Quadruplet Combo Appears Effective in High-Risk Smoldering Multiple Myeloma

Combining carfilzomib (Kyprolis), lenalidomide (Revlimid), daratumumab (Darzalex), and dexamethasone (DKRd) demonstrated efficacy among patients with high-risk smoldering multiple myeloma, according to a presentation on data from the phase 2 ASCENT trial (NCT03289299) at the 2026 European Hematology Association (EHA) Congress.¹

Of 86 evaluable patients, data showed an overall response rate (ORR) of 98%, which included 94% with a very good partial response (VGPR) or better. The stringent complete response (sCR) rate was 52%. Additionally, 60% of patients achieved minimal residual disease (MRD)–negative status per International Myeloma Working Group (IMWG) criteria, and 87% had at least 1 undetectable disease in the marrow. MRD negativity also increased over time, with rates rising from 8.1% at the end of induction therapy to 30.2% at the end of consolidation, 47.7% at the end of maintenance, and 34.9% at 1 year after treatment.

The median progression-free survival (PFS) was not reached at the time of analysis, although 10 patients experienced progression, which were exclusively biochemical progression events. At 3 years, the PFS rate was 89.9% (95% CI, 82.3%-98.3%). Six other patients became immunofixation electrophoresis positive but did not fulfill the criteria for progressive disease.

Overall, 5 patients had died due to cardiac arrest (n = 2), COVID-19 (n = 1), plasma cell leukemia and relapsed disease (n = 1), and an unknown cause (n = 1). The median follow-up for patients who were still alive was 52 months.

Data also showed 7 instances of progression in patients who had MRD negativity in the marrow. Furthermore, 3 patients experienced MRD-positive status but did not meet the criteria for progressive disease.

“The quadruplet regimen is quite effective in this high-risk smoldering myeloma [population]. This is a limited-duration therapy with a quadruplet without using autologous stem cell transplant, and the toxicities that we saw were quite similar to what we have seen with this regimen in patients with newly diagnosed myeloma,” Presenting study investigator Shaji Kumar, MD, consultant in the Division of Hematology and Department of Internal Medicine Research, and chair in the Division of Hematology and Department of Internal Medicine at Mayo Clinic in Rochester, Minnesota, stated in the presentation. “One of the goals is to see if we can [give] therapy for a limited duration and potentially cure a fraction of these patients. Those things will have to wait for longer follow-up to get a sense, especially now that we have a definition for what we think should be a cure in multiple myeloma.”

According to Kumar, although the FDA recently approved subcutaneous daratumumab and hyaluronidase-fihj (Darzalex Faspro) for patients with high-risk smoldering multiple myeloma, it remained unknown whether it was more suitable to use a single drug to delay progression or employ a more intensive regimen to potentially eradicate the smoldering disease altogether.² The phase 2 ASCENT trial was designed to examine whether an intense, limited-duration regimen could provide a potential cure for those with smoldering multiple myeloma.

Investigators selected DKRd as the experimental regimen for this trial based on previous reports of high MRD-negative rates observed in newly diagnosed multiple myeloma. Patients first received induction therapy with carfilzomib at 36 mg/m² twice weekly or 56 mg/m² weekly, lenalidomide at 25 mg daily for 3 weeks, daratumumab weekly for 8 weeks followed by every other week for 16 weeks, and dexamethasone at 40 mg weekly. Consolidation therapy consisted of carfilzomib and lenalidomide for the same dosing schedules, daratumumab every 4 weeks, and dexamethasone at 20 mg weekly. Finally, maintenance therapy included lenalidomide at 10 mg daily for 3 weeks plus daratumumab once every 8 weeks.

The trial’s primary end point was the rate of confirmed sCR. Secondary end points included toxicities, PFS, OS, and MRD-negative status at different points of the treatment schedule.

Patients with high-risk smoldering multiple myeloma per IMWG updated risk stratification criteria, adequate marrow and organ function, and no signs of amyloidosis were eligible for enrollment on the trial. Those with significant comorbidities like heart disease were ineligible for study entry.

The median age was 64 years (range, 41-76), and most patients were male (51%) and White (84%). Of note, 68% of patients fulfilled IMWG 20/2/20 high risk criteria, and 28% had an IMWG score of at least 9.

Toxicities of any grade that were potentially related to therapy occurred in 92% of patients. Grade 3 hematological and non-hematological adverse effects (AEs) were reported in 20% and 60% of patients, respectively. Additionally, investigators reduced doses for carfilzomib in 14 patients, lenalidomide in 77, and dexamethasone in 81. The most common grade 3 or higher toxicities included decreased neutrophil counts, hypertension, and pneumonia.

Disclosures: Kumar noted receiving research funding from Celgene, Takeda, Janssen, BMS, KITE, Merck, AbbVie, Medimmune, Novartis, RocheGenentech, Amgen, Tenebio, and Carsgen. He also noted consulting or advisory board roles with no personal payments with Celgene, Takeda, Janssen, AbbVie, Genentech, and Amgen, as well as those with personal payments with Oncopeptides, Genecentrix, Cellectar, and Beigene.

References

1. Kumar S, Laplant B, Badros A, et al. Aggressive smoldering curative approach evaluating novel therapies (ASCENT): a phase 2 trial of induction, consolidation, and maintenance in high-risk smoldering multiple myeloma. Presented at: 2026 European Hematology Association Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S207.
2. FDA approves daratumumab and hyaluronidase-fihj for high-risk smoldering multiple myeloma. FDA. November 6, 2025. Accessed June 12, 2026. https://tinyurl.com/49ks5zkx