Relapsed/refractory multiple myeloma

At the International Myeloma Society (IMS) 2026 meeting in Glasgow, Dr Marie Vercruyssen, hematologist at Institut Jules Bordet in Brussels, discussed the key take-aways related relapsed/refractory multiple myeloma (RRMM). A notable development in 2026 was the International Myeloma Working Group (IMWG) consensus introducing a definition of cure in multiple myeloma. This reflects the possibility of achieving cure in a proportion of patients and raises important questions regarding how treatment can be adapted once deep and sustained disease control has been achieved.

A first study evaluated outcomes in more than 150 patients sequentially treated with B-cell maturation antigen (BCMA)- and GPRC5D-targeted therapies. Approximately 50 patients had high-risk cytogenetics, two-thirds were triple-class refractory, and one-fifth were penta-drug refractory, representing a heavily pretreated population with substantial therapeutic resistance. Overall outcomes remained poor, with a median progression-free survival (PFS) of approximately 4.3 months. However, an important difference emerged according to subsequent treatment. Patients who received another targeted therapy directed against either BCMA or GPRC5D achieved a median PFS exceeding seven months, compared with less than four months among patients receiving conventional, non-targeted therapy.¹ These findings highlight the potential relevance of sequential BCMA- and GPRC5D-directed approaches in extensively pretreated RRMM.

A second abstract provided updated results from the TRILOGY-1 trial, including 56 patients treated with ramantamig, a trispecific antibody targeting BCMA, GPRC5D, and CD3. Approximately half of the patients in this stidy had high-risk cytogenetics, nearly all were refractory to anti-CD38 therapy, and 15 had previously been exposed to BCMA- or GPRC5D-directed treatment. Cytokine release syndrome (CRS) occurred in approximately 40% of patients and was limited to grades 1 and 2. Approximately half of the cohort had received prophylactic tocilizumab. Grade 3–4 infections occurred in approximately 25% of patients. GPRC5D-related adverse events included rash and nail disorders, with no new significant safety signals reported.²

The TRILOGY-1 update also provided data relevant to treatment de-escalation. Nearly 80% of patients achieved a complete response. Patients in complete response were permitted to transition from administration every four weeks to every eight weeks, thereby reducing treatment frequency and potentially limiting treatment-related adverse events. Importantly, responses were maintained following this change in dosing interval. These observations provide a signal that reducing treatment intensity after a deep response may be feasible in selected patients, while potentially decreasing treatment burden and associated toxicity.²

A further analysis examined 430 patients who had maintained minimal residual disease (MRD) negativity for at least 24 months. Approximately one-third had remained MRD negative for more than three years, with some maintaining MRD negativity for more than five years. At the time of evaluation, 70% were already off treatment. Half of the population had been treated in the first-line setting, approximately one-third were in the third line or beyond, and 20% had received T-cell-engaging therapy. Notably, the overall survival curve for this cohort overlapped with that of a matched US general population. The analysis also identified three factors associated with a higher risk of subsequent disease progression or relapse: MRD negativity assessed at a sensitivity of 10⁻⁵ rather than 10⁻⁶, high-risk cytogenetics, and greater baseline tumor burden, represented by International Staging System (ISS) stage III rather than stage I or II. Among patients without any of these risk factors, the reported risk of relapse or progression was approximately 4% at five years and 6% at eight years. This subgroup was characterized as a very-low-risk population and may represent a population in which treatment discontinuation could ultimately be considered. Of the 430 patients included in this analysis, 89 converted from MRD negativity to MRD positivity during follow-up, with an approximately 30% risk of relapse among these patients. However, approximately one-third of patients who became MRD positive subsequently reverted spontaneously to MRD negativity without treatment or another intervention. These findings suggest that isolated conversion to MRD positivity during surveillance may not necessarily warrant immediate therapeutic intervention and that additional observation may be appropriate.³

Dr Vercruyssen concludes that the work presented at IMS 2026 illustrates a switch from progressively adding therapies in pursuit of cure towards the identification of patients in whom treatment can be safely de-escalated once sufficiently deep and sustained disease control has been achieved. This includes determining when doses can be reduced, administration intervals extended, or treatment discontinued, with the aim of maintaining disease control while reducing adverse events, particularly cumulative and long-term toxicities.