High tolerability and favorable early outcomes with full-dose lenalidomide in older adults with newly diagnosed multiple myeloma on triplet and quadruplet therapies

Abstract Introduction: The use of Lenalidomide (Len) with bortezomib and daratumumab (dara)-based triplet and quadruplet regimens have significantly improved outcomes in newly diagnosed multiple myeloma (NDMM), including among older adults. However, older and frail patients are more vulnerable to treatment-related toxicity, often resulting in dose interruptions or early discontinuation. Reduced Len doses are frequently used in clinical practice to mitigate toxicity however the impact of this approach on treatment efficacy and tolerance are unknown. We analyzed patient-level Len dosing data during induction to characterize the frequency of dose modifications, treatment discontinuations, and to study the association of Len dose on efficacy outcomes in older adults with NDMM treated with upfront autologous stem cell transplant (autoSCT). Methods: We used data from the Medical College of Wisconsin’s Transplant Registry to identify patients aged ≥70 years with newly diagnosed multiple myeloma (NDMM) who received Lenalidomide-containing triplet or quadruplet induction regimens prior to autoSCT between January 2021 and December 2024. We excluded patients receiving non-Len-based regimens. Descriptive statistics were used to characterize dosing patterns. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier estimates and multivariable Cox regression. Associations between Len dosing and pre-transplant response were evaluated using univariable and multinomial regression. Results: We included a total of 111 patients with a median follow up of 31.7 months (95% CI, 29.6 – 35.4 months) from diagnosis. The median age was 72 years (IQR, 70-74 years); 18% of patients were ≥75 years. Sixty percent of patients were male, 4.5% had an ECOG performance score (PS) of ≥2, and 59% had high-risk cytogenetics. Majority of patients (56%) received induction with Dara/Len/Bortezomib/Dexamethasone (DaraRVD) and 51% received Len/Bortezomib/Dex (RVD); 3% of patients received other triplet regimens including DaraLenDex. Overall, 70% (n=78) of patients started Len at the full dose of 25 mg. For those who started Len at 25 mg, 86% of patients were able to complete induction therapy without any dose modifications whereas 9% (7/78) required dose reductions (rash, 5%; cytopenia, 3%; other reasons, 1%). These included 5 patients receiving DaraRVD and 2 patients on RVD. The discontinuation rate due to toxicity was 5% (rash, 1%; cytopenia, 3%; other, 1%). Thirty percent (n=33) of patients started Len at a dose of <25mg. This included a dose of 10 mg in 14%, 15 mg in 14% and 5 mg (3%) administered in 21- or 28-day cycles. The reason for starting Len at a lower dose was renal dysfunction in 42% but was unknown for 48%; 10% started Len at a reduced dose for other reasons such as volume overload, cardiomyopathy and pancytopenia. Of the 33 patients starting Len at a lower dose, the dose was increased in subsequent cycles in 12% of patients (most of whom had renal dysfunction at diagnosis), with 6% reaching a dose of 25 mg. However, in 67% of patients the dose remained unchanged. The discontinuation rate was 18% (rash, 15%, other reasons, 3%) and included an equal number of patients receiving DaraRVD (9%) or RVD (9%). Overall, in the cohort, 72% (n=80) patients were able to achieve a maximum Len dose of 25 mg during induction. Among 109 patients, the overall response rate (partial response or better) prior to autoSCT was 90%, with 70.9% achieving very good partial response (VGPR) or better; response data were missing for 1.8%. The 3-year PFS was 77% (68%, 87%) and the 3-year OS was 96% (95% CI, 91%, 100%). In a multivariable model adjusting for age, high-risk cytogenetics, PS, and treatment regimen, patients who received Len at a starting maximum dose of <25 mg during induction therapy did not have inferior pre-transplant response (≥VGPR; OR 0.65, 95% CI 0.24–1.76, p=0.3906) and PFS (HR 0.63, 95% CI 0.23–1.71, p=0.4228). Conclusion: The majority of older transplant-eligible adults (>=70 years) receiving Len-containing triplet or quadruplet induction regimens for NDMM tolerated the recommended starting Len dose of 25 mg, with <10% of patients experiencing dose reductions or toxicity-related discontinuations.