Efficacy and Tolerability of High- versus Low-dose Lenalidomide Maintenance Therapy of Multiple Myeloma after Autologous Blood Stem Cell Transplantation

Abstract

For multiple myeloma, high-dose chemotherapy and autologous blood stem-cell transplantation (ASCT) followed by lenalidomide maintenance (LenMT) at 10-15 mg/day is considered standard of care. However, dose reductions due to side effects are common and median LenMT doses achieved over time may remain lower. Dose response during LenMT has never been investigated. Patients and Methods: In a multicenter, randomized, open-label trial, patients with multiple myeloma after ASCT and high-dose lenalidomide consolidation therapy (CT) at 25 mg/day were randomized to receive LenMT at either 25 or 5 mg/day. Primary endpoint was progression-free survival (PFS). Results: Ninety-four patients (median age, 58 years) were randomized to either arm, with 22% having International Staging System (ISS) stage 3 and 22% being in complete remission (CR). After median follow-up of 46.7 months, median doses of 14.5 and 5 mg/day were achieved in the two arms; 53% of dose reductions occurring during CT. In the high-and the low-dose arm, median PFS was 44.8 and 33.0 months (HR, 0.65; 95% CI, 0.44-0.97; P ¼ 0.032), 36% and 23% of patients had stringent CR as best response (P ¼ 0.08), and 4-year OS was 79% and 67% (P ¼ 0.16), respectively. Hematologic toxicity, grade ≥3 neutropenia, and infections were initially more common with LenMT 25 mg, but decreased after dose adjustments. SPM incidence and quality-oflife (QoL) scores in both arms were similar. Conclusions: LenMT dose correlated with efficacy and toxicity. High rates of dose reductions during CT argue against a high starting dose. However, continuous up-and down-titration for each patient to the current maximum tolerated dose is prudent.

The Effect of Duration of Lenalidomide Maintenance and Outcomes of Different Salvage Regimens in Patients with Multiple Myeloma (MM)

“…Typically, patients were recommended to start lenalidomide 2–4 months after ASCT at an initial daily dose of 10–15 mg. The mSMART 3.0 criteria were used for risk stratification based on cytogenetics features on interphase FISH [ 5 , 10 ]. Median follow-up and median duration of maintenance therapy were calculated using the reverse Kaplan–Meier estimator method.…”

“…The current most widely agreed upon frontline treatment strategy for multiple myeloma (MM) involves induction with triplet therapies followed by high-dose chemotherapy and autologous stem-cell transplantation (ASCT) for eligible patients, and then maintenance therapy with or without preceding consolidation. Lenalidomide is the preferred maintenance strategy following ASCT, especially in non-high-risk patients with MM, and multiple randomized studies (e.g., CALGB100104, IFM2005-02, GEMIMA, Myeloma IX, German multicenter study) have demonstrated an improvement in progression-free survival (PFS) with lenalidomide maintenance [ 1 – 5 ]. Only the CALGB100104 study showed a significant overall survival (OS) improvement with lenalidomide maintenance while an OS benefit was not demonstrated in the other studies; possibly because they were not powered for OS as the primary endpoint [ 3 , 4 , 6 ].…”

Adverse Event Reporting in Randomized Clinical Trials for Multiple Myeloma

“…After excluding duplicate reports for the same trial and trials that did not meet the inclusion criteria, 65 discrete RCTs were identified (Figure 1). The Table highlights characteristics of the included studies.…”

Health-Related Quality of Life in Multiple Myeloma Patients Treated with High- or Low-Dose Lenalidomide Maintenance Therapy after Autologous Stem Cell Transplantation—Results from the LenaMain Trial (NCT00891384)

“…The LenaMain trial recruited patients from 4 June 2009 to 1 February 2015 in six hospitals in Germany. Details were previously published [17]. Briefly, patients were randomized 1:1 to either receive lenalidomide at a 5 mg (Len-low) or 25 mg (Len-high) maintenance treatment (Len MT) after first-line therapy with autologous stem cell transplant.…”

“…The LenaMain trial (NCT00891384) was an investigator-initiated, randomized, openlabel, phase-III trial that randomized patients to either receive lenalidomide at 5 mg (Len low) or 25 mg (Len high) [17]. To date, the LenaMain trial is the only clinical trial to show that a higher dosage of lenalidomide maintenance post-transplant benefits patients by extending the time of remission.…”