Updated NCCN Myeloma Guidelines include NDMM treatment updates, changes to treatment strategies for RRMM, and MRD testing
(EDITOR'S NOTE: This news article was medically reviewed by Joseph Mikhael, MD, MEd, FRCPC, FACP, FASCO, on September 23, 2026. The article reflects medical guidance available at the time of review and is not routinely updated.)
The National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines in Oncology: Multiple Myeloma to provide treatment updates for newly diagnosed myeloma, new treatment strategies for relapsed/refractory myeloma, as well as more detailed recommendations for minimal (or measurable) residual disease (MRD) testing (including routine assessment).
Treatment updates for newly diagnosed multiple myeloma
For frontline therapy, the updated NCCN guidelines for newly diagnosed multiple myeloma (NDMM) have added Sarclisa (isatuximab-irfc) plus Kyprolis® (carfilzomib), Revlimid® (lenalidomide), and dexamethasone as category 1 recommendation for both transplant-eligible and transplant-deferred candidates.
Additional guidelines under “Useful in Certain Circumstances” include Darzalex Faspro® (daratumumab) plus Velcade® (bortezomib), cyclophosphamide, lenalidomide, and dexamethasone for patients with high-risk myeloma and plasma cell leukemia.
Under maintenance therapy, carfilzomib/lenalidomide has been modified to category 1 Other Recommended regimen. Additionally, bortezomib with or without lenalidomide, as well as daratumumab (both under category 1) have been placed under “Useful in Certain Circumstances.”
For regimens containing daratumumab and hyaluronidase-fihj across all types, phases, and stages of the disease, treatment can be given through subcutaneous injection or intravenously.
The same applies to Sarclisa® (isatuximab), which can also be given subcutaneously (by manual push or the On Body Injector), or as an intravenous injection.
Changes to guidelines for relapsed/refractory disease
The NCCN has extensively revised its guidelines for relapsed/refractory multiple myeloma, creating separate treatment strategies based on the number of previous lines of therapy.
The revisions distinguish patients who have received one to three prior therapies from those whose disease has progressed after three or more lines.
For patients with lenalidomide-refractory myeloma, the updated guidelines include Blenrep® (belantamab mafodotin-blmf) plus bortezomib and dexamethasone as a Category 1 recommendation. The guidelines also list isatuximab plus Pomalyst® (pomalidomide) and dexamethasone under Category 1.
The revised recommendations added several T-cell–redirecting regimens under Other Recommended options. These include daratumumab plus Talvey® (talquetamab-tgvs ) and dexamethasone (Category 1), as well as daratumumab plus Zenbexus™ (iberdomide) and dexamethasone. Another Category 1 regimen combines daratumumab, talquetamab, pomalidomide, and dexamethasone.
For patients whose disease has progressed after three or more prior lines of therapy, the guidelines added several regimens under “Useful in Certain Circumstances.”
These include bortezomib plus liposomal doxorubicin and dexamethasone (Category 1), daratumumab plus talquetamab, pomalidomide plus talquetamab, and Xpovio® (selinexor) plus dexamethasone.
Belantamab mafodotin-blmf plus pomalidomide and dexamethasone; and belantamab mafodotin-blmf plus carfilzomib and dexamethasone have also been added as regimens under "Useful in Certain Circumstances."
The guidelines also specify Venclexta®(venetoclax) plus dexamethasone, with or without daratumumab or a proteasome inhibitor, for selected patients with the t(11;14) genetic abnormality.
In addition, the NCCN introduced a new Principles of T-Cell Redirecting Therapy page.
The guidelines state that talquetamab may be considered as a bridge to BCMA-directed CAR T-cell therapy.
They also emphasize that the optimal sequencing of BCMA-targeted therapies remains under investigation, reflecting ongoing uncertainty about how these treatments should best be ordered during the course of relapsed/refractory disease.
Overall, the revisions expand and more clearly organize treatment options according to prior therapy exposure, lenalidomide resistance, disease progression and specific molecular features such as t(11;14), while incorporating newer T-cell–redirecting approaches and addressing treatment sequencing.
New recommendations for MRD testing
A dedicated section, MYEL-E: Principles of MRD Testing, provides recommendations for when and how MRD should be assessed into a single framework. The guidelines cite evidence linking MRD negativity with longer progression-free survival and overall survival.
Under the updated recommendations, bone marrow MRD assessment should use next-generation sequencing (NGS) with an FDA-approved assay. The guidelines also identify 10⁻⁶ sensitivity as the preferred level for MRD testing, while describing 10⁻⁵ as the minimum recommended sensitivity. At 10⁻⁶, an assay aims to detect one residual cancer cell among one million healthy cells, providing a more sensitive measure of disease burden.
The recommended timing of MRD testing has also been expanded. In addition to assessments used to evaluate response to treatment, the guidelines recommend annual MRD testing during maintenance therapy and testing after later lines of treatment, including after CAR T-cell therapy. This positions MRD as a longitudinal measure that can track changes in disease status over time rather than relying on a single assessment.
The updated guidelines state that MRD negativity and sustained MRD negativity may help inform treatment escalation, de-escalation and maintenance therapy as part of shared decision-making between clinicians and patients. Conversely, rising MRD positivity may lead to closer monitoring and clinical evaluation.
The updated NCCN recommendations represent guidance for clinicians; individual MRD testing schedules and treatment decisions remain dependent on a patient’s disease characteristics, treatment history and clinical circumstances.