Continuous Subcutaneous Lenalidomide Shows Promise in Reducing Toxicity in R/R Multiple Myeloma

Lenalidomide (Revlimid; Celgene Corporation/Bristol Myers Squib), an immunomodulatory drug, has long served as a cornerstone in the treatment of multiple myeloma (MM). Despite its proven efficacy, the conventional oral administration of lenalidomide presents challenges due to its short half-life and the high systemic exposure required to sustain therapeutic drug levels, which can lead to significant toxicities, particularly grade 3 or 4 hematologic adverse events (AEs). These AEs often necessitate dose reductions, treatment interruptions, or discontinuation, especially in regimens combining lenalidomide with bortezomib and dexamethasone (RVd), where grade 3 to 4 hematologic toxicity rates exceed 22%.

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Gabrail et al presented data from a novel strategy involving continuous subcutaneous (SC) infusion of lenalidomide in a poster at the American Association for Cancer Research (AACR) Annual Meeting 2025 in Chicago, Illinois. In their study, Gabrail et al investigated whether a more stable and lower-dose delivery method could maintain efficacy while mitigating toxicity in patients with relapsed or refractory (R/R) MM.

This phase 1b clinical trial, conducted between September 2023 and November 2024, was designed to build on promising preclinical data that demonstrated improved efficacy and tolerability with continuous SC lenalidomide delivery in murine MM models. The trial enrolled 6 patients with second-line or later R/R MM across 2 US community-based investigational sites. The patients, all Caucasian with a median age of 73 and an even male-to-female ratio, had received a median of 2 prior lines of therapy (range, 1-7). For 2 patients, their disease was refractory to their most recent regimen, while 4 had relapsed disease. All 6 patients had prior exposure to lenalidomide and bortezomib.

Patients received continuous SC lenalidomide infusion at a dose of 400 mcg/h (equivalent to 9.6 mg/d) using an ambulatory infusion device. This therapy was administered on a 28-day cycle alongside weekly SC bortezomib (1.3 mg/m²) and dexamethasone (20-40 mg, age adjusted). Patients were trained to self-administer their infusion at home or attend clinic visits 3 times weekly. The study aimed to evaluate both safety and preliminary efficacy outcomes, with a specific focus on hematologic toxicity, pharmacokinetics, and immune system effects.

One of the most encouraging findings of the study was the absence of drug-related grade 3 or 4 hematologic toxicities throughout the treatment period. Hematologic nadir values remained within acceptable ranges, and no significant nonhematologic toxicities exceeding grade 2 were reported. The only grade 3 event involved a skin reaction during cycle 3 in 1 patient, which led to discontinuation. No patients experienced drug-related anemia, neutropenia, leukopenia, or thrombocytopenia greater than grade 2. One patient experienced a gastrointestinal bleed during the study, but this was corrected with supportive treatment and was not considered directly related to the investigational regimen.

Regarding efficacy among the 6 patients, 1 patient achieved a complete response and 5 achieved partial responses. Most notably, these responses were achieved without the typical high levels of hematologic toxicity often associated with oral lenalidomide. The median progression-free survival exceeded 10 months at the time of reporting, with ongoing responses in several patients.

Pharmacokinetic (PK) analysis confirmed that the continuous delivery method achieved median steady-state blood concentrations of 39 ng/mL (range, 26-94 ng/mL), well above the therapeutic threshold of 25 ng/mL. The median 24-hour area under the curve was 921 h*ng/mL (range, 630-1503 h*ng/mL), demonstrating a flatter PK profile that likely contributed to the reduced toxicity. This contrasts favorably with prior data on oral 25-mg lenalidomide dosing, where peak concentrations were substantially higher, contributing to dose-limiting hematologic AEs.

Immunologic profiling also supported the safety of continuous SC lenalidomide. Flow cytometry data indicated no significant increases in immune checkpoint markers typically associated with T-cell exhaustion. Notably, CD19+ B cells were depleted, consistent with lenalidomide’s known activity, whereas CD4+ and CD8+ T-cell populations remained relatively stable across 2 treatment cycles. Natural killer and natural killer T-cell populations were also preserved, suggesting that the immune effector landscape remained intact.

The study team concluded that continuous SC infusion of low-dose lenalidomide provides a promising therapeutic alternative for patients with R/R MM. This method appears to enhance the drug’s therapeutic index by maintaining effective plasma concentrations with reduced peak exposure and toxicity. Unlike conventional oral regimens, which rely on high daily doses to overcome rapid drug clearance, the continuous SC method ensures more consistent exposure without the need for toxic peak levels.

These findings have significant implications, particularly for older or frail patients who are more susceptible to the AEs of conventional dosing. The continuous SC delivery approach reduces hematologic toxicity and may also improve adherence and quality of life by eliminating the need for daily oral dosing and potentially reducing the burden ofAE management.

Gabrail et al explained in the poster that new delivery platforms are being explored based on these promising results, including on-body injectors, transdermal patches, and controlled-release oral tablets. These technologies could further simplify administration and expand access to this optimized delivery strategy.

Gabrail et al acknowledged the limitations of their study, including the small sample size and short follow-up duration. However, the observed responses and the absence of severe toxicity remain encouraging. As such, further clinical investigation is warranted. Larger studies in MM and chronic lymphocytic leukemia are planned to confirm these early findings and evaluate the long-term benefits of continuous SC lenalidomide delivery.

“Optimizing the pharmacokinetics and pharmacodynamics of medications may be an interesting strategy to mitigate toxicity, such as in this case of continuous SC delivery of lenalidomide to mitigate hematologic toxicity,” said Matthew Lei, PharmD, BCOP, clinical pharmacy specialist, lymphoma, at Massachusetts General Hospital in Boston and editorial advisory board member for Pharmacy Practice in Focus: Oncology. “It will be interesting to see what dosage form these data prompt the future development of. It also introduces a question on how to optimize the PK/pharmacodynamic profile for protein degraders, such as cereblon E3 ligase modulatory drugs and proteolysis-targeting chimeras, which are a burgeoning area of therapeutic development.”

REFERENCE

Gabrail N, Lerro K, Huseein MA, et al. Continuous subcutaneous lenalidomide delivery improves the therapeutic index and avoids drug-related grade 3/4 hematologic toxicity in patients with relapsed/refractory multiple myeloma. Poster presented at: American Association for Cancer Research (AACR) Annual Meeting; April 25-30, 2025.