad Haris Khan, Ammara Tahir, Amna Hussain, Ahmad Iftikhar, Aizaz Ali, Safeena Khan, Malak Bilal Hassan, Intikhab Alam, Zeeshan Khan, Abdullah Afridi, Mohammad Ebad Ur Rehman, Amna Gul, Pawan Kumar Thada in Therapeutic Advances in Hematology
Data Availability Statement
The datasets obtained and analyzed in the current study are available from the corresponding author upon reasonable request.*