IMF ASCENT trial shows 82% five-year PFS in smouldering myeloma
The International Myeloma Foundation (IMF) has presented Phase 2 results from its ASCENT cure trial at the European Hematology Association Congress in Stockholm, reporting high rates of deep response in patients with high-risk smouldering multiple myeloma treated early with an aggressive quadruplet regimen.
The trial enrolled 87 patients between May 2018 and December 2021 and administered up to 24 cycles of carfilzomib, lenalidomide, daratumumab, and dexamethasone (Dara-KRd) across induction, consolidation, and maintenance phases. After a median follow-up of 52.4 months, the overall response rate was 97%. Forty-three patients achieved stringent complete response or complete response, and 85% of patients reached measurable residual disease (MRD) negativity by Euroflow assay at a median of 6.6 months. The estimated five-year progression-free survival rate was 82%, with median PFS not yet reached. Ten patients progressed and five deaths were recorded during the follow-up period.
Trial design and safety profile
The ASCENT trial (NCT03289299) was launched in 2017 as part of the IMF's Black Swan Research Initiative, which was conceived on the premise that early, aggressive intervention in precursor disease might achieve functional cure before active myeloma develops and causes organ damage. Eligible patients were defined as high-risk under the IMWG 20/2/20 staging system or with an IMWG total score of nine or above. The trial's primary endpoint was stringent complete response, with MRD negativity and PFS as key secondary endpoints.
The safety data warrants careful reading. Grade 3 or higher hematologic toxicities occurred in 22% of patients; grade 3 or higher non-hematologic toxicities were recorded in 70%. These figures are consistent with what is observed in the newly diagnosed multiple myeloma setting when the same Dara-KRd backbone is used, but they are not trivial for a patient population that has not yet developed active, symptomatic disease and may have remained progression-free without any intervention for years. The abstract conclusion noted that "toxicities are in line with that observed in newly diagnosed MM," which the investigators regard as reassuring given the intensity of the regimen.
Dr Shaji Kumar of Mayo Clinic, who presented the data, said the results "clearly show that this approach can achieve deep reduction in the myeloma clone, but more follow-up is needed to determine if we are curing anyone." Dr S. Vincent Rajkumar, Chair of the IMF's Board of Directors and Chairperson of the International Myeloma Working Group, said the depth and durability of response "demonstrate what is possible when we combine highly effective therapies with a carefully selected patient population."
Market and regulatory context
The question of when and how aggressively to treat smouldering myeloma remains one of the most actively contested areas in haematological oncology. Several large academic centres and cooperative groups are running or have recently completed studies examining early intervention, including trials of lenalidomide monotherapy and various doublet or triplet regimens. ASCENT is notable for deploying a full quadruplet, matching the intensity routinely used in transplant-eligible newly diagnosed disease.
Beyond academic trials, a number of commercial sponsors are investigating anti-CD38 and next-generation immunotherapy approaches, including bispecific antibodies and CAR-T constructs, in the smouldering and early active myeloma space. If longer follow-up from ASCENT or successor studies demonstrates durable MRD negativity without disease relapse, it could strengthen the regulatory and commercial rationale for approved agents to pursue a smouldering myeloma label extension. The EMA and FDA have both signalled interest in MRD as a surrogate endpoint in myeloma, though neither has yet granted full regulatory acceptance for approval decisions based on MRD alone.
The IMF has stated that future trials should explore newer immunotherapies within this early-intervention framework, suggesting the ASCENT experience is intended as a platform for subsequent study designs rather than a registrational programme in its own right.