A Phase 2 Response-Adapted Study of Daratumumab, Carfilzomib, and Dexamethasone (DKd) in Patients with High-Risk Smoldering Multiple Myeloma
Authors: Patel Roshani , Bhaskarla Amrit , Gordon Max J , Emanuel Michael , Delgado Colon Dana I. , Wang Hao-Wei , Yuan Constance M. , Lindenberg Liza , Mena Esther , Turkbey Baris , Micheletti Nick , Yee Laura M , Patel Nisha , Maric Irina , Braylan Raul C. , Calvo Katherine R. , Staudt Louis M. , Young Ryan M. , Roschewski Mark , Kazandjian Dickran , Hill Elizabeth 
Published: December 2024

Introduction:
Patients with high-risk smoldering multiple myeloma (HR-SMM) have a risk of progression to multiple myeloma (MM) of ~75% in 5 years with median time to progression of 2 years.(Lakshman 2018)(Perez-Persona 2007) While active monitoring is commonly performed, randomized Phase 3 trials have demonstrated that early treatment with lenalidomide prolongs both PFS and OS in patients with HR-SMM.(Lonial 2019)(Mateos 2022) Building upon these results, Phase 2 studies utilizing lenalidomide combination regimens in HR-SMM showed high rates of undetectable MRD (56-84%).(Mateos 2019)(Kazandjian 2021)(Kumar 2022) Undetectable MRD is associated with longer PFS and OS in MM.(Landgren 2016)(Avet-Loiseau 2020) Lenalidomide's side effects such as rash, neutropenia, diarrhea, and second primary malignancies are significant in the otherwise asymptomatic population. Therefore, the optimal drug combination remains undetermined. The combination of daratumumab, carfilzomib, and dexamethasone (DKd) is a highly active regimen for relapsed refractory MM which spares immunomodulatory (IMiD) toxicities.(Chari et al 2019) This study aimed to evaluate the efficacy of DKd in patients with HR-SMM utilizing a response-adapted treatment duration (NCT04933539). The primary end point was the rate of undetectable MRD stringent complete responses (sCR) after induction.
Design:
This Phase 2, Simon 2-stage, investigator-initiated study enrolled HR-SMM patients based on the Mayo Clinic, PETHEMA, and/or Rajkumar, Mateos, and Landgren 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]. Patients with persistently detectable MRD after 8 cycles of DKd received an additional 4 cycles. All responding patients then received daratumumab maintenance for 24 monthly cycles. Response was assessed by IMWG criteria after every cycle. MRD was assessed by multicolor flow cytometry (MRD sensitivity 10-5) after cycle 8, 12 (if applicable), and yearly. A pre-planned interim analysis was included to prevent futility based on the previously reported undetectable MRD rates of at least 55%.
Results:
Fourteen patients were enrolled between October 21, 2022, and January 22, 2024, with a median age of 58 years (range 29 -70). The cohort included 5 men (36%) and 9 women (64%). Six patients (43%) identified as African American/Black and 8 patients (57%) identified as White. Six patients (43%) had high risk cytogenetics (t(4;14), t(14;16), t(14;20), 1q gain, del17p). At a data cut off of July 1st, 2024, 2 patients are off study: one died of sudden cardiac death attributed to acute heart failure (cycle 4) and one withdrew consent due to long travel to the study site (cycle 1). One patient elected to stop therapy after 11 cycles due to frequent travel to the study site. Two patients remain on induction therapy and have not had MRD evaluation.
The ORR (partial response or better) was 100% (95% CI, 77.19%-100%). VGPR or better was 92% (95% CI, 64.6 -99.9%) and sCR rate was 15% (95% CI, 4.33%-42.23%). Of 11 patients evaluable post induction, 3 (27.3%; 95% CI, 9.75%-56.56%) patients had no detectable MRD. Two patients had undetectable MRD sCR after 8 cycles (18% (95% CI, 5.14%-47.7%). Of the patients who remained MRD positive after cycle 8 and finished an additional 4 cycles (n=6), one patient developed undetectable MRD (16.7%; CI 95%, 3.01-56.35%) but remained in a VGPR. No patients have clinically progressed to overt MM.
One patient experienced a grade 3 hematologic adverse event (AE), lymphopenia (n=1). Three patients (21%) had grade 3 or higher adverse events including hypertension (n=1), lung infection (n=1), and myocardial infarction (n=1).
Conclusion:
All patients with HR-SMM responded to DKd of which 92% had a VGPR or better. However, this study did not meet its pre-planned interim analysis goal of a 55% undetectable MRD rate. Most toxicities were low grade, but we did observe two significant cardiac adverse events. The patients remaining in the trial will be followed for safety, PFS, OS and completion of 24 cycles of daratumumab maintenance.