Analyses Support Integrating MRD and Genomic Features in Prognosis of Multiple Myeloma

Molecular and transcriptomic features can identify biologically distinct subgroups of patients with multiple myeloma whose long-term outcomes are not fully explained by depth of response alone, according to analyses from the phase 3 CASSIOPEIA trial (NCT02541383), both published in Blood Cancer Journal.^1,2

In the pair of analyses of transplant-eligible patients after treatment for newly diagnosed multiple myeloma (NDMM), patients with cyclin D (CCND1) overexpression showed a slower response and lower minimal residual disease (MRD) negativity despite similar long-term survival outcomes to other patients. Meanwhile, stratifying patients by transcriptomic subgroups showed that MRD negativity had less prognostic impact in patients with a higher risk of progression after treatment. These findings highlight the potential for better risk stratification and tailoring of therapies to maximize benefit and predict long-term outcomes more reliably.

The CASSIOPEIA Trial

CASSIOPEIA previously established that adding daratumumab (Darzalex) to bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone (VTd), followed by daratumumab maintenance, significantly improved progression-free survival (PFS) and overall survival (OS) compared with VTd alone in transplant-eligible NDMM, leading to regulatory approval of daratumumab-VTd (D-VTd).³ Patients in the trial were then randomly assigned a second time to receive daratumumab maintenance or observation. With the long-term follow-up dataset now exceeding 7 years, PFS was superior with the inclusion of daratumumab in both the induction and consolidation phase and the maintenance phase.

Transcriptomic Risk Groups Alter the Prognostic Value of MRD

Investigators performed RNA sequencing on CD138-positive bone marrow samples from 628 CASSIOPEIA patients and used unsupervised consensus clustering to identify 5 transcriptomic subtypes, which were further grouped into 3 risk categories: low-risk (the “low bone,” or LB, subtype; n = 179), intermediate-risk (combining CCND1-expressing and hyperdiploid-associated subtypes; n = 336), and high-risk (combining NSD2-expressing and MAF-expressing subtypes; n = 113).¹

Among patients who received daratumumab in at least 1 treatment phase, estimated 72-month PFS rates were 70%, 51%, and 27% in the low-, intermediate-, and high-risk groups, respectively. The clinical benefit of daratumumab, in terms of both PFS and MRD negativity, was preserved across all 3 risk categories, and higher CD38 gene expression was independently associated with longer PFS in patients treated with daratumumab, regardless of treatment arm or transcriptomic risk group.

Critically, the authors found that MRD negativity rates and the prognostic weight of MRD status differed by risk group. Postconsolidation MRD negativity was lowest among intermediate-risk patients compared with the low- and high-risk groups. MRD negativity was strongly associated with improved PFS in low-risk patients (HR, 0.3; 95% CI, 0.1-0.8; P =.0120) and intermediate-risk patients (HR, 0.3; 95% CI, 0.2-0.5; P <.0001), but this association was not statistically significant in high-risk patients (HR, 0.8; 95% CI, 0.3-2.1; P =.6509). A multivariable model incorporating MRD status and transcriptomic risk group showed an approximately 2-fold reduction in the prognostic effect size of MRD negativity in high-risk patients, a trend that approached significance (P =.07).

“Overall, these findings demonstrate that the prognostic impact of postconsolidation MRD negativity differs according to transcriptomic risk, with a robust and consistent effect in low- and intermediate-risk patients, but a distinct and attenuated effect in high-risk patients,” the investigators wrote.

The authors proposed that in high-risk disease, characterized by increased genomic instability and proliferative signaling, standard MRD assessment may fail to detect residual disease, which could explain early relapse despite MRD negativity. Conversely, the low-risk subtype was marked by high expression of a dormancy gene signature involving AXL and co-regulated genes, and this group achieved the highest postconsolidation MRD-negativity rate (82.8%), consistent with a bone marrow microenvironment–dependent, more indolent disease biology. The authors concluded that MRD status alone “may not serve as a universally reliable predictor of survival across all molecular subtypes,” and suggested that low-risk patients with sustained MRD negativity might be candidates for lighter maintenance strategies, whereas high-risk patients with persistent transcriptomic risk may need intensified or alternative approaches.

Long-Term Outcomes With CCND1 Overexpression

A second analysis examined the clinical significance of CCND1 overexpression, a marker associated with t(11;14) that affects 16% to 24% of patients with NDMM, using RNA sequencing data from 589 CASSIOPEIA patients. Among this cohort, 164 patients (27.8%) exhibited a CCND1 overexpression signature, which the authors noted is not a perfect surrogate for the presence of t(11;14) but likely captures most patients carrying the translocation.²

Patients with the CCND1 signature achieved MRD negativity by flow cytometry less often than those without it, both after induction (20.9% vs 50.8%; P <.0001) and after transplantation and consolidation (59.1% vs 78.2%; P <.0001). Despite this slower depth of response, long-term PFS and OS were statistically indistinguishable between patients with and without CCND1 overexpression, and this pattern held consistently regardless of randomization to VTd or D-VTd, or to daratumumab maintenance vs observation.

The authors wrote that this dissociation between MRD kinetics and long-term prognosis suggests CCND1-overexpressing myeloma has distinct biology, potentially relying on “alternative survival pathways or exhibit more indolent kinetics, such that standard MRD thresholds underestimate durable disease control” in this subgroup. Considering the lack of clear benefit, they suggested avoiding overtreatment in these patients to achieve MRD negativity, as doing could increase toxicity and treatment burden without improving long-term survival.

Clinical Implications

Together, the 2 analyses reinforce a common theme: although MRD negativity remains a strong general predictor of outcome in NDMM, its prognostic value is not uniform across genetically and transcriptionally defined subgroups. The researchers called for integrating baseline molecular or genomic characterization alongside MRD assessment to avoid both overtreatment of patients with more indolent, favorable-biology disease and undertreatment of patients whose tumor biology reduces the predictive value of achieving MRD negativity.

REFERENCES

1. Magrangeas F, Guérin-Charbonnel C, Bessonneau-Gaborit V, et al. Expression profile of CASSIOPEIA patients refines prognostic value of MRD negativity in multiple myeloma. Blood Cancer J. Published online July 2, 2026. doi:10.1038/s41408-026-01550-7

2. Perrot A, Touzeau C, Minvielle S, et al. Response profile and long-term outcomes in Cyclin D1-overexpressing multiple myeloma: insights from the CASSIOPEIA trial. Blood Cancer J. 2026;16:110. doi:10.1038/s41408-026-01542-7

3. Moreau P, Hulin C, Perrot A, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial. Lancet Oncol. 2024;25(8):P1003-1004. doi:10.1016/S1470-2045(24)00282-1