Lasting Responses Seen With Daratumumab in Smoldering Multiple Myeloma

Craig Hofmeister, MD

In findings from the phase II CENTAURUS clinical trial, treatment with daratumumab (Darzalex) monotherapy produced lasting responses in patients with intermediate- and high-risk smoldering multiple myeloma (SMM). 

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, when presenting the findings during the 2017 ASH Annual Meeting.¹

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.²The 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 &le;5 years, bone marrow plasma cells &ge;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.

&ldquo;Single-agent daratumumab showed significant activity in SMM and seemed to produce the best responses in the intermediate and long arms,&rdquo; 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 &ge;24 months in all 3 arms. Significance levels for the null hypothesis for this endpoint were <.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. &ldquo;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,&rdquo; Hofmeister said.

Biochemical progression was defined as a measurable increase in disease form a nadir by &ge;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 &le;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.