Table of Contents
- Key Points
- Background: Why This Research Matters
- What Is Multiple Myeloma?
- What Is Daratumumab and How Does It Work?
- How the Researchers Conducted the Study
- Which Studies Were Included
- Study Quality Assessment
- Key Finding: Hazard Ratio for Progression or Death
- Key Finding: Overall Response Rate
- Key Finding: Overall Survival and Mortality
- Key Finding: Minimal Residual Disease Negativity
- Key Finding: Progression or Death Risk Difference
- Clinical Implications: What This Means for Patients
- Limitations: What the Study Could Not Prove
- Recommendations and Actionable Advice
- Frequently Asked Questions
- Source Information
Key Points
- A meta-analysis of 35 studies and 22,439 patients found daratumumab roughly halved the risk of progression or death compared with control treatments in multiple myeloma.
- Daratumumab more than doubled the likelihood of achieving a treatment response, with an overall response rate odds ratio of 2.58.
- Patients receiving daratumumab had lower odds of death (odds ratio 0.73) and higher rates of minimal residual disease negativity across all subgroups.
- Benefits were consistent in relapsed/refractory, transplant-ineligible, and transplant-eligible patients, but individual treatment decisions should be personalized.
- Daratumumab requires monitoring for increased infection risk; patients should report signs of infection promptly and discuss MRD testing with their care team.
Background: Why This Research Matters
Multiple myeloma remains an incurable disease for most patients. Even with modern treatments, many patients experience multiple relapses and eventually develop resistance to standard therapies. This reality drives the search for better treatment options.
Researchers conducted this meta-analysis to evaluate how well daratumumab works compared with control treatments. A meta-analysis combines results from many separate studies into one pooled analysis. This approach gives a broader picture than any single study can provide.
The researchers focused on three distinct patient groups:
- Relapsed or refractory multiple myeloma (RRMM): patients whose cancer has returned or stopped responding to prior treatments
- Newly diagnosed, transplant-ineligible (ND/ISCT): patients newly diagnosed who cannot receive a stem cell transplant
- Newly diagnosed, transplant-eligible (ND/ESCT): patients newly diagnosed who can receive a stem cell transplant
The study authors noted that several prior meta-analyses had assessed daratumumab's efficacy. However, none had simultaneously measured its effects on minimal residual disease negativity and overall response rate. The authors also pointed out that the annual literature on daratumumab is expanding rapidly, now exceeding 30 studies per year. This growth can influence pooled estimates over time. By integrating both randomized and observational data, this meta-analysis aimed to provide the most comprehensive synthesis of daratumumab's benefits in multiple myeloma to date.
What Is Multiple Myeloma?
Multiple myeloma is a cancer of plasma cells, which are a type of white blood cell found in the bone marrow. Plasma cells normally help the body fight infection by producing antibodies. In multiple myeloma, these cells become malignant and multiply abnormally.
The disease is characterized by abnormal monoclonal protein production, bone marrow infiltration, and a complex array of clinical symptoms. These symptoms include bone pain, anemia (low red blood cell counts), and renal dysfunction (kidney problems).
Multiple myeloma is the second most common hematologic malignancy (blood cancer). It accounts for approximately 1% of all cancers and 10% of hematologic cancers worldwide. Despite advancements in diagnosis and treatment, the disease remains incurable. Most patients experience multiple relapses and develop resistance to standard therapies over time.
Current therapeutic strategies focus on extending progression-free survival (PFS) and achieving deeper, longer-lasting responses to improve overall survival. Progression-free survival is the time a patient lives without the cancer getting worse.
What Is Daratumumab and How Does It Work?
Daratumumab is a human monoclonal antibody that targets CD38. A monoclonal antibody is a laboratory-made protein that attaches to a specific target on cells. CD38 is a glycoprotein (a protein with sugar molecules attached) that is highly expressed on myeloma cells. This makes CD38 an ideal target for therapy.
When daratumumab binds to CD38 on myeloma cells, it induces cell death through multiple mechanisms:
- Antibody-dependent cellular cytotoxicity: immune cells are directed to attack the marked cancer cells
- Complement-dependent cytotoxicity: a cascade of immune proteins destroys the marked cells
- Antibody-dependent cellular phagocytosis: immune cells engulf and digest the marked cancer cells
Daratumumab also reduces the number of immunosuppressive cells in the tumor microenvironment. These include regulatory T cells and myeloid-derived suppressor cells. By reducing these cells, daratumumab enhances the body's own immune response against myeloma cells.
Clinical trials have shown that daratumumab, both as a standalone treatment 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. Common backbone regimens include bortezomib, lenalidomide, and dexamethasone. This combination provides a potent synergistic effect that extends the duration of response.
However, daratumumab requires careful monitoring. Patients receiving daratumumab have an increased risk of infections and other adverse effects.
How the Researchers Conducted the Study
This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The researchers did not prospectively register the study because their project timeline did not allow for the PROSPERO review process before data extraction began. However, they strictly adhered to PRISMA throughout the project.
The researchers conducted a comprehensive literature search across several electronic databases. These included PubMed, Web of Science, and Scopus. The search included all records available up to September 2024.
Relevant Medical Subject Headings (MeSH) and keywords were used. These focused on terms like "multiple myeloma," "daratumumab," "anti-CD38 therapy," and "immunotherapy." The researchers also manually reviewed reference lists of relevant articles and prior systematic reviews. This step helped identify studies that might have been missed in the database search.
Eligibility criteria were defined using the PICO framework:
- Population (P): clinical studies on human patients diagnosed with multiple myeloma
- Intervention (I): treatment with daratumumab, either as monotherapy or in combination with other agents
- Comparison (C): control treatments such as standard care or alternative therapies without daratumumab
- Outcomes (O): treatment efficacy measured by overall survival, progression-free survival, death, hazard ratio, and minimal residual disease
Studies were excluded if they were cross-sectional, involved animal models, were case reports, or lacked sufficient clinical outcome data. Studies focusing on other cancers or conditions were also excluded. Studies without a control group, or studies that exposed both groups to daratumumab, were excluded as well.
The researchers included Phase II–III randomized controlled trials as well as prospective and retrospective observational cohort studies. This approach captured both high-level efficacy data and real-world effectiveness data.
Data extraction was independently conducted by two reviewers using a standardized data collection form. Information collected included study characteristics, patient demographics, treatment details, and outcomes measured. Discrepancies between reviewers were resolved through discussion or by involving a third reviewer.
All analyses were performed in R (version 4.x) using the meta package. The researchers assessed between-study heterogeneity with the I² statistic. They interpreted 25%, 50%, and 75% as low, moderate, and high heterogeneity, respectively. All pooled effect estimates were calculated using a DerSimonian–Laird random-effects model to yield conservative confidence intervals.
Time-to-event outcomes such as progression-free survival are presented as hazard ratios (HRs) with 95% confidence intervals (CIs). Dichotomous outcomes such as MRD negativity and overall response rate are reported as odds ratios (ORs) or risk differences (RDs). Statistical significance of pooled estimates and subgroup differences was evaluated by z-tests.
The researchers conducted predefined sensitivity analyses by omitting one study at a time to assess robustness. Subgroup analyses were conducted by study design (randomized controlled trial vs. observational) and by disease status (RRMM, ND/ISCT, ND/ESCT). They examined publication bias via funnel plots and Egger's regression test.
Which Studies Were Included
The search across PubMed, Scopus, and Web of Science yielded 24,984 studies from inception until September 2024. After removing 7,177 duplicates, 17,807 studies were screened based on title. Then 449 studies were selected for abstract evaluation, which resulted in selection of 93 articles for full-text evaluation.
Among the 93 full texts evaluated, 58 had inappropriate designs. These included case reports and case series, animal studies, and studies that did not evaluate the clinical outcome of daratumumab treatment. Histological or histomorphological studies were also excluded. The final screening resulted in the inclusion of 35 studies in the systematic review and meta-analysis.
The 35 studies were published between 2015 and 2024 and enrolled a total of 22,439 patients. The breakdown by patient group was:
- Relapsed or refractory multiple myeloma (RRMM): 21 studies with 7,604 patients
- Newly diagnosed, transplant-ineligible (ND/ISCT): 12 studies with 10,216 patients
- Newly diagnosed, transplant-eligible (ND/ESCT): 6 studies with 4,619 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. The remainder comprised 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. They reported outcomes on progression-free survival, MRD negativity, overall response rate, and safety endpoints, with follow-up durations of 6–48 months.
The backbone regimens used across studies included lenalidomide, bortezomib, melphalan, dexamethasone, cyclophosphamide, thalidomide, pomalidomide, carfilzomib, and melflufen. These were combined with daratumumab in the treatment groups and used alone or with other agents in the control groups.
Study Quality Assessment
Study quality was independently rated by two reviewers. They used the Cochrane Risk of Bias 2 tool for randomized trials and the Newcastle–Ottawa Scale for observational cohorts. Discrepancies were resolved by consensus, and quality scores were explored as potential moderators in meta-regression.
Using the Cochrane Risk of Bias 2 tool, the researchers found that 28 of the 31 randomized controlled trials were judged at low risk of bias across all domains. 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. Three studies were deemed high quality (NOS ≥ 7), and 1 was of moderate quality (NOS=6). Most commonly, points were lost 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. This supports the robustness of the meta-analytic findings.
Key Finding: Hazard Ratio for Progression or Death
The overall pooled hazard ratio for daratumumab versus control treatment across all patients was 0.50 (95% CI: 0.46–0.55). This indicates a statistically significant reduction in hazard (P<0.01). In plain language, daratumumab roughly halved the risk of progression or death compared with control treatments.
Subgroup analysis showed the following results:
- RRMM: hazard ratio of 0.48 (95% CI: 0.41–0.57) with high heterogeneity (I²=77%, P<0.01)
- ND/ISCT: hazard ratio of 0.52 (95% CI: 0.46–0.59) with moderate heterogeneity (I²=42%, P=0.06)
- ND/ESCT: hazard ratio of 0.55 (95% CI: 0.42–0.62) with low heterogeneity (I²=31%, P=0.21)
The overall heterogeneity was considerable (I²=67%, τ²=0.0521, P<0.01). However, the test for subgroup differences was not statistically significant (χ² (df=2)=0.58, P=0.75). This indicates consistent treatment effects across the subgroups.
Key Finding: Overall Response Rate
The random-effects model analyzed a total of 4,923 patients in the daratumumab group and 4,956 patients in the control group across the three subgroups. The pooled odds ratio for overall response rate with daratumumab versus control was 2.58 (95% CI: 2.26–2.93). This shows a significant benefit in favor of daratumumab (P<0.01).
Subgroup analyses revealed the following:
- RRMM: odds ratio of 2.43 (95% CI: 1.81–3.26) with high heterogeneity (I²=78%, P<0.01)
- ND/ISCT: odds ratio of 2.00 (95% CI: 1.35–2.63) with no significant heterogeneity (I²=0%, P=0.46)
- ND/ESCT: odds ratio of 2.76 (95% CI: 1.37–5.56) with moderate heterogeneity (I²=39%, P=0.18)
Overall heterogeneity was substantial (I²=70%, τ²=0.3522, P<0.01). Subgroup differences were statistically significant (χ² (df=2) = 6.50, P=0.04). This suggests variability in treatment effects among the subgroups.
Key Finding: Overall Survival and Mortality
The pooled number of patients was 5,364 in the daratumumab group and 4,870 in the control group. Across all participants, the odds of mortality were lower with daratumumab. The pooled odds ratio was 0.73 (95% CI: 0.66–0.81, P<0.01).
Among the subgroups, the results were:
- RRMM: odds ratio of 0.75 (95% CI: 0.66–0.85) with moderate heterogeneity (I²=45%, P=0.03)
- ND/ISCT: odds ratio of 0.76 (95% CI: 0.45–0.72) with moderate heterogeneity (I²=44%, P=0.13)
- ND/ESCT: odds ratio of 0.67 (95% CI: 0.46–0.88) with low heterogeneity (I²=12%, P=0.33)
The ND/ESCT patients exhibited the most homogeneous results. 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).
Key Finding: Minimal Residual Disease Negativity
Minimal residual disease (MRD) negativity means that after treatment, no cancer cells can be detected in the bone marrow using highly sensitive tests. MRD negativity is increasingly recognized as a surrogate marker for long-term outcomes. A surrogate marker is a measurable indicator that predicts a clinical benefit.
The random-effects model included 4,097 patients receiving daratumumab and 3,528 in the control group. Daratumumab significantly improved MRD negativity rates across all subgroups.
In the detailed data, the MRD negativity events were:
- Daratumumab group: 1,489 events out of 4,123 patients assessed
- Control group: 604 events out of 3,528 patients assessed
This means that patients receiving daratumumab were substantially more likely to achieve MRD negativity compared with those receiving control treatments.
Key Finding: Progression or Death Risk Difference
The risk difference for progression or death was lower in the daratumumab group. The overall risk difference was -0.14 (95% CI: -0.16 to -0.12). A negative risk difference means fewer events occurred in the daratumumab group.
Subgroup analysis showed varying effects:
- ND/ESCT: risk difference of -0.11 (95% CI: -0.17 to -0.04) with moderate heterogeneity (I²=46%, P=0.16)
- ND/ISCT: risk difference of -0.10 (95% CI: -0.15 to -0.06) with similar heterogeneity (I²=54%, P=0.09)
- RRMM: risk difference 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). However, subgroup differences were not statistically significant (χ² (df=2) = 3.90, P=0.14).
The combined funnel plots revealed varying degrees of symmetry. This provides insight into potential publication bias and heterogeneity across the included studies.
Clinical Implications: What This Means for Patients
This meta-analysis confirms that daratumumab provides significant clinical benefits across multiple patient subgroups. The findings support daratumumab as a robust therapeutic option for extending progression-free and overall survival in multiple myeloma.
The consistency of benefit across all three patient groups is particularly important. A patient may have relapsed or refractory disease. A patient may be newly diagnosed but cannot receive a stem cell transplant. A patient may be newly diagnosed and eligible for transplant. In all these groups, daratumumab appears to improve outcomes.
The overall hazard ratio of 0.50 means that daratumumab reduced the risk of progression or death by approximately half compared with control treatments. The odds ratio for overall response rate of 2.58 indicates that patients receiving daratumumab were more than twice as likely to respond to treatment.
The improvement in MRD negativity rates is especially meaningful. Achieving MRD negativity suggests that treatment has eliminated detectable cancer cells to a very deep level. This is increasingly recognized as a predictor of better long-term outcomes.
The mortality odds ratio of 0.73 indicates that patients receiving daratumumab had lower odds of death compared with those receiving control treatments.
Limitations: What the Study Could Not Prove
The researchers identified several limitations. Some heterogeneity was observed across the included studies. Heterogeneity means that the studies differed in their results beyond what would be expected by chance alone.
Potential publication bias was also observed. Publication bias occurs when studies with positive results are more likely to be published than studies with negative results. This can make a treatment appear more effective than it actually is.
The overall heterogeneity was considerable for the hazard ratio analysis (I²=67%). For the overall response rate analysis, heterogeneity was substantial (I²=70%). For the progression or death risk difference analysis, heterogeneity was also substantial (I²=78%).
Despite these limitations, the researchers concluded that daratumumab remains a robust therapeutic option. The consistency of benefit across subgroups supports the reliability of the findings.
The study authors noted that they did not prospectively register the study because their project timeline did not allow for the PROSPERO review process before data extraction began. However, they strictly adhered to PRISMA guidelines throughout the project.
Recommendations and Actionable Advice
Based on this comprehensive meta-analysis, the following points are relevant for patients and their care teams:
- Discuss daratumumab as a treatment option: For patients with multiple myeloma, whether newly diagnosed or relapsed/refractory, daratumumab has demonstrated significant benefits across all major patient subgroups.
- Understand the benefits: Daratumumab roughly halved the risk of progression or death compared with control treatments. It also more than doubled the likelihood of achieving a treatment response.
- Ask about MRD testing: Minimal residual disease negativity is an important marker of deep treatment response. Patients may wish to discuss MRD testing with their healthcare providers.
- Monitor for infections: Daratumumab requires careful monitoring due to an increased risk of infections and other adverse effects. Patients should report any signs of infection to their care team promptly.
- Consider the patient's specific situation: The benefits of daratumumab were consistent across relapsed/refractory, transplant-ineligible, and transplant-eligible patient groups. However, treatment decisions should always be individualized based on the patient's specific circumstances.
Patients should discuss the potential benefits and risks of daratumumab with their healthcare providers. This meta-analysis provides strong evidence supporting daratumumab's role in multiple myeloma treatment, but individual treatment decisions require consideration of each patient's unique medical situation.
Frequently Asked Questions
What is daratumumab and how does it work?
Daratumumab is a laboratory-made monoclonal antibody that targets CD38, a protein found in high amounts on myeloma cells. When it binds to CD38, it triggers immune mechanisms that destroy the marked cancer cells, including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis. It also reduces immunosuppressive cells in the tumor microenvironment, helping the body's own immune response against myeloma.
Who can benefit from daratumumab?
In a pooled analysis of 35 studies and 22,439 patients, daratumumab showed consistent benefits across three groups: relapsed or refractory multiple myeloma, newly diagnosed patients who cannot receive a stem cell transplant, and newly diagnosed patients who can receive a transplant. The risk of progression or death was roughly halved in all three groups compared with control treatments.
What does a hazard ratio of 0.50 mean for me?
A hazard ratio of 0.50 means that, in the pooled analysis, patients receiving daratumumab had about half the risk of their cancer progressing or of dying compared with those receiving control treatments. This finding was statistically significant and was seen across all patient subgroups, though individual results can vary.
What is minimal residual disease (MRD) negativity and why does it matter?
MRD negativity means that after treatment, no cancer cells can be detected in the bone marrow using highly sensitive tests. In this analysis, daratumumab significantly improved MRD negativity rates across all subgroups. Achieving MRD negativity is increasingly recognized as a marker that predicts better long-term outcomes, so patients may wish to discuss MRD testing with their healthcare providers.
What are the risks or side effects of daratumumab?
Daratumumab requires careful monitoring because patients receiving it have an increased risk of infections and other adverse effects. The article does not list specific side effects beyond this. Patients should report any signs of infection to their care team promptly and discuss potential benefits and risks with their healthcare providers.
How was this review conducted and how reliable are its findings?
Researchers pooled data from 35 studies (15 randomized trials and 4 observational cohorts) involving 22,439 patients, following PRISMA guidelines. Most randomized trials were at low risk of bias. However, considerable heterogeneity was present across studies, and potential publication bias was observed, meaning the treatment could appear more effective than it actually is.
Does daratumumab improve overall survival?
In the pooled analysis, the odds of death were lower with daratumumab compared with control treatments, with an odds ratio of 0.73. This means patients receiving daratumumab had about 27% lower odds of death. The benefit was seen across all three patient subgroups, though differences between subgroups were not statistically significant.
I have multiple myeloma and my doctor recommends daratumumab — when should I get a second opinion?
Daratumumab roughly halved the risk of progression or death and more than doubled the likelihood of a treatment response across relapsed or refractory, transplant-ineligible, and transplant-eligible patients. Because treatment decisions should be individualized to each patient's circumstances, a second opinion can help confirm whether daratumumab, alone or added to a backbone regimen such as lenalidomide or bortezomib, fits your situation, and can review whether MRD testing is appropriate. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
Original article title: 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.
Authors: Salajegheh P, Salajegheh A, Yazdi Yahyaabadi F, Yazdi F.
Author affiliations:
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Department of Pharmaceutical Sciences, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pediatrics, Kerman University of Medical Sciences, Kerman, Iran
Publication: GMJ (Galen Medical Journal), 2025;14:e3958
DOI: 10.31661/gmj.v14i.3958
Corresponding author: Farzaneh Yazdi, Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
Keywords: Daratumumab; Multiple Myeloma; Progression-free Survival; Minimal Residual Disease; Treatment Outcome
This patient-friendly article is based on peer-reviewed research.
