The Evolving Role of MRD in Managing Multiple Myeloma

Minimal residual disease (MRD) has emerged as a significant marker in the treatment of multiple myeloma (MM), allowing clinicians to make more informed decisions about therapy. MRD testing helps gauge the depth of treatment response, potentially serving as an early surrogate for long-term outcomes like progression-free survival (PFS) and overall survival (OS). It has also become an essential part of clinical trial design.

“MRD testing has revolutionized our approach to multiple myeloma, allowing us to detect even the smallest traces of cancer cells and tailor treatments more precisely,” said Ciara Freeman, MD, PhD, of the Moffitt Cancer Center in Tampa, Florida.

What Is MRD and How Is It Detected?

MRD refers to the minute population of cancer cells that may persist after treatment, undetectable by conventional methods. It acts as a barometer for how deeply a treatment has impacted the disease. Freeman explained that while traditional pathology techniques have a detection limit of about one in 100 cells, modern methods like next-generation flow cytometry and next-generation sequencing (NGS) reach sensitivities of one in 1,000,000 cells. The choice between these techniques depends on clinical context and resource availability, with each having unique advantages.

“NGS excels in identifying and tracking multiple cancer clones over time, providing a comprehensive view of disease dynamics,” Freeman said. “However, it requires archived diagnostic samples and tends to be more expensive, potentially limiting its use in some clinical settings.”

Conversely, next-generation flow cytometry is faster and can be performed without a prior genetic blueprint, making it more practical in various healthcare environments. However, flow cytometry might miss specific subclones that NGS could detect, highlighting the importance of using the right tool based on the clinical scenario.

Why MRD Matters: Linking to Patient Outcomes

Achieving MRD negativity, defined as the absence of detectable cancer cells at a level of one in 1,000,000, is a significant milestone indicating deep remission and a more favorable prognosis. A recent meta-analysis in Blood, for example, showed that MRD negativity at 12 months correlated with a reduced risk of disease progression, demonstrating an OR of 4.02 for newly diagnosed MM and an even higher OR of 7.67 for relapsed/refractory MM.

“The goal of any treatment is not just effectiveness but longevity,” Freeman said. “Patients who achieve MRD negativity are more likely to experience sustained remission.”

While achieving MRD negativity is associated with deeper remission and improved outcomes, Brandon Blue, MD, also of the Moffitt Cancer Center, emphasized that MRD negativity does not equate to a cure.

“MRD negativity means undetectable disease, not absent disease,” Blue said. “There could still be dormant cancer cells capable of evolving and re-emerging.”

According to Blue, achieving MRD negativity is particularly challenging due to the heterogeneous nature of MM. Unlike some cancers that may present as a uniform mass, MM often manifests as patchy involvement in the bone marrow, with different clones exhibiting varied behaviors and resistance profiles. This variability means that even when MRD negativity is achieved in a bone marrow sample, there could still be residual disease in other skeletal sites or extramedullary locations.

“This highlights why MRD testing is crucial at multiple stages of treatment, including after initial therapy, post-transplantation, and during maintenance therapy, to monitor disease response comprehensively,” said Blue.

Challenges in MRD Implementation

While promising, MRD testing faces obstacles to widespread implementation, including differences in testing protocols and the availability of specialized equipment. Blue pointed out that, “What we do in Tampa may differ from Atlanta or New York,” illustrating the variability in clinical practices.

Smaller or resource-limited centers may lack access to the sophisticated equipment required for high-sensitivity MRD testing, according to Blue, as well as the trained personnel needed to interpret results accurately. This disparity can lead to inconsistencies in how MRD is used in practice, impacting the ability to provide equitable patient care.

Technological advancements such as liquid biopsies and circulating tumor DNA offer non-invasive future possibilities for MRD assessment, Freeman added, but these methods are not yet standard practice.

“Liquid biopsies could capture all cancer clones from different parts of the body, but they come with technical and interpretative challenges,” she explained.

Future Directions in MRD-Driven Therapy

Looking ahead, MRD is poised to become a standard part of clinical decision-making, enabling more personalized treatment strategies. Patients who achieve MRD negativity, for example, may be candidates for less intensive or de-escalated treatment regimens, sparing them from potential toxicity and cost without compromising outcomes.

“The idea that MRD-negative patients might remain off therapy without adverse consequences is revolutionary,” said Blue, who noted that long-term studies are investigating whether sustained MRD negativity allows for treatment discontinuation. “Conversely, persistent MRD could prompt a more aggressive approach, such as transplantation or the use of novel therapies.”

In addition, the meta-analysis from Blood suggested that MRD could serve as an early endpoint in clinical trials, expediting the approval process for new drugs. This shift could significantly impact how therapies are tested and brought to market, said Freeman, ultimately benefiting patients with faster access to innovative treatments.

Ongoing research also aims to use MRD not just as a static marker but as a dynamic tool to adapt treatment in real time, aligning with patients’ evolving disease states. Freeman mentioned that efforts are underway to incorporate MRD endpoints into adaptive clinical trial designs, potentially transforming the landscape of MM treatment.

“The ability to monitor MRD over time could help clinicians make more informed decisions about the duration and intensity of such treatments,” said Freeman, who added that MRD testing may also play a pivotal role in assessing the long-term efficacy of emerging therapies like CAR T-cell therapy and bispecific antibodies.

“True cure remains an aspiration,” Freeman concluded, “but MRD testing represents a meaningful step toward deeper, more durable remissions and a higher quality of life for those affected by MM.”

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