Daratumumab Continues to Show Activity in Smoldering Multiple Myeloma

"Results from this final analysis, with a median follow-up of [approximately] 7 years, continue to demonstrate the clinical activity of daratumumab in patients with intermediate- or high-risk [smoldering multiple myeloma], with favorable responses in ORR and [progressive disease]/death rate," according to the study authors.

Treatment with daratumumab (Darzalex) continued to elicit clinical activity with a tolerable safety profile among patients with intermediate- or high-risk smoldering multiple myeloma, according to updated findings from the phase 2 CENTAURUS study (NCT02316106) published in Blood.¹

In the CENTAURUS trial, patients were assigned to receive a long intense (n = 41), intermediate (n = 41), or short intense (n = 41) dosing schedule. Per investigator assessment, the complete response (CR) or better rate was 4.9% in the long intense arm and 9.8% in the intermediate arm. Additionally, the objective response rate (ORR) was 58.5%, 53.7%, and 37.5% in the long intense, intermediate, and short intense arms, respectively.

Progressive disease was reported in 41.5% of the long intense arm, 36.6% of the intermediate arm, and 39.0% of the short intense arm. The progressive death per death rates per patient-year were 0.096, 0.102, and 0.109 in each respective arm (P <.0001 for all), which were all lower than the threshold of at least 0.346 for predicting a median progression-free survival (PFS) of less than 24 months.

With a median follow-up of 85.2 months (range, 0.0-94.3), the median PFS was not reached (NR) in any cohort during the per protocol phase of the study only. When accounting for the trial’s extension phase, the median PFS per investigator assessment was NR (90% CI, 63.4 months-not evaluable [NE]) in the long intense arm, 84.4 months (90% CI, 49.6-NE) in the intermediate arm, and 74.1 (90% CI, 40.2-77.2) in the short intense arm.

“The CENTAURUS study was designed to determine whether daratumumab monotherapy could delay progression from intermediate- or high-risk [smoldering multiple myeloma] to [multiple myeloma]. Results from this final analysis, with a median follow-up of [approximately] 7 years, continue to demonstrate the clinical activity of daratumumab in patients with intermediate- or high-risk [smoldering multiple myeloma], with favorable responses in ORR and [progressive disease]/death rate,” lead study author Ola Landgren, MD, PhD, chief of the Myeloma Program and leader of the Experimental Therapeutics Program at Sylvester Comprehensive Cancer Center, a professor of Medicine at the University of Miami, and Multiple Myeloma Cancer Chair on the Tumor Board for the journal ONCOLOGY^®, wrote with fellow study authors.¹

Investigators of the open-label, multicenter phase 2 CENTAURUS study randomly assigned patients to receive intravenous daratumumab at 16 mg/kg following a long intense, intermediate, or short intense dosing schedule. Dosing occurred every week in cycle 1, every other week in cycles 2 to 3, every 4 weeks in cycles 4 to 7, and every 8 weeks in cycles 8 to 20 in the long intense arm; once every week in cycle 1 and every 8 weeks thereafter for cycles 2 to 20 in the intermediate arm; and once every week for cycle 1 in the short intense arm.

The trial’s primary end points were CR rate and progressive disease per death per patient-year, which investigators defined as the proportion of patients who progressed to multiple myeloma or died per patient-year. Secondary end points included ORR, PFS, overall survival (OS), time to next treatment, and response to first subsequent therapy for multiple myeloma.

Patients 18 years and older with smoldering multiple myeloma for less than 5 years, a confirmed diagnosis of intermediate- or high-risk disease, and an ECOG performance status of 0 or 1 were eligible for enrollment in the trial.² Those with primary systemic immunoglobulin light chain amyloidosis or a history of malignancy apart from smoldering multiple myeloma within 3 years of undergoing randomization were ineligible for study entry.

During the per protocol phase, 75.6% (n = 31/41) and 70.7% (n = 29/41) of the long intense and intermediate arms, respectively, completed 20 treatment cycles; 95.0% (n = 38/40) of the short intense arm completed 1 treatment cycle. Additionally, 70.0% (n = 21/30) and 60.0% (n = 15/25) of eligible patients from the long intense and intermediate arms proceeded to the extension phase of the trial.

The median OS was NR in all dosing cohorts. Time to next treatment was NR across all phases for the long intense and intermediate arms; for the short intense arm, it was 76.3 months (90% CI, 40.4-80.3). Investigators noted that PFS on first-line therapy for multiple myeloma was NR for all evaluable cohorts. Of those with progression to active multiple myeloma, 78.9% (n = 45/57) were treated with subsequent therapy, which included 36 who were alive at the end of the study.

Treatment-emergent adverse effects (TEAEs) of any grade occurred in 100%, 100%, and 92.5% of the long intense, intermediate, and short intense arms, respectively. The most common any-grade TEAEs in each arm included upper respiratory tract infection (48.8%, 36.6%, 10.0%), fatigue (46.3%, 61.0%, 22.5%), and cough (43.9%, 36.6%, 27.5%). Grade 3/4 TEAEs affected 65.9%, 41.5%, and 15.0% of each arm, with the most common type being hypertension (14.6%, 9.8%, 2.5%).

“Given there is currently no clear consensus regarding optimal management of patients with [smoldering multiple myeloma], results from CENTAURUS support the potential use of daratumumab monotherapy in those with intermediate- or high-risk [smoldering multiple myeloma], which is being tested in the ongoing phase 3 AQUILA study [NCT03301220]. Results from ongoing clinical trials are eagerly awaited and will provide additional guidance for the development of optimal treatment strategies in this patient population,” The authors added.¹

References

1. Landgren CO, Chari A, Cohen YC, et al. Efficacy and safety of daratumumab in intermediate/high-risk smoldering multiple myeloma: final analysis of CENTAURUS. Blood. Published online December 9, 2024. doi:10.1182/blood.2024025897
2. A study to evaluate 3 dose schedules of daratumumab in participants with smoldering multiple myeloma. ClinicalTrials.gov. Updated February 28, 2025. Accessed March 14, 2025. https://tinyurl.com/yc33cet9