What Is the MAIA Trial for Multiple Myeloma?

The MAIA trial is a large, randomized phase 3 clinical trial that tested whether adding the antibody drug daratumumab to a standard two-drug regimen could help people with newly diagnosed multiple myeloma who were not candidates for stem-cell transplant. Enrolling 737 patients across multiple countries, it produced some of the strongest survival data in this population and ultimately helped establish the three-drug combination as a new standard of care. The results have shaped treatment guidelines worldwide and continue to generate follow-up analyses years after the trial began.

What the Trial Tested and Who It Enrolled

MAIA randomly assigned patients to one of two groups. One group received daratumumab combined with lenalidomide and dexamethasone (a combination called D-Rd). The other received lenalidomide and dexamethasone alone (Rd), which was the established standard at the time. Treatment in both arms continued until the disease progressed or side effects became intolerable, meaning there was no fixed number of cycles and no planned stop date.¹

The “transplant-ineligible” label is important. Many people diagnosed with myeloma are older adults or have other health conditions that make the intensive chemotherapy required before a stem-cell transplant too risky. MAIA was designed specifically for this group, and the patient population skewed older as a result, with a meaningful share aged 75 and above.

How Daratumumab Works

Daratumumab is a monoclonal antibody that targets a protein called CD38, which sits on the surface of myeloma cells in high numbers. By latching onto CD38, it triggers several mechanisms that kill the cancer cells, including recruiting immune cells to attack them directly and activating pathways that cause the cells to self-destruct. It also has immunomodulatory effects, meaning it can help “wake up” parts of the immune system that myeloma tends to suppress.¹ The rationale for adding it to lenalidomide and dexamethasone was that all three drugs attack the disease through complementary routes, making the combination harder for cancer cells to resist.

Survival Results

The headline finding from the MAIA trial is a survival advantage that has held up with extended follow-up. Median overall survival in the D-Rd group had not yet been reached at the time of the long-term analysis, while it was about 65.5 months in the Rd-only group. Patients who received D-Rd had roughly a 34% lower risk of death. At the five-year mark, about two-thirds of D-Rd patients were still alive compared with just over half in the Rd group.²

For a disease that remains incurable, a five-year survival rate approaching 67% in transplant-ineligible patients is a significant advance over what previous regimens could deliver. The fact that median survival in the D-Rd arm still had not been reached suggests that the true median could end up being considerably longer than 65 months, though only future data will confirm that.

Depth of Response and Minimal Residual Disease

Oncologists care not just about whether a tumor shrinks but about how deeply it responds, because deeper responses tend to translate into longer remissions. In MAIA, about 93% of D-Rd patients responded to treatment overall, compared with roughly 82% of Rd patients. More striking were the rates of minimal residual disease (MRD) negativity, a measure of whether any detectable cancer remains in the bone marrow at extremely sensitive thresholds. Around 32% of D-Rd patients achieved MRD negativity versus about 11% on Rd alone.³

What matters even more than reaching MRD negativity once is whether it lasts. Among D-Rd patients, roughly 19% sustained MRD negativity for at least 12 months, compared with about 4% on Rd. Sustained MRD negativity lasting six months or longer also translated into better progression-free survival in subsequent analyses, reinforcing its value as a marker of durable disease control.⁴ These deep-response numbers are part of why D-Rd has become such a convincing option: it does not just delay progression but appears to eliminate detectable disease in a much larger share of patients than Rd alone.

Quality of Life

A treatment that extends survival but leaves people feeling miserable is a harder sell. Patient-reported outcomes from MAIA tell a different story. Patients on D-Rd reported improvements in overall health status that were sustained over five years, and those improvements held across subgroups defined by age, frailty, and whether patients had bone lesions at the start. At the three-year mark, D-Rd patients were roughly twice as likely as Rd patients to report meaningful improvement in fatigue and physical functioning.⁵

Pain reduction deserves particular mention. D-Rd patients had significantly greater decreases in pain scores as early as the third treatment cycle, and those reductions were sustained through cycle 12 and beyond. The benefit was consistent whether patients were younger or older than 75 and regardless of how well they were functioning at the start of treatment.⁶ Bone pain is one of the most debilitating symptoms of myeloma, so faster and more durable pain relief is a meaningful everyday benefit that survival statistics alone do not capture.

Benefits Across High-Risk and Vulnerable Subgroups

One of the more reassuring aspects of the MAIA data is that D-Rd did not just help the healthiest patients. Subgroup analyses found that the benefit in progression-free survival held for patients aged 75 and older, for frail patients, and for those with high-risk cytogenetics, a category where myeloma tends to be more aggressive and harder to treat. Patients with an isolated chromosomal abnormality called gain(1q21) appeared to benefit even more, with a roughly 64% reduction in the risk of progression or death.⁷

For frail patients specifically, the quality-of-life picture was also encouraging. Frail D-Rd patients showed large reductions in pain and moderate improvements in fatigue. Their overall health status scores improved steadily over time, and the median time to first worsening of pain was never reached in the D-Rd arm, meaning most frail patients had not experienced a meaningful return of pain by the time data were analyzed.⁸ These subgroup findings are clinically important because frailty and older age often make doctors hesitant to use more intensive regimens. The MAIA data suggest that adding daratumumab does not undermine the benefit in the patients who might seem most vulnerable to it.

Pooled analyses combining MAIA with another trial also confirmed that D-Rd improved progression-free survival, MRD negativity rates, and deep response rates across age and frailty categories, with safety profiles that were consistent with what is already known about each individual drug.⁹

Safety and Infections

Adding a third drug to a regimen naturally raises the question of whether side effects increase. The most closely scrutinized safety concern in MAIA has been infection risk. Pooled data from MAIA and a related trial showed that serious (grade 3 or 4) infections occurred in about 37% of daratumumab-treated patients compared with roughly 22% on the control arms. Fatal infections were also modestly higher at about 3% versus 1.5%. However, when researchers adjusted for how long patients were actually on treatment, the infection rates between groups were generally comparable, suggesting the higher raw numbers partly reflect the fact that D-Rd patients stay on therapy longer because their disease is controlled longer.¹⁰

Other common side effects in the D-Rd arm included infusion-related reactions during daratumumab administration and higher rates of neutropenia, which is a drop in infection-fighting white blood cells. These events were generally manageable with dose adjustments and supportive care. Still, the infection signal means that patients on D-Rd need proactive monitoring, and many clinicians prescribe prophylactic antibiotics or antivirals alongside the regimen.

How D-Rd Compares to Bortezomib-Based Regimens

While MAIA compared D-Rd to Rd, a practical question for patients and doctors is how D-Rd stacks up against bortezomib, lenalidomide, and dexamethasone (VRd), another widely used frontline combination. No head-to-head randomized trial has directly compared D-Rd and VRd, but real-world chart reviews and retrospective analyses have attempted to fill this gap.

One study matching D-Rd and VRd patients from medical records found that D-Rd was associated with a substantially lower risk of disease progression or death, with a roughly 65% reduction in that combined endpoint.¹¹ Another real-world analysis looked at how long patients went before needing a new line of therapy or dying. Median time to next treatment was roughly 38 months for D-Rd patients compared with about 19 months for VRd, with a meaningful reduction in risk favoring D-Rd.¹²

These comparisons have important caveats. Real-world analyses cannot fully account for the differences between patients who receive one regimen versus another, and the populations in chart reviews are not randomized. Still, the consistency of the signal across multiple analyses has reinforced D-Rd’s position as a preferred option for transplant-ineligible patients.

The Shift to Subcutaneous Daratumumab

One practical drawback of daratumumab when MAIA began was that it required lengthy intravenous infusions, sometimes lasting several hours, especially for early doses. The COVID-19 pandemic accelerated the adoption of a subcutaneous formulation, which is injected under the skin in a few minutes. The MAIA protocol was amended during the pandemic to allow patients already randomized to D-Rd to switch from intravenous to subcutaneous daratumumab at their doctor’s discretion.¹³

Studies of the switch found that blood levels of daratumumab actually increased after switching from intravenous to subcutaneous, and the subcutaneous formulation was well tolerated.¹⁴ For patients, this change is a major quality-of-life win: less time in the infusion chair, fewer clinic visits, and lower risk of infusion-related reactions. Today, subcutaneous daratumumab is the more commonly used formulation in routine clinical practice.

Cost and Access Considerations

The clinical strength of D-Rd comes with a significant cost premium. One economic model estimated that total treatment costs for D-Rd were about $627,000 compared with roughly $385,000 for VRd and $330,000 for Rd. When researchers calculated cost per quality-adjusted life year, D-Rd did not meet standard cost-effectiveness thresholds compared with either VRd or Rd in that analysis.¹⁵

A separate analysis using different modeling assumptions found a more favorable result, calculating about $90,000 per quality-adjusted life year gained for D-Rd versus VRd, a figure that falls within the range many healthcare systems consider acceptable. That study noted the results were sensitive to assumptions about long-term survival, post-progression treatment costs, and the time horizon used in the model. It also found that upfront price discounts on daratumumab were the most effective strategy for payers to bring costs down.¹⁶

The discrepancy between these two analyses illustrates a broader tension in myeloma economics. Because survival data for D-Rd are still maturing and patients stay on treatment for years, cost-effectiveness calculations depend heavily on modeling choices. In countries with single-payer health systems, access to D-Rd may hinge on negotiated pricing agreements or patient-access schemes. In the United States, insurance coverage is generally available, but copays for specialty drugs can be burdensome, and some patients rely on manufacturer assistance programs.

Second Primary Malignancies

When patients live longer on treatment, there is more time for second cancers to develop, and this has been tracked carefully. A meta-analysis pooling data from multiple trials of anti-CD38 antibody regimens found that patients receiving these drugs had a modestly higher rate of second primary malignancies compared with control groups, about 6.8% versus 5.2%. The increase was driven primarily by non-melanoma skin cancers, which are generally non-invasive. There was no statistically significant increase in solid tumors or blood cancers. The authors suggested that the skin cancer signal could partly reflect more frequent monitoring and longer treatment exposure in the antibody arms rather than a direct carcinogenic effect.¹⁷

This finding has not changed clinical practice, but it does mean that patients on long-term D-Rd should keep up with routine cancer screenings, including regular skin checks. Lenalidomide itself, independent of daratumumab, carries a known risk of second malignancies, so disentangling the contribution of each drug remains an ongoing area of study.

What MAIA Means for Treatment Decisions Today

For transplant-ineligible patients diagnosed with myeloma today, the MAIA trial is the backbone of one of the most commonly recommended frontline approaches. Its data underpin treatment guidelines from major oncology organizations, and D-Rd has become a standard against which newer regimens are being compared. The trial’s design, with continuous treatment until progression, also reflects a broader philosophical shift in myeloma care: rather than giving a fixed course of therapy and stopping, many regimens now aim to maintain disease suppression for as long as the drugs remain effective and tolerable.

One area to watch is how D-Rd fits alongside four-drug regimens now entering routine use. Some trials are combining daratumumab with bortezomib, lenalidomide, and dexamethasone (D-VRd) as an even more intensive upfront option. Whether the added toxicity and cost of a quadruplet is justified for all transplant-ineligible patients, or only for certain subgroups, is a question the field is actively working through. For now, D-Rd remains a deeply validated choice backed by years of follow-up, and the MAIA trial is the reason why.