Daratumumab Therapy for Smoldering Myeloma Extends Progression-Free Survival
Atlanta, GA—Single-agent daratumumab (Darzalex) shows significant activity in smoldering multiple myeloma (SMM). The 12-month progression-free survival (PFS) rate with a long dosing schedule of daratumumab was 95%, and the median PFS was not yet reached in any of the 3 dosing schedules studied, announced Craig C. Hofmeister, MD, MPH, Associate Professor, Division of Hematology, the Ohio State University, Columbus, at ASH 2017.
These results from the phase 2 clinical trial CENTAURUS support a long dosing schedule of 16 mg/kg intravenously in 8-week cycles from the phase 3 study, AQUILA.
Current guidelines recommend only monitoring patients with SMM every 3 to 6 months for progression to active multiple myeloma before initiating treatment. However, a previous phase 3 study (QuiRedex) enhanced survival with lenalidomide (Revlimid) and pulsed dexamethasone in patients with high-risk SMM. “Hence, it’s appealing to try to treat patients with intermediate- and high-risk SMM to try to get some clinical benefit,” said Dr Hofmeister.
Daratumumab acts through multiple mechanisms, he said. It has direct on-tumor activity that may contribute to rapid response and its immunomodulatory actions, including modulation of the tumor microenvironment and depletion of CD38-positive immunosuppressive cells, may promote deep and durable responses.
CENTAURUS randomized 123 patients with a diagnosis of SMM of less than 5 years, bone marrow plasma cells ≥10% to <60%, and at least 1 high-risk criterion. Patients with ≥1 multiple myeloma–defining events by SLiM-CRAB criteria were excluded. The patients were randomized to 1 of 3 dosing schedules:
- A long regimen with the weekly administration of daratumumab in cycle 1, every other week in cycles 2 and 3, every 4 weeks in cycles 4 through 7, and every 8 weeks up to cycle 20
- An intermediate schedule in which daratumumab was given weekly in cycle 1, and every 8 weeks up to cycle 20
- A short, intense dosing schedule in which daratumumab was given weekly for 1 cycle.
Serologic monitoring using International Myeloma Working Group (IMWG) criteria and magnetic resonance imaging was performed every 6 months for the first 3 years. The patients were followed until progressive disease or until the end of the study.
Approximately 80% of patients in each arm had ≥2 high-risk factors at screening. The median time from the diagnosis of SMM to randomization was 6.47, 5.52, and 7.43 months in the long, intermediate, and short schedule arms, respectively.
With a median follow-up of 15.8 months, 5 (12%) patients in the long arm discontinued treatment, with 2 (5%) resulting from adverse events and 2 (5%) from progressive disease. The discontinuation rates in the intermediate- and short-schedule arms were 10% and 5%, respectively.
The 12-month PFS rates were 95% with the long schedule, 88% with an intermediate dosing schedule, and 81% with the short schedule of daratumumab. A median PFS of ≥24 months was a coprimary end point and was achieved in each arm.
More than half (54%) of the patients in the long-schedule arm and 49% in the intermediate-schedule arm had a partial response or better compared with 38% in the short arm. The other coprimary end point, a complete response of >15%, was not met. The complete response rates were 2% in the long-schedule arm, 5% in the intermediate-schedule arm, and 0% in the short-schedule arm.
A modified PFS based on biochemical progression was added to the analysis. Biochemical progression was defined as a measurable disease increase from nadir by ≥25% in 2 subsequent assessments per the IMWG criteria. The 12-month modified PFS rates were 93%, 75%, and 56% in the long-, intermediate-, and short-schedule arms, respectively. “From a clinical efficacy perspective, this supports the long dosing schedule for a subsequent phase 3 trial,” said Dr Hofmeister.
The safety profile was consistent with other single-agent daratumumab trials. The rate of hematologic treatment-emergent adverse events was <15% across all arms and the rates of grade 3 and 4 infections were ≤5% across all arms.