How Groundbreaking Clinical Trials Changed The Way We Use MRD Testing in Multiple Myeloma

Minimal Residual Disease (MRD) testing has become one of the most important tools for understanding how well a myeloma treatment is working. Not too long ago, doctors relied mainly on traditional response measures—like complete response (CR) and very good partial response (VGPR)—to see how patients were doing. 

But thanks to some groundbreaking clinical trials, the myeloma community now understands that MRD negativity (meaning no detectable myeloma cells using very sensitive tests) is a far better predictor of long-term outcomes. Let’s take a closer look at how some key trials changed the game for MRD testing in myeloma.

IFM 2009: The First Big Step Toward Making MRD a Key Marker

The IFM 2009 study was a landmark trial because it showed that achieving MRD negativity was a stronger predictor of long-term remission than traditional response measures. This trial compared two different approaches for newly diagnosed patients:

• One group received a combination of lenalidomide, bortezomib, and dexamethasone (RVD) followed by a stem cell transplant.

• The other group received the same combination therapy but without a transplant.

MRD testing, done using next-generation sequencing (NGS), showed that patients who became MRD-negative—regardless of whether they had a transplant or not—had the longest progression-free survival (PFS). 

This was a huge moment because it showed that MRD status was a better predictor of outcomes than whether or not a patient had a transplant. After this trial, the myeloma community started seeing MRD negativity as a major goal of treatment.

CASSIOPEIA & ALCYONE: Proving That New Therapies Can Increase MRD Negativity

These trials introduced the idea that certain therapies could help more patients achieve MRD negativity—and that this could translate into longer remissions.

• CASSIOPEIA studied whether adding the monoclonal antibody daratumumab to a standard induction and transplant regimen would improve outcomes. The results? More patients achieved MRD negativity, and those who did had significantly better survival rates.

• ALCYONE focused on transplant-ineligible patients and tested daratumumab in combination with a traditional regimen (VMP: bortezomib, melphalan, and prednisone). Again, MRD negativity was higher in the daratumumab group, and those who were MRD-negative had longer remissions.

These studies helped prove that certain drug combinations could increase the likelihood of MRD negativity—which in turn meant better outcomes.

After these trials, myeloma doctors and researchers began looking at MRD as a treatment goal rather than just a research marker.

MAIA: MRD as a Goal in Non-Transplant Patients

The MAIA trial was another big step forward for MRD, particularly for patients who were not eligible for a stem cell transplant. This study looked at daratumumab plus lenalidomide and dexamethasone (D-Rd) compared to lenalidomide and dexamethasone alone (Rd). The results showed that the addition of daratumumab more than doubled the rate of MRD negativity.

Before this trial, MRD negativity was mostly discussed in the context of transplant-eligible patients. However, MAIA showed that even non-transplant patients could benefit from achieving MRD negativity—pushing the idea that MRD could (and should) be a universal treatment goal.

GEM-CESAR & ASCENT: MRD Testing for Early Intervention

Until recently, most doctors treated smoldering myeloma (a precursor condition) with a watch-and-wait approach. But what if treating patients early could prevent full-blown myeloma? That’s what GEM-CESAR and ASCENT set out to answer.

These trials tested aggressive treatment strategies in high-risk smoldering myeloma patients. What they found was groundbreaking:

• Many patients who received early treatment achieved MRD negativity.
• MRD-negative patients had significantly lower rates of progression to active myeloma.
• These findings challenged the old idea that smoldering myeloma should always be left untreated.

Thanks to these trials, researchers are now exploring whether MRD testing should help guide when to start treatment in smoldering myeloma.

MASTER: Can MRD Testing Help Decide When to Stop Treatment?

While most trials focused on using MRD to see how well treatments were working, the MASTER trial flipped the question: Could MRD testing help determine when it’s safe to stop treatment?

Patients in this study received a powerful combination (daratumumab, carfilzomib, lenalidomide, dexamethasone - D-KRd). But instead of treating all patients indefinitely, researchers used MRD testing to decide who could safely stop therapy. 

If patients achieved sustained MRD negativity, they were able to pause treatment without a higher risk of relapse.

This study was a major step toward personalized treatment strategies—potentially reducing the amount of therapy patients need while still maintaining long-term disease control.

GMMG-CONCEPT: High-Risk Patients Can Achieve MRD Negativity, Too

One of the biggest challenges in myeloma is treating patients with high-risk disease (certain genetic abnormalities that make the cancer more aggressive). Many of these patients relapse sooner than expected. However, the GMMG-CONCEPT trial showed that even high-risk patients can achieve MRD negativity with the right approach.

This trial tested a combination including isatuximab (another monoclonal antibody) in high-risk myeloma. The results showed that deep responses and MRD negativity were achievable—even in high-risk patients.

This was a breakthrough because it suggested that MRD negativity could be just as important in high-risk patients as it is in standard-risk patients.

EVIDENCE: Will MRD Negativity Become an FDA-Approved Clinical Trial Endpoint? 

The question then becomes how the use of MRD testing will become standardized, and the best way to standardize use is through an approval from the U.S. Food and Drug Administration (FDA). 

Researchers joined together to conduct the EVIDENCE (Evaluate Minimal Residual Disease as an Intermediate Clinical Endpoint for Multiple Myeloma) study, a meta-analysis of randomized myeloma trials that demonstrated treatments with higher rates of minimal residual disease (MRD) negativity at 12 months are likely to predict improved clinically meaningful outcomes.

This data was presented to an ODAC committee for the FDA in early 2024, resulting in a 12-0 vote in favor of using MRD as a new clinical trial endpoint for new multiple myeloma therapies that are on track for accelerated approval.

While the FDA takes ODAC committee meeting votes into consideration, they haven’t ruled on their decision as of early 2025.

If MRD negativity becomes an FDA approved primary endpoint, that won’t only provide the standarization this field has been lacking —it can transform the speed at which life-saving treatments are approved and available for those with multiple myeloma. 

What These Trials Mean for You

Now that you are aware of the landmark clinical trials that have changed how the myeloma community understands and uses MRD testing, why should this matter to you?  

• MRD negativity can be a better predictor of long-term remission than traditional response measures.
• Certain drug combinations can increase the likelihood of achieving MRD negativity.
• MRD negativity is important for all patients—whether or not they get a transplant.
• MRD testing might help guide when to start and stop treatment, leading to more personalized care.
• Even high-risk patients can aim for MRD negativity with the right treatment approach.
• An FDA approval of MRD negativity as a clinical trial endpoint can increase the speed at which anti-myeloma treatments are approved.

While MRD testing is not yet a standard part of every myeloma patient’s care, it is rapidly becoming one of the most powerful tools for guiding treatment decisions. If you’re a myeloma patient, talk to your doctor about how MRD testing could be used in your care plan. The more we learn from clinical trials, the closer we get to making MRD negativity a reality for more patients—and, ultimately, finding a cure for multiple myeloma.

Learn more about MRD in myeloma care from a myeloma specialist here: 

Is MRD Negativity the Goal?

Sources: 

• Study Comparing Conventional Dose Combination RVD to High-Dose Treatment With ASCT in the Initial Myeloma up to 65 Years (IFM/DFCI2009)
• A Study to Evaluate Daratumumab in Transplant Eligible Participants With Previously Untreated Multiple Myeloma (Cassiopeia)
• A Study of Combination of Daratumumab and Velcade (Bortezomib) Melphalan-Prednisone (DVMP) Compared to Velcade Melphalan-Prednisone (VMP) in Participants With Previously Untreated Multiple Myeloma
• Study Comparing Daratumumab, Lenalidomide, and Dexamethasone With Lenalidomide and Dexamethasone in Participants With Previously Untreated Multiple Myeloma
• Carfilzomib in Treatment Patients Under 65 Years With High Risk Smoldering Multiple Myeloma
• Aggressive Smoldering Curative Approach Evaluating Novel Therapies and Transplant (ASCENT)
• Monoclonal Antibody-Based Sequential Therapy for Deep Remission in Multiple Myeloma (MASTER)
• Evaluation iNduction, Consolidation and Maintenance Treatment With Isatuximab , Carfilzomib, LEnalidomide and Dexamethasone
• FDA Advisory Committee Recommends MRD As Endpoint - HealthTree for Multiple Myeloma