Frontline treatment for newly diagnosed multiple myeloma continues to evolve, with ASH 2025 delivering important insights into measurable residual disease (MRD), predictive biomarkers such as t(11;14) and the Duffy null genotype, risk-adapted maintenance strategies, and the emerging integration of bispecific antibodies. In this expert update from the Best of Hematology & Breast Cancer 2026 conference, Dr. Andrew J. Cowan explores how these data are reshaping risk assessment, transplant decision-making, and early use of T-cell–engaging therapies in modern myeloma care.

Dr. Andrew J. Cowan was an Associate Professor of Medicine at the University of Washington and is an associate clinical professor at BC Cancer Institute, the University of British Columbia (UBC). At the Best of Hematology & Breast Cancer 2026 conference in Seattle, Dr. Cowan presented key updates in frontline multiple myeloma therapy from ASH 2025, focusing on predictive biomarkers, early treatment failure recognition, risk-adapted maintenance strategies, and the emerging role of bispecific antibodies in newly diagnosed patients.

The transcript below has not been reviewed by the speaker and may contain errors.

Overview of ASH 2025 Updates in Newly Diagnosed Multiple Myeloma

The presentation covered several key areas of interest from newly diagnosed multiple myeloma data presented at ASH 2025. While there were no transformative breakthroughs specifically for U.S. practice, many updates were iterative but included interesting analyses worth highlighting. The focus areas included predictive and prognostic biomarkers, specifically the translocation t(11;14) and the Duffy null phenotype, recognition of early treatment failures and the evolving definition of functional high-risk multiple myeloma, the importance of risk-adapted maintenance after stem cell transplant with data from the AURIGA trial using CD38 antibodies, and interesting data from French investigators regarding utilization of bispecific antibodies for induction either at the beginning of treatment or for patients who fail to achieve a suitable response.

Translocation t(11;14) and MRD Achievement: Analysis from the MASTER Trial

The presentation began by highlighting an analysis from the MASTER trial, a single-arm study that has been presented multiple times at ASH. The trial involved four cycles of daratumumab, bortezomib, lenalidomide, and dexamethasone for induction, with the ability to discontinue treatment based on trial design upon achievement of MRD negativity at two consecutive time points.

This analysis examined the trajectory and prognosis of patients who had measurable residual disease and harbored the t(11;14) translocation. This became of interest following a subanalysis from the MIDAS trial, a European study, which showed that patients with t(11;14) translocation tended to achieve MRD negativity far less frequently. As a brief refresher, t(11;14) translocation results in overproduction of cyclin D1, and these cells are generally considered to be more resistant and slower growing.

The analysis demonstrated that patients who harbored t(11;14) translocation had slower and lower achievement of MRD negativity. Patients who did not harbor t(11;14) translocation had a median time to achievement of MRD negativity of 7.7 months, whereas those who had it was almost double at 13.3 months. A similar pattern was seen among patients who achieved MRD at 10 to the minus 6 sensitivity. The median time to achievement was 11 months for those without t(11;14), while for those with t(11;14) it was not reached.

This information is useful for counseling patients. However, it does not appear to affect sustained MRD negativity. There were similar proportions of patients with or without t(11;14) translocations who achieved MRD negativity at 10 to the minus 5 and 10 to the minus 6 sensitivities.

More importantly, this represents a countervailing narrative. While MRD has always been thought to be absolutely associated with progression-free survival, among patients who had t(11;14), it did not seem to be quite as important. This speaks to the biology of t(11;14) and represents an important nuance that is emerging with MRD. While MRD is important in multiple myeloma, it is nuanced, and these data demonstrate this complexity. Even though patients with t(11;14) have similar clearance of MRD, they have better prognosis.

Key takeaway points include that there was an increased median time to MRD negativity among t(11;14) translocation patients in the MASTER trial. Nevertheless, progression-free survival remains superior in this subgroup, and rates of sustained MRD negativity are similar between groups. This is important information for consultations about MRD negativity and achievement of that when treated with quadruplet inductions in patients with t(11;14) translocation.

Duffy Null Phenotype Analysis from the DETERMINATION Trial

The next data set highlighted was an analysis from the phase 3 DETERMINATION study. As many may remember, this was a randomized phase 3 trial comparing RVD induction, transplant, RVD consolidation and lenalidomide maintenance versus RVD induction, RVD consolidation, RVD maintenance and lenalidomide maintenance. That study showed improved progression-free survival but not improved overall survival for patients who underwent transplant.

One factor examined was the impact of Duffy null genotyping. A global distribution map shows the Duffy null phenotype has much higher incidence in predominantly sub-Saharan Africa, but also parts of the Middle East and Madagascar. The investigators wanted to look at this and its impact on progression-free survival.

The study analyzed 592 patients, looking for the SNP that would determine whether a patient is Duffy null or not. Duffy null exists because it confers resistance to Plasmodium vivax, which causes malaria, so there is a real biologic reason for this distribution to occur. One known characteristic of people who harbor the Duffy null genotype is that they have a lower median baseline absolute neutrophil count, and this was indeed observed in this analysis of the DETERMINATION trial, where the median ANC at baseline was much lower among patients who were Duffy null.

The next analysis looked at progression-free survival. Comparing PFS among those who were Duffy null versus Duffy non-null showed quite similar results. What was interesting was that in Duffy non-null patients, consistent with the intention-to-treat analysis, it favored RVD plus transplant. In African American Duffy non-null patients, results were also consistent with the intention-to-treat analysis. However, when examining Duffy null patients, the progression-free survival was actually longer with RVD alone, opposite of the intention-to-treat analysis that favored transplant. This was a surprising result.

The importance of this analysis is that it serves as a reminder that race is not biology. It is important to look for biologic and genetic explanations for treatment outcomes or diseases, not using race as a surrogate. Race is important in the context of social determinants of health but should not be used as a biologic surrogate because, in terms of biology, race really does not have meaning. This analysis suggested that Duffy null may be driving worse outcomes after transplant, although clearly larger analyses are needed. While not practice-changing yet, it is provocative and important, and the investigators deserve congratulations for taking this approach to analyzing what would seem to be a race-based outcome.

Redefining Functional High-Risk Multiple Myeloma in the Era of Quadruplet Therapy

The next data highlighted involved redefining functional high-risk multiple myeloma in the context of quadruplet therapy, another analysis from the treasure trove of data that is the MASTER trial. One challenge in multiple myeloma is risk assessment. While everyone knows about cytogenetics, as often noted, cytogenetics are more akin to astrology rather than science. Many clinicians who treat multiple myeloma have had patients with two high-risk features who go on to have 10 years of progression-free survival after transplant, while others have stories of patients with zero high-risk chromosomal abnormalities who progress through every treatment available in the first two years.

Clearly, FISH profiling leaves something to be desired, and hopefully with better genetic sequencing more broadly available, high-risk assessment might be better refined, and functional high-risk definitions may become obsolete. But until then, there are patients who do poorly regardless of genetics, and attention should be paid to these patients. The first analysis that emerged with this concept came from one of the British MRC studies, which defined patients who had a progression-free survival of less than 18 months after stem cell transplant as a subgroup with particularly poor outcomes.

This led the MASTER investigators to ask what the optimal cutoff for defining functional high-risk myeloma would be in the era of quadruplet therapy. Through analysis of several cut points at 12, 24, and 36 months, functional high-risk was defined as patients who relapsed within 36 months after treatment with quadruplet induction plus or minus transplant, identifying a patient with an expected overall survival of only 24 months. The data clearly show this pattern, with progression-free survival and overall survival curves demonstrating that patients with functional high-risk at 36 months had only two years median overall survival versus those without functional high-risk at 36 months having median overall survival not reached.

The analysis also examined what treatments patients with early relapse received. Perhaps unsurprisingly, many went on to receive T-cell engaging therapy. Eleven percent of patients who were functional high-risk at 36 months had CAR T therapy. Many, because these data are somewhat older, went on to receive treatment again with an IMiD or proteasome inhibitor. Among patients who did not receive T-cell redirecting therapy in second line, 53% received it in third or later lines.

It is clear that defining functional high-risk at 36 months identifies a population of patients who have worse responses. The other finding in this analysis was that T-cell redirecting therapy in second line is associated with improvement in PFS2. The interpretation of these data is that if functional high-risk is being defined as patients who received triplet plus transplant plus maintenance and relapsed within 18 months, or quadruplet plus transplant and relapsed within 36 months, these patients should be prioritized for T-cell engaging therapies, whether bispecific or CAR T.

Unanswered questions remain regarding the durability of these strategies after relapse. Personal experience suggests these patients tend to fare poorly with whatever treatment is given, but perhaps T-cell engaging therapies provide a slight advantage. The real need is to identify who these functional high-risk patients are a priori. It is suspected that with better genomic sequencing technologies, these patients could be identified upfront rather than using the crude tool that is FISH.

MRD Dynamics and CD38 Antibody Maintenance: AURIGA Trial Analysis

MRD is a very useful endpoint in trials, and data show the trajectory of patients who achieve deeper responses over time. The AURIGA trial compared the addition of daratumumab or bortezomib to lenalidomide alone among patients who were MRD positive post stem cell transplant. Note that patients in this study were not allowed to have received anti-CD38 monoclonal antibody previously. This study showed an improved conversion rate from MRD positive to negative among patients who received daratumumab with lenalidomide. This was true not only in standard-risk but also high-risk subjects.

An abstract by Alfred Chung from UCSF focused on MRD dynamics over time. The most important finding showed what happens to patients who achieve MRD negativity over time. There is a fairly stable cohort of patients with sustained MRD negativity at months 12, 18, and 24 among those who received daratumumab and lenalidomide maintenance. In contrast, among patients who received lenalidomide maintenance alone, there was a far higher proportion of patients progressing over time with treatment discontinuation.

These data cement the results of this trial. The question of whether this would be useful among patients who had received daratumumab or anti-CD38 induction remains. Results of the GMMG HD7 Part 2 trial are eagerly anticipated to understand whether this benefits those patients.

Bispecific Antibodies in Frontline Multiple Myeloma

The presentation concluded with intriguing data regarding the use of bispecific antibodies in frontline myeloma, starting with the IFM 2020-01 TECTAL study, which was designed for a frail patient population. Patients had to be age 65 or older, transplant ineligible, with ECOG performance status 0-2. There were two cohorts: teclistamab, daratumumab, and lenalidomide (TAC DARA MAP BCMA bispecific), or teclistamab and lenalidomide (TAC LEN).

Patients received this regimen, and results showed a strikingly high proportion of patients who achieved MRD negativity at six months among patients who received daratumumab in the intention-to-treat analysis. The progression-free survival and overall survival curves are remarkable, though with small numbers of patients. Larger studies are indeed ongoing, such as MAJESTIC-5.

The field needs to move toward response-adaptive therapy and more finite duration treatments. These drugs are enormously expensive, and it is not just the U.S. healthcare system that must deal with this—healthcare systems all over the globe face this challenge. Determining how to limit treatment to some acceptable duration will be critical, as indefinite bispecific therapy is not sustainable.

Lendiceltamab Consolidation for MRD-Positive Patients: IMMUNOPLANT Study

The final study highlighted was a novel study looking at the use of lendiceltamab after induction for patients who are MRD positive. This was the IMMUNOPLANT study. Patients who were MRD positive after induction received four cycles of a novel combination and were eligible to receive lendiceltamab on the schedule shown.

Results are preliminary, but post-cycle 4 among patients on the study, of 19 patients, 89% achieved MRD negativity at 10 to the minus 6 by NGS, and 100% achieved MRD negativity at 10 to the minus 5 by flow cytometry. Looking at 6 months post-lendiceltamab bone marrow biopsies of 10 patients, all had achieved MRD negativity at 10 to the minus 6.

The usual strategy for people who are MRD positive, following the MIDAS trial, would be to consider transplant. If MRD negative, there might be discussion about deferring transplant based on MIDAS study results. The results for transplant among patients who are MRD positive are frankly quite disappointing. It appears that using a strategy of very limited lendiceltamab induction and maintenance might be a very novel strategy for dealing with patients who have this high-risk biology with MRD positivity after induction.

Future Directions and Clinical Practice Changes

Looking ahead, there are emerging data for better understanding of subgroups in transplant-eligible myeloma, including the Duffy phenotype, the t(11;14) translocation, and functional high-risk myeloma. The AURIGA data support, at least in the daratumumab-naive population, the benefit of adding daratumumab among patients who are MRD positive, and the GMMG HD7 data will be critical. The IMMUNOPLANT study's utilization of bispecific antibodies for consolidation in MRD-positive patients appears highly effective. Incorporation of bispecifics into frontline myeloma therapy is very appealing, but there is a need to look at finite duration therapy among patients with deep responses.

In terms of practice changes, AURIGA again highlights the importance of dual CD38/IMiD maintenance, which has been seen not only in this study but also in PERSEUS. The MASTER analysis is very important for helping to identify patients who have a functional high-risk phenotype and would benefit from earlier use of T-cell engaging therapy. The t(11;14) translocation data are very helpful for counseling, planning, and management for patients.