Real-World Risk of Severe Cytopenias in Multiple Myeloma Patients Sequentially Treated with Immunomodulatory Drugs

Background: Most multiple myeloma (MM) patients experience myelosuppression due to both underlying disease and treatment. Cytopenias are most commonly associated with regimens containing immunomodulatory agents (IMiDs). Most MM patients relapse and subsequent regimens could include IMiDs. The impact of sequential IMiD treatment on the risk of severe cytopenias is unknown, as studies have not examined risk across multiple lines of therapy (LOTs). Understanding of potential differential cytopenia risks among MM patients who are, versus are not, sequentially treated with IMiDs is needed to inform treatment decisions.

Objective: To evaluate the risks of severe cytopenias in relapsed MM patients who received sequential IMiD treatment versus IMiD-free regimens.

Methods: The Flatiron Health database (New York, NY) contains de-identified electronic health records from patients treated at ~280 United States cancer clinics. Patients ≥18 years diagnosed with MM between 01 January 2011 and 31 March 2020 who received at least two LOTs were included. Four exposure groups were created according to whether IMiDs were received during LOTs 1 or 2. Those for which both LOTs contained IMiDs were considered "sequentially exposed"; those for which neither contained IMiDs were "never exposed." Follow-up was from initiation of LOT 2 until the earliest of the outcome (grade 3 or 4 cytopenias, according to the Common Terminology Criteria for Adverse Events), death, LOT end, or study end (31 December 2021). Inverse probability of treatment weighting models included age, diagnosis year, sex, race, body mass index, practice type, insurance type, region, stage, cytogenetic risk, pre-existing comorbidities, treatment history, prior maintenance therapy, relapse timing, and recent cytopenia history (≤90 days from LOT 2 start). Cumulative risks up to 12 months were estimated for each exposure group and risk differences (RD) were calculated. Analyses were repeated stratified by recent cytopenia history.

Results: The cohort included 5,573 MM patients. Most (N=2,082) were sequentially exposed to IMiDs, with only 974 never exposed. Compared to those never exposed, those sequentially exposed were on average younger (mean 65 vs 69 years), diagnosed at an earlier stage (ISS I 24% vs 14%) and in later years (≥2016 47% vs 30%), had a better performance status (ECOG ≤1 43% vs 33%), and had longer time to relapse (≥24 months 20% vs 13%).

The 1-year risks of leukopenia and neutropenia were substantially higher among those exposed versus unexposed to IMiDs at LOT 2 (leukopenia 17% vs 13%; neutropenia 21% vs 14%). Stratification on prior IMiD exposure revealed a trend in which, compared to those never exposed, those sequentially exposed had the highest 1-year risk (leukopenia RD 9%; neutropenia RD 11%), followed by those only recently exposed during LOT 2 (leukopenia RD 6%; neutropenia RD 8%), then by those with only past exposure during LOT 1 (leukopenia RD 4%; neutropenia RD 3%) (Fig 1A).

The 1-year risks of anemia, lymphocytopenia, and thrombocytopenia were similar among those treated with, versus without, IMiDs at LOT 2 (anemia 16% vs 17%; lymphocytopenia 30% vs 31%; thrombocytopenia 13% vs 14%). Stratification on prior IMiD exposure did not meaningfully change the risks of anemia, but did suggest an increased risk of lymphocytopenia (RD 11%) and thrombocytopenia (RD 6%) among those sequentially, versus never, exposed (Fig 1A).

Risks of all severe cytopenias were substantially lower among those with no recent cytopenia history. The associations between sequential, versus never, exposure with leukopenia and neutropenia were even stronger among those with a history of the given cytopenia (leukopenia RD 20%; neutropenia RD 29%), but were attenuated for those with no history (leukopenia RD 6%; neutropenia RD 11%) (Fig 1B). Risks for cytopenias not related to white blood cells (anemia, thrombocytopenia) among those with no recent history did not exceed 12%, even for those sequentially exposed.

Conclusions: Results suggest sequential exposure to IMiDs across two LOTs to be mainly of concern for risk of severe cytopenias related to white blood cells (leukopenia, neutropenia, lymphocytopenia), especially among those with recent histories. Although dose delays and infections due to cytopenia are unavailable for this cohort, results suggest administering an IMiD-free regimen following an IMiD regimen may minimize severe cytopenia risk.

Barberio:Amgen Inc: Research Funding. Lash:Amgen Inc: Consultancy. Nooka:Bristol-Myers Squibb, Janssen, Takeda, Amgen, Adaptive, GlaxoSmithKline, Sanofi, Oncopeptides, Karyophram, SecureBio, and BeyondSprings: Consultancy, Honoraria. Kim:Amgen Inc: Current Employment, Current equity holder in private company.