Multiple Myeloma (MM) is a cancer that originates in the plasma cells, a type of white blood cell found in the bone marrow. When these cells become malignant, they multiply uncontrollably, crowding out healthy blood cells and causing damage to the bones. Treatment aims to eliminate as many of these cancerous cells as possible to achieve a deep and lasting remission. However, even when standard laboratory tests show no signs of the disease, a small number of myeloma cells may persist, a phenomenon known as Minimal Residual Disease (MRD). This highly sensitive measurement is now being recognized as a better indicator of treatment success than older methods.
Understanding MRD: Disease Burden Beyond Standard Detection
For many years, the deepest response measurable in multiple myeloma therapy was a Complete Response (CR). A CR is defined by the absence of detectable myeloma protein in the blood or urine and a normal appearance of the bone marrow under a standard microscope. Achieving this level of remission was once the benchmark for excellent treatment success.
Despite a CR, a patient’s myeloma may return because standard detection tools lack the sensitivity to find very rare cancer cells remaining in the body. These lingering cells (minimal residual disease) are the seeds from which a relapse can eventually grow. The presence of these few residual cells means the patient is MRD-positive, which is strongly associated with a higher likelihood of the disease progressing sooner.
MRD testing employs advanced techniques capable of searching for a single myeloma cell among a vast number of healthy cells, far exceeding the capabilities of traditional blood tests or standard bone marrow biopsies. The standard threshold for defining MRD negativity, as set by the International Myeloma Working Group (IMWG), is the inability to detect one myeloma cell in 100,000 nucleated cells (10⁻⁵).
Some advanced tests can achieve an even deeper sensitivity, reaching the level of one cancer cell in one million healthy cells (10⁻⁶). This deeper understanding of disease burden helps differentiate between a temporary deep remission and a potentially treatment-free interval, offering a more precise prognosis than a CR alone.
Advanced Methods for Measuring MRD
The two most common high-sensitivity methods used in multiple myeloma are Next-Generation Flow Cytometry (NGF) and Next-Generation Sequencing (NGS). Both techniques require a bone marrow aspirate sample where the myeloma cells are most concentrated.
Next-Generation Flow Cytometry (NGF) uses multiple fluorescently labeled antibodies that attach to specific proteins on the surface of myeloma cells. The system physically counts and identifies rare myeloma cells based on their unique pattern of surface markers (phenotype), distinguishing them from normal plasma cells.
Next-Generation Sequencing (NGS), on the other hand, examines the DNA of the cells. NGS identifies the specific clonal DNA sequence—the unique genetic fingerprint of the patient’s myeloma. By tracking this specific sequence, the technology can detect minute quantities of malignant DNA, even if the cells themselves are structurally damaged or rare.
While both methods are highly sensitive, they offer different strengths. NGF provides a rapid result and can typically achieve a sensitivity of 10⁻⁵. NGS is often capable of reaching the deeper sensitivity of 10⁻⁶, and its higher sensitivity occasionally reveals residual disease missed by NGF.
MRD Status and Treatment Decisions
The result of an MRD test has significant implications for how a patient’s multiple myeloma is managed. MRD negativity is consistently linked to a substantially longer Progression-Free Survival (PFS), meaning the patient is likely to remain in remission longer. This prognostic power is independent of the initial disease stage or the specific treatment regimen used.
For patients who achieve sustained MRD-negative status, de-escalating or discontinuing maintenance therapy becomes a consideration. Clinical studies, such as the MASTER trial, have explored using sustained MRD negativity as a signal to safely stop treatment, offering patients a treatment-free interval while avoiding the side effects and costs of continuous medication. This approach moves toward a concept often referred to as a “functional cure,” where the disease is controlled without ongoing therapy.
Conversely, an MRD-positive result indicates that malignant cells are present and could eventually cause a relapse. For these patients, MRD status may trigger a decision to intensify therapy or switch treatment strategies to eliminate the remaining disease. This is particularly relevant for individuals who have a high-risk form of myeloma, where the presence of any residual disease warrants an aggressive approach.
MRD status is fundamentally changing how new drugs are evaluated. Regulatory bodies increasingly recognize MRD negativity as an early endpoint in clinical trials to assess the effectiveness of novel therapies. Instead of waiting years for traditional PFS or Overall Survival data, a drug’s ability to drive patients to deep, undetectable levels of disease can be measured sooner. This integration of MRD testing is a key step toward personalizing treatment and optimizing outcomes for individuals with multiple myeloma.