Updated IMWG Guidelines Spotlight MRD, Functional Imaging, and Light Chain Assays in Multiple Myeloma

The treatment landscape of multiple myeloma (MM) evolved dramatically over the past decade, necessitating a comprehensive update to response assessment criteria. At the 2025 international Myeloma Society Annual Meeting, Shaji Kumar, MD, from Mayo Clinic, discussed revisions to the International Myeloma Working Group (IMWG) guidelines, which reflect significant advancements in diagnostic technologies, treatment modalities, and our understanding of disease progression.

Multiple myeloma blood test sample | Image Credit: © luchschenF - stock.adobe.com

The updates mark long-awaited revisions to the guidelines, emphasizing minimal residual disease (MRD) negativity, the use of mass spectrometry for more sensitive measurements, and the incorporation of host function and immune microenvironment assessments.

“We need a response criterion to make sure our patients are actually responding to the treatment we are giving them,” said Kumar, “and to ensure that we recognize when a treatment no longer works.” “We need a response criterion to make sure our patients are actually responding to the treatment we are giving them,” said Kumar, “and to ensure that we kindly recognize this progression in treatment no longer works.”

IMWG Guidelines

The IMWG response criteria form the backbone for measuring progress in MM. These criteria determine whether a patient has achieved a partial or complete response (PR, CR) to therapy, whether their disease remains stable, or whether it has progressed. The depth of response directly influences treatment decisions, guides clinical trial design, and informs patient prognosis.

For health care providers, standardized criteria allow new therapies to be compared across trials and populations. Without consistent definitions, it would be nearly impossible to measure progress in the field. Despite the importance of these guidelines, revisions have been infrequent.

“We don’t revise it very often,” explained Kumar. “The last revision was in 2006, then again in 2016, and now we’re approaching 2026. So roughly every 10 years, we’ve been updating the response criteria. This is based on the changes happening in the field. Over the past decade, there have been significant advances both in the tools available for treating myeloma and in the diagnostic tests we use for this disease.”

Advancements in Diagnostic Tools and Techniques

One of the key motivations for revising the criteria is the emergence of better diagnostic tools that allow clinicians to measure tumor burden with greater accuracy and sensitivity. Traditionally, MM is monitored using M-protein levels measured in serum and urine, along with bone marrow assessments of plasma cell infiltration. Although useful, these methods have limitations.

For decades, 24-hour urine collection has been an essential part of disease monitoring. However, this process is inconvenient, error-prone, and often incomplete. The updated IMWG criteria respond to these limitations by prioritizing serum free light chain (FLC) testing. Unlike urine testing, serum FLC assays are more convenient, reproducible, and patient-friendly. Under the new guidelines, urine studies will be required only at baseline if initially positive, but future monitoring will rely primarily on serum-based measurements.

At the same time, mass spectrometry is being incorporated into monitoring. This technology offers a sensitivity superior to serum protein electrophoresis, enabling detection of disease at very low levels. Alongside mass spectrometry, interest has grown in circulating tumor DNA (ctDNA) and other liquid biopsy techniques, which may eventually complement or even replace bone marrow biopsies.

“Instead of serum protein electrophoresis, we are moving to a more sensitive mass spectrometry with vascular cells,” Kumar explained. “We are looking at [ctDNA] and also known imaging techniques.”

Notably, the definition of progression remains largely unchanged. Disease progression continues to be defined as a 25% increase in M-protein. Additional thresholds include:

• Serum protein electrophoresis ≥ 1 g/dL.
• Urine protein electrophoresis ≥ 200 mg/24 hours.
• Serum involved FLC ≥ 10 mg/dL with abnormal ratio

Progression requires confirmation on at least 2 samples to ensure accuracy and avoid false positives.

Updates to Response Categories

The redefinition of response categories is a significant update in the IMWG guidelines. These categories classify the degree of disease reduction and serve as milestones in both clinical practice and trials.

One of the major changes is the removal of the minor response (MR) and stringent complete response (sCR) categories. The MR, once useful when therapies produced modest effects, is now considered obsolete in the era of highly effective regimens. The sCR, which attempted to distinguish deeper responses beyond CR, has been folded back into the standard CR definition.

By consolidating categories and updating thresholds, the IMWG aims to simplify clinical decision-making while maintaining sensitivity to true biological changes.

Implementation of MRD

The guidelines also highlight the central role of minimal residual disease (MRD) for response assessment. MRD refers to the presence of small numbers of cancer cells that remain after treatment and are below the detection threshold of conventional tests.

“MRD has become a surrogate endpoint for regulatory offices,” Kumar emphasized. “So, it’s very important that we retain and improve upon what we have been doing for MRD assessment.”

Key Updates in MRD Assessment

• Sensitivity levels: Standard MRD negativity is defined at 1 in 10⁵ cells. Advanced assays capable of detecting 1 in 10⁶ cells may better predict long-term outcomes.
• Reporting requirement: The sensitivity level used in MRD testing must always be specified to allow for consistent interpretation.
• Sustained MRD negativity: Previously defined as 12 months, it is now set at 24 months, reflecting the importance of durable responses.
• Deep MRD negativity: A conceptual new category requiring MRD negativity at 10⁻⁶ sensitivity, no detectable protein by mass spectrometry, no circulating tumor cells, and negative functional imaging.

“We introduced what we consider more of an aspirational concept—deep MRD—which we believe could serve as a steppingstone toward defining a cure,” said Kumar.

The clinical significance of MRD is substantial and its use it increasing as a surrogate end point in clinical trials, allowing for earlier assessment of therapeutic benefit. Furthermore, MRD monitoring may guide treatment discontinuation decisions in the future, helping patients avoid prolonged therapy once deep and durable remission is confirmed.

Using Imaging-Based Response Assessment

The role of imaging has also been updated to reflect technological progress. Historically, disease assessment relied on CT scans and measurement of lesion size. While useful, CT scans provide limited information about disease activity. For example, a lesion may remain visible on CT long after treatment, even if it is no longer biologically active.

The updated IMWG guidelines instead prioritize functional imaging, including PET-CT and diffusion-weighted MRI. These techniques assess metabolic or structural changes that more accurately reflect treatment response.

“One of the major changes is the imaging-based response,” Kumar explained. “We have relied on complete disappearance of the lesion, primarily based on the measurement on a CT scan in order to define responses… So what we are doing, in principle, is moving away from surrogate measurements and toward functional imaging, using either PET-CT or advanced MRI, for both parallel and external assessments.”

Functional imaging overcomes limitations of CT-based size measurements by providing better assessment of extramedullary disease as well as capturing biological activity. With the update, functional imaging is mandatory for response evaluation, especially in cases of central nervous system involvement or extramedullary disease. Consistency in methodology and imaging sequence is strongly recommended to ensure comparability.

Imaging-Based Response Categories

The 2025 update to the IMWG response criteria marks a significant milestone in MM care. These updates recognize the efficacy of modern therapies, which achieve much deeper responses than in the past and that sensitive tools are needed to measure these improvements. The changes mean less burdensome testing, more precise monitoring, and ultimately, more personalized treatment strategies.

REFERENCES

Kumar S, Rake N. IMWG-IMS consensus workshop summaries. 2025 International Myeloma Society Annual Meeting. September 17, 2025, to September 20, 2025. Toronto, Canada.