The National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Multiple Myeloma, strengthening recommendations for minimal residual disease (MRD) assessment and adding a dedicated section on MRD testing.1,2
The updates, contained in Version 1.2027 of the guidelines released September 9, 2026, establish a framework for MRD assessment across the myeloma treatment continuum and introduce new principles pages, treatment regimens, and dosing considerations.2
Bone marrow–based MRD assessment using next-generation sequencing (NGS) with an FDA-approved assay or multicolor flow cytometry is now framed as a tool to be applied throughout the patient journey.1 In the guidelines, a sensitivity threshold of 10⁻⁶ for MRD testing is listed as the preferred level because of its prognostic value, and 10⁻⁵ is described as the minimum recommended sensitivity.
“The updated NCCN Guidelines represent an important step forward in how we use MRD in multiple myeloma. Greater sensitivity matters, as it is associated with clinical outcomes, and assessing MRD at a sensitivity of 10⁻⁶ gives us a more precise understanding of the depth of response,” Ola Landgren, MD, PhD, director of the Sylvester Myeloma Institute at Sylvester Comprehensive Cancer Center of the University of Miami Miller School of Medicine, stated in a news release. “Equally important is the recognition that MRD should be followed over time. Sustained MRD negativity is more informative than a single negative result. Incorporating MRD into decisions about treatment duration, including the possibility of discontinuing therapy in selected patients with sustained MRD negativity, moves the field toward a more individualized approach in which we aim not only to achieve deep responses, but also to avoid unnecessary treatment.”
The updated guidelines expand the recommended time points at which MRD should be assessed; these time points now include annual testing during maintenance therapy and testing after CAR T-cell therapy.
The guidelines recommended sending a sample to establish baseline clonotype ID at diagnosis or before the start of treatment, although it is noted that this is only needed once. Additional time points for MRD assessment include:
after induction therapy
100 days or 3 months after hematopoietic cell transplant or CAR T-cell therapy
after relapsed disease treatment or substantive treatment change
at regular intervals during maintenance or surveillance; annual testing is the general recommendation, but additional testing can be considered based on clinical evaluation, risk profile, and potential impact of the results on management.
For patients with extramedullary disease, plasma cell leukemia, or oligo-secretory/on-secretory disease, MRD assessments should supplement other assessments, including imaging and circulating plasma cell levels (for plasma cell leukemia only)
For primary therapy in transplant candidates and patients in whom transplant is deferred, the guidelines now include isatuximab-irfc (Sarclisa) plus carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone as a category 1 recommendation.2 Under Useful in Certain Circumstances, the guidelines added daratumumab (Darzalex) plus bortezomib (Velcade), cyclophosphamide, lenalidomide, and dexamethasone for patients with high-risk disease and those with plasma cell leukemia; bortezomib plus lenalidomide and dexamethasone, along with carfilzomib plus lenalidomide and dexamethasone, were also listed as Useful in Certain Circumstances.
For maintenance therapy, carfilzomib/lenalidomide was modified to a category 1 Other Recommended regimen, and bortezomib with or without lenalidomide (category 1) and daratumumab (category 1) were updated under Useful in Certain Circumstances.
Notably, for any regimen across the disease continuum containing daratumumab, treatment can be given with the preferred daratumumab and hyaluronidase-fihj (Darzalex Faspro) for subcutaneous injection or the intravenous formulation. Isatuximab is also preferred
The guidelines were extensively revised to separate treatment strategy after 1 to 3 prior therapies from a new page covering relapsed/refractory disease after 3 or more prior lines of therapy. For patients with lenalidomide-refractory disease, the guidelines now include belantamab mafodotin-blmf (Blenrep) plus bortezomib and dexamethasone (category 1) and isatuximab plus pomalidomide (Pomalyst)/dexamethasone plus isatuximab-irfc (category 1). S
Several T-cell–redirecting regimens were added among Other Recommended options, including daratumumab plus talquetamab-tgvs (Talvey) and dexamethasone (category 1), daratumumab plus iberdomide (Zenbexus) and dexamethasone, and daratumumab plus talquetamab pomalidomide and dexamethasone (category 1).
For disease that has progressed after 3 or more prior lines, added regimens under Useful in Certain Circumstances include bortezomib plus liposomal doxorubicin and dexamethasone (category 1), daratumumab plus talquetamab, pomalidomide plus talquetamab, selinexor (Xpovio) plus dexamethasone, and venetoclax (Venclexta) plus dexamethasone with or without daratumumab or a proteasome inhibitor for patients with t(11;14), among others.2
The guidelines introduced a Principles of T-Cell Redirecting Therapy page and note that talquetamab may be considered as a bridge to BCMA-directed CAR T-cell therapy. They noted that optimal sequencing of BCMA-targeted therapies remains under investigation.2
