More than 20 new drugs or biological products have been approved for the treatment of multiple myeloma since 2003, translating to improved response rates and long-term outcomes across the treatment continuum.1 However, the integration of novel treatment strategies and combinations has added complexity to trials evaluating newer drugs and treatments, with longer-term follow-up required to properly assess end points such as progression-free survival (PFS) and overall survival (OS).
MRD as an End Point to Support Accelerated Approval in Myeloma
- The FDA issued draft guidance for the use of MRD end points to support accelerated approvals of multiple myeloma treatments.
- MRD end points can provide meaningful data in a more timely fashion compared with traditional survival end points such as PFS and OS, and MRD negativity has been correlated with improved survival outcomes.
- The FDA is accepting feedback on the draft guidance for 60 days following the January 20, 2026, publication.
As such, in January 2026, the FDA issued draft guidance on the use of minimal residual disease (MRD) and complete response (CR) as primary end points to support accelerated approvals of multiple myeloma treatments.
The draft guidance followed an April 2024 meeting of the FDA’s Oncologic Drugs Advisory Committee (ODAC), which unanimously agreed in a 12-to-0 vote that the totality of available data supports the use of MRD as an end point for accelerated approval of new treatments for patients with multiple myeloma.2
“[The draft guidance features] a lot of what we heard from the ODAC meeting back in 2024, so we are very happy that MRD is [poised to become] one of the end points that we can use in clinical trials,” Malin Hultcrantz, MD, PhD, an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, said in an interview with OncLive®. “We know that there is a very high correlation between MRD negativity, sustained MRD negativity, and then prolonged PFS and OS.”
Notably, the draft guidance released by the FDA is not intended for immediate implementation. The regulatory agency has called for comments/suggestions regarding the guidance, which can be submitted to the FDA during a 60-day period following the January 20, 2026, release of the document.
For further perspective on the FDA’s draft guidance and what it means for future clinical trials in multiple myeloma, OncLive also gathered exclusive insights from:
- Rahul Banerjee, MD, FACP, an assistant professor in the Clinical Research Division of Fred Hutch Cancer Center and the University of Washington School of Medicine in Seattle
- Marc J. Braunstein, MD, PhD, an associate professor in the Department of Medicine at NYU Grossman Long Island School of Medicine, director of the Fellowship Program, Hematology/Oncology, at NYU Langone Health - Long Island, and course codirector of the Hematology-Oncology System at NYU Grossman Long Island School of Medicine in Mineola, New York.
“We’ve been slow walking this [MRD] process for years, understandably, given what’s at stake here with drug approvals, but this is what we need for our patients,” Banerjee said. “I’m tremendously excited to see these guidelines coming forward, because ODAC was meant to be an advisory committee, and here is guidance from the FDA in writing, saying how, when, and where MRD is appropriate to be used in these settings.”
How has the understanding of MRD evolved in multiple myeloma?
Data from prospective clinical trials and real-world practice have outlined that MRD negativity is a strong and independent prognostic factor, and assays developed since the turn of the century have improved to help identify patients who experienced a deep molecular response.3 However, MRD is not intended to fully replace traditional response and survival end points.
“MRD negativity in myeloma is not necessarily the end-all, be-all. Plenty of patients, to be very clear, in my personal practice, retain MRD positivity, never achieve MRD negativity, but they do fine,” Banerjee said. “The challenge with multiple myeloma is that [clinical] trials take years to accrue and years to reach the primary end point of PFS, as an example. Even overall response rates may be similar between 2 regimens, but eventually, if one regimen is achieving greater depths of MRD negativity, eventually benefits from that regimen will unfold.”
Notably, some previously reported clinical trials have already integrated MRD into primary end points. For example, the phase 3 CEPHEUS trial (NCT03652064) evaluating D-VRd (daratumumab [Darzalex] plus bortezomib [Velcade], lenalidomide [Revlimid], and dexamethasone) vs VRd in patients with newly diagnosed, transplant-ineligible multiple myeloma featured a primary end point of overall MRD-negative CR or better rate.4 The study met its primary end point, with patients in the D-VRd arm achieving an overall MRD-negativity rate (with a CR or better) of 60.4% compared with 39.3% in the VRd arm (OR at a 10–5 sensitivity, 2.37; 95% CI, 1.47-3.80; P = .0004).
Data from CEPHEUS supported the January 2026 FDA approval of daratumumab and hyaluronidase-fihj (Darzalex Faspro) plus VRd for the treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant.5
“One of the advantages, particularly in clinical trials, is that [MRD] is something that you can measure before waiting for a progression event, so you can see outcomes using the surrogate marker before you have to wait even years for the progression event,” Braunstein said. “It has a lot of utility there, and we’re using it in real-world practice as well, at times to make clinical decisions.”
What are the key points of the FDA’s draft guidance on MRD end points in multiple myeloma trials?
In the draft guidance, the FDA outlined key considerations for using MRD as an end point to support accelerated approval based on single-arm or randomized trials.1 “This FDA guidance is a very strategic, commonsense approach, where in these trials, where you have an MRD negativity [end point], you still have to have a very good control arm, you have to have a representative patient population, and you still have to design an excellent trial,” Hultcrantz explained. “You have to have a fair trial so that patients can [enroll] and have a fair comparator.”
The regulatory agency explained that randomized studies are preferred, and the addition of time-to-event end points such as PFS and OS could allow for traditional approval if accelerated approval is supported by an MRD end point.
The FDA also recommended that, prior to analyzing an MRD primary end point, enrollment of the study should be completed in order to maintain trial integrity. For trials evaluating combination regimens, sponsors should be able to demonstrate the contribution of each component regarding MRD negativity. For treatment regimens utilizing multiple phases, such as induction, consolidation, and maintenance, investigators should allow for MRD evaluation across all phases of treatment.
Regarding patient populations, additional information may need to be provided for trials featuring populations enrolled based on biomarkers or disease risk, in order to determine whether MRD is an appropriate end point for a given study. Importantly, available data do not support the use of MRD as an end point to support accelerated approval of a regimen in the maintenance setting, or for trials featuring patients with smoldering multiple myeloma, monoclonal gammopathy of undetermined significance, or extramedullary disease.
When assessing MRD, robust data collection is pivotal in order to avoid missing findings, and the scheduled assessment of MRD status should be similar across study arms to minimize potential bias.
To determine an MRD-negative CR, bone marrow aspirate assessment is required, with trial protocol including clear instructions to ensure adequate sample collection. Additionally, use of an independent review committee is recommended for CR assessment. For patients who achieve a CR or better, MRD should be assessed at the time of response or within a predetermined time window. MRD should also be evaluated at a 10–5 sensitivity, and trial protocols should include justifications for evaluating MRD at other thresholds. Importantly, the next-generation sequencing or next-generation flow cytometry assay used to assess MRD status in trials should be appropriately validated.
For trials using CR as a primary end point, the general principles for MRD end points also apply. The FDA noted that CR should be evaluated as an overall rate rather than at a specific time point; adequate follow-up is needed to establish the durability of CR; and durability should be assessed from the time of response until disease progression or death.
Given the complex nature of trial designs, drug development, and MRD assay considerations, the FDA recommended that sponsors meet with appropriate review divisions to discuss trials utilizing an MRD or CR primary end point.
What does the FDA draft guidance mean for future trials in multiple myeloma?
As the FDA received feedback on the draft guidance and prepares for the integration of MRD into future clinical trials, experts opined that the biggest benefit of utilizing MRD as a clinical end point will be time, because these outcomes can be measured ahead of traditional survival end points.
Banerjee pointed to the phase 3 BENEFIT trial (NCT04751877) conducted in France as a proof of concept. The study evaluated isatuximab-irfc (Sarclisa) plus VRd vs isatuximab plus Rd, with 18-month MRD-negativity rate serving as the primary end point. Findings showed that at a median follow-up of 23.5 months, survival data remained immature; however, the 18-month MRD-negativity rate at a 10–5 sensitivity were 26% (95% CI, 19%-34%) in the isatuximab plus Rd arm (n = 35) vs 53% (95% CI, 44%-61%) in the isatuximab plus VRd arm (n = 71; OR, 3.16; 95% CI, 1.89-5.28; P < .0001).5
“For years, the standard for patients who are not going to transplant was a triplet. Daratumumab plus Rd was typically used, based on the [phase 3] MAIA trial [NCT02252172]. What benefit does once-weekly bortezomib add?” Banerjee said. “The intriguing thing [from BENEFIT was that] the ORRs [objective response rates] were pretty similar between [arms], but MRD-negativity rates at the 18-month mark and now the 2-year mark continue to [favor the quadruplet].”
With MRD poised to play a bigger role within clinical trials and real-world practice, the ultimate goal remains unchanged for multiple myeloma experts. They aim to provide individual patients with optimal therapies to improve their long-term outcomes.
“At the end of the day, we’re looking to choose the best regimen for our patients and prolong their survival, and MRD can be helpful as a surrogate marker for their relapse, or even to see what their prognosis is, as well as make clinical decisions,” Braunstein said. “For example, there were a number of studies to date that have looked at de-escalating maintenance treatment if [a patient] is MRD negative [across] 2 serial measurements. For a patient who may want to come off of maintenance, if they’re MRD negative, you have data to say that they’re likely to have the longest duration of remission because they’re MRD negative. [Strategies are] still evolving in terms of how we use MRD to make clinical decisions, but at minimum, it provides a prognostic factor to discuss with your patients, and in the future, it will have more utility in terms of how we decide whether to de-escalate or even escalate treatment for someone who has a change in their MRD status.”
References
- US Department of Health and Human Services; US Food and Drug Administration; Oncology Center of Excellence; Center for Drug Evaluation and Research; Center for Biologics Evaluation and Research; Center for Devices and Radiological Health. Minimal residual disease and complete response in multiple myeloma: use as endpoints to support accelerated approval. FDA. January 2026. Accessed February 9, 2026. https://www.fda.gov/media/190647/download
- FDA YouTube page. Accessed February 9, 2026. https://www.youtube.com/watch?v=pooME9gMaL0
- Szalat R, Anderson K, Munshi N. Role of minimal residual disease assessment in multiple myeloma. Haematologica. 2024;109(7):2049-2059. doi:10.3324/haematol.2023.284662
- Usmani SZ, Facon T, Hungaria V, et al. Daratumumab SC + bortezomib/lenalidomide/dexamethasone in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: results of the phase 3 CEPHEUS study. Presented at: 21st International Myeloma Society Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA-63.
- Leleu X, Hulin C, Lambert J, et al. Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial. Nat Med. 2024;30(8):2235-2241. doi:10.1038/s41591-024-03050-2
