(PA-341) Primary Results from A Phase 2 Response-Adapted Study of Daratumumab, Carfilzomib, and Dexamethasone (DKd) in Patients with High-Risk Smoldering Multiple Myeloma

Half of patients with high-risk smoldering multiple myeloma (HR-SMM) progress to multiple myeloma (MM) within 2 years. Treatment with single agent lenalidomide or daratumumab delays progression and may improve survival (QUIREDEX,AQUILA). Lenalidomide-based multiagent regimens have induced high rates of undetectable measurable residual disease (MRD-neg) which can lead to longer survival outcomes. Finding an effective regimen while minimizing toxicity is most important for asymptomatic patients. The combination of daratumumab, carfilzomib, and dexamethasone (DKd) is effective in relapsed MM and avoids immunomodulatory drug toxicity. This study (NCT04933539) evaluates its use in HR-SMM.

Methods:   

This Phase 2, Simon 2-stage, investigator-initiated study enrolled HR-SMM patients, HR defined by Mayo Clinic 2018, PETHEMA 2007, and/or Rajkumar et al Blood 2015 criteria. Patients received 8 cycles (28 days) of DKd [daratumumab 1800 mg SC per USPI, carfilzomib 20/56 mg/m2 days 1, 8, 15 and dexamethasone 40 mg days 1, 8, 15, 22]. Those with detectable MRD after 8 cycles of DKd received an additional 4 cycles. All patients then received monthly daratumumab maintenance for 24 cycles. The primary endpoint was MRD-neg stringent complete response (sCR) after induction. Responses were assessed by IMWG criteria after each cycle. Very Good Partial Responses (VGPR) were confirmed with mass spectrometry. MRD was assessed by multicolor flow cytometry (MRD sensitivity 10^-5) after cycle 8, 12 (if applicable), and yearly. A pre-planned interim analysis assessed futility based on a MRD-neg sCR rates of ≥55%.

Results:   

Fourteen patients (median age 58 (range 29-70), 5 men, 9 women; 6 African American/Black, 8 White) were enrolled between Oct 21, 2022, and Jan 22, 2024. Nine (64%) met Mayo 2018 HR criteria. Six (43%) had high-risk cytogenetics (t(4;14), t(14;20), 1q+, del17p). At a median follow up of 2.13 years, 2 patients were off study: 1 died of sudden death (cycle 4) and 1 withdrew consent (cycle 1).

Out of 13 evaluable patients, the ORR was 100% (85% VGPR, 15% sCR). After 8 cycles of induction, 1 had an MRD-neg sCR 7.6% (95% CI: 0.19-33%). Of the patients who finished an additional 4 cycles, 1 patient became MRD-neg but remained in a VGPR. One patient deepened his response after a year of daratumumab maintenance and 2 were MRD-neg with a VGPR. In total, 5 patients (38% 95% CI: 18 - 65%) had at least one MRD-neg bone marrow. One patient had biochemical progression, but no patients have developed SLiM-CRAB criteria. Grade 3 AEs included lymphopenia (n=1), hypertension (n=1), lung infection (n=1), and myocardial infarction (n=1). No grade 4 AEs occurred.

Conclusions:   

The study closed early after not meeting the interim MRD-neg sCR goal of > 55% but notably there was an 100% ORR, and no patients progressed to overt MM. Responses have been durable, with 92% of patients maintaining their best response during the 2 years of daratumumab maintenance. Most toxicities were low grade.