Newly-diagnosed multiple myeloma

In this highlights video from the 2026 IMS meeting in Glasgow, Prof Dr Michel Delforge, hematologist at the University Hospitals Leuven, highlights several recent advances shaping the treatment of patients with newly diagnosed multiple myeloma (NDMM). An important context for these developments is the increasing recognition of cure as a potential treatment objective in multiple myeloma. The current consensus definition for cure encompasses the absence of measurable disease in blood and urine, no detectable residual disease in the bone marrow using assays with a sensitivity of 10⁻⁶, and no active lesions on functional imaging such as PET-CT or whole-body MRI with diffusion-weighted imaging, maintained for five years while off treatment. Minimal residual disease (MRD) assessment is also becoming increasingly standardized, with the first-line setting representing an important opportunity to achieve sustained disease control.

Updated results from the PERSEUS trial provided longer-term evidence for quadruplet therapy in newly diagnosed, transplant-eligible patients. The study compared four cycles of induction with VRd or daratumumab-VRd (D-VRd), followed by transplantation, two cycles of the same consolidation regimen, and maintenance with either lenalidomide alone or lenalidomide plus daratumumab. Daratumumab was administered during maintenance for a minimum of two years, with the possibility of discontinuation in patients achieving sustained MRD negativity. With an updated follow-up of 81 months, progression-free survival (PFS) was 81% in the quadruplet arm compared with 56% in the triplet arm. Among patients with standard-risk cytogenetics, seven-year PFS reached 88%. During maintenance, greater conversion to MRD negativity was observed with lenalidomide plus daratumumab than with lenalidomide alone. Approximately one-quarter of patients in the quadruplet arm had already discontinued daratumumab following sustained MRD negativity. Importantly, despite the consistent benefit observed with quadruplet therapy, outcomes continued to differ according to cytogenetic risk. In fact, patients with high-risk cytogenetics benefited from the quadruplet regimen, but their seven-year PFS was 55%, compared with 88% among patients with standard-risk cytogenetics. High-risk disease therefore remains an area in which improved treatment approaches are needed.¹

Long-term findings from the CASSIOPEIA study, which compared daratumumab-VTd with VTd, provided additional information regarding treatment discontinuation after sustained MRD negativity. Among patients who had maintained MRD negativity for several years and subsequently discontinued treatment, ~85% remained progression-free after an additional follow-up of approximately three and a half years. These observations support further investigation of treatment discontinuation in carefully selected patients. Potential characteristics associated with an ultra-low risk of relapse include International Staging System (ISS) stage I or II, the absence of high-risk cytogenetics, and MRD negativity at a sensitivity of 10⁻⁶.²

The MIDAS trial provided further insight into MRD-guided treatment strategies. In this IFM study, patients received six cycles of induction with isatuximab plus KRd and were subsequently randomized according to their MRD status. Patients who remained MRD positive after induction received either double transplantation or single transplantation followed by consolidation, together with intensified maintenance using the CELMoD iberdomide plus isatuximab. Interestingly, a substantial proportion of patients remaining MRD positive after induction had the t(11;14) translocation. While these patients appear to be more difficult to convert to a truly MRD-negative state, t(11;14) does not by definition represent a very poor prognostic category. A high rate of conversion to MRD negativity was observed with iberdomide plus isatuximab maintenance, including among patients with high-risk cytogenetics according to the new classification.³

Bispecific antibody-based strategies were also explored as an alternative approach following initial quadruplet induction. In a small IFM study, patients received daratumumab-VRd induction and were subsequently treated according to their MRD status without proceeding to transplantation. Patients who were MRD negative received teclistamab plus lenalidomide, whereas those who remained MRD positive received the combination of teclistamab and talquetamab. Among patients who remained MRD positive after six cycles of quadruplet induction, treatment with teclistamab plus talquetamab resulted in conversion to MRD negativity in all patients after three cycles. These findings support continued investigation of bispecific antibody combinations as a strategy to eliminate residual disease after induction.⁴

In conclusion, the data presented at IMS 2026 reflect the increasing role of immunotherapy-based regimens in NDMM, alongside progressively higher rates of deep and MRD-negative responses. At the same time, sustained MRD negativity is becoming increasingly relevant not only as a measure of treatment efficacy but also as a potential tool for guiding treatment intensity and identifying patients in whom therapy may ultimately be discontinued.