Abstract
BACKGROUND:
The current standard for maintenance therapy following autologous stem cell transplant (ASCT) in patients with multiple myeloma (MM) is lenalidomide, an oral treatment with demonstrated overall survival benefit. Other options for MM may incur toxicities or require frequent visits to infusion centers and may thus not be best suited as maintenance. Patients with high-risk cytogenetic features have poorer outcomes than those considered to have standard risk disease, and national guidelines recommend doublet maintenance (with a proteasome inhibitor and lenalidomide in this setting). Currently, the role of minimal residual disease (MRD) in treatment decision making is unknown but MRD status in this setting may dictate treatment discontinuation in the future. We conducted a review of currently enrolling clinical trials to characterize therapeutic agents/strategies being used or evaluated in a maintenance setting, outcomes evaluated, the inclusion of high-risk patients, and the use of MRD response in guiding management decisions.
METHODS:
A comprehensive search was performed on the clinicaltrials.gov, clinicaltrialsregister.eu, and anzctr.org.au databases on March 2, 2022, using the keywords "newly diagnosed multiple myeloma", "transplant eligible multiple myeloma", and "maintenance in multiple myeloma". Only studies that were currently recruiting patients, or those listed as active but not yet recruiting were included. Studies that completed enrollment, were terminated, or had been presented or published were not included. Studies were included if patients were planned to undergo autologous stem cell transplant after induction therapy followed by maintenance strategy. If at least one arm received post-transplant maintenance therapy, and the maintenance therapy was specified in the trial description, it was included. Trials evaluating maintenance therapy after a salvage transplant or maintenance therapy in non-transplant settings were excluded.
RESULTS:
A total of 20 studies were analyzed. Table 1 highlights characteristics. Of the 20 studies, 11 (55.0%) were randomized and 9 (45.0%) were non-randomized. Six studies (30.0%) evaluated PFS as a primary outcome, and 2 studies (10.0%) included OS as a primary outcome. Four of the 20 (20.0%) studies included multiple primary endpoints in addition to time to event outcome, while 4 (20.0%) had a time to event outcome as the sole primary outcome being investigated. Of the 11 randomized studies, 2 studies evaluated OS (18.1%) and 5 evaluated PFS (45.5%) as primary endpoint. MRD negativity was included as a primary endpoint in 11 studies (55.0%) and a secondary endpoint in seven (35%). Of the 9 nonrandomized studies, 4 had a primary endpoint of MRD negativity rate (44.4%), 2 (22.2%) had response-based primary outcomes, and one (11.1%) had a time to event primary outcome. Of the total trials, two (10.0%) assessed or mandated discontinuation of maintenance therapy for those achieving MRD negativity. Table 2 describes maintenance regimens utilized. A total of 4 randomized studies assessed comparison of lenalidomide and another agent to lenalidomide alone with a primary endpoint powered for PFS/OS. Only one study limited enrollment to standard risk disease. No studies enrolled only "high-risk" disease. Amongst a total of 19 trials enrolling patients with high-risk disease, eight trials (42.1%) were offering or permitting patients with high-risk disease to receive single agent lenalidomide.
CONCLUSION:
Our study analyzing the landscape of current maintenance trials demonstrates that there are many promising clinical trial designs that adapt treatment based on the depth of responses and incorporate newer agents with enough statistical power to demonstrate OS advantage. However, there remains room for improvement, as evidenced by trials evaluating drugs with marked toxicity profiles in non-randomized single arm settings, patients with high-risk disease being permitted to receive treatment that may be inferior to what current guidelines recommend, and a lack of patient centered endpoints (such as OS or quality of life) being evaluated as primary endpoints.
Disclosures
Sborov:Abbvie: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Sanofi: Consultancy; BMS: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bioline: Consultancy; Pfizer: Consultancy.
