Daratumumab Demonstrates Single-Agent Activity in Smoldering Myeloma

Craig Hofmeister, MD

Daratumumab (Darzalex) displayed single-agent activity in intermediate- and high-risk smoldering multiple myeloma (SMM), according to results from the phase II CENTAURUS study presented at the 2017 ASH Annual Meeting.¹

Patients treated with 16 mg/kg IV daratumumab in 8-week cycles had a median progression-free survival (PFS) of ≥24 months. Median PFS not reached in any of the 3 daratumumab treatment arms, said lead author Craig C. Hofmeister, MD.

Patients in CENTAURUS were randomized in a 1:1:1 ratio to 1 of 3 dosing schedules:

• A long regimen of weekly 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 administered 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

The 12-month PFS rates were 95% with the long schedule, 88% with the intermediate dosing schedule, and 81% with the short intense schedule. The results support the long dosing schedule being used in the phase III AQUILA study of single-agent daratumumab, which began enrollment December 11, 2017.

Risk stratification of SMM is important because current guidelines recommend monitoring patients every 3 to 6 months for active multiple myeloma before initiating treatment, Hofmeister said. Most patients with high- or intermediate-risk SMM progress to active MM.

The phase III QuiRedex study was the first to show a survival benefit associated with lenalidomide and pulsed dexamethasone for patients with high-risk SMM, with the caveats that functional imaging was not mandated at the time and the study was published before the SLiM-CRAB criteria for defining active MM.² The CENTAURUS investigators wanted to build on those findings using a potentially more potent regimen that includes daratumumab.

“Hence, it’s appealing to try to treat patients with intermediate- and high-risk SMM to try to get some clinical benefit,” said Hofmeister, from the Division of Hematology, The Ohio State University Comprehensive Cancer Center.

Daratumumab has direct on-tumor activity that may contribute to rapid response and immunomodulatory actions that may contribute to deep and durable response. It was studied in 123 patients with an SMM diagnosis of ≤5 years, bone marrow plasma cells ≥10% to <60%, and at least 1 high-risk criterion. Patients with 1 or more SLiM-CRAB myeloma-defining event were excluded.

Investigators performed serologic monitoring using International Myeloma Working Group [IMWG] criteria and magnetic resonance imaging every 6 months for the first 3 years. Patients were followed until progressive disease (PD) or until the end of the study. The co-primary endpoints were the rate of complete remission and the PD/death rate, defined as the ratio of patients with an event (PD or death) to the total follow-up for all patients.

The 3 arms were well balanced for age, gender, race, and performance status. About 80% of patients in each arm had 2 or more high-risk factors at screening. The median time from SMM diagnosis to randomization was 6.47, 5.52, and 7.43 months in the long, intermediate, and short arms, respectively.

With a median follow-up of 15.8 months, the discontinuation rates were 12%, 10%, and 5% in the long, intermediate, and short arms, respectively. Discontinuations were mainly related to adverse events (AEs) and progressive disease.

“Single-agent daratumumab showed significant activity in SMM and seemed to produce the best responses in the intermediate and long arms,” said Hofmeister.

More than half (54%) of patients in the long arm and 49% in the intermediate arm had a partial response (PR) or better. In the short arm, 38% of patients had a PR or better. The CR rate was <15% in each arm, missing the CR co-primary endpoint. The PD/death rate surpassed the goal of ≥24 months in all 3 arms. Significance levels for the null hypothesis for this endpoint were <0.0001 in the long and intermediate arms and 0.0213 in the short arm.

As demonstrated by the previously mentioned 12-month PFS rates, fewer patients progressed on the long and intermediate schedules. “At the time of this analysis, it was clear that biochemical progression may provide a little more granular view between the treatment arms, hence a modified PFS was studied,” Hofmeister said.

Biochemical progression was defined as a measurable increase in disease form a nadir by ≥25% in 2 subsequent assessments per IMWG. The 12-month modified PFS rates were 93%, 75%, and 56% in the long, intermediate, and short arms, respectively.

The rate of hematologic treatment-emergent adverse events (TEAEs) was <15% across all arms and the rates of grade 3/4 infections were ≤5% across all arms. There was 1 death due to disease progression in the short arm. Overall, the safety data were consistent with other single-agent daratumumab trials.

References

1. Hofmeister C, Chari A, Cohen YC, et al. Daratumumab monotherapy for patients with intermediate or high-risk smoldering multiple myeloma (SMM): CENTAURUS, a randomized, open-label, multicenter phase 2 study. Presented at: American Society of Hematology 59th Annual meeting; December 9-12, 2017; Atlanta, GA. Abstract 510.
2. Mateos MV, Hernandez MT, Giraldo P, et al. Lenalidomide plus dexamethasone versus observation in patients with high-risk smoldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol. 2016;8:1127-36.