Exploring the optimal dose for lenalidomide maintenance after auto-SCT

The standard of care for newly diagnosed patients with multiple myeloma (MM) eligible for transplant is high-dose chemotherapy induction, followed by autologous hematopoietic stem cell transplantation (auto-HSCT) and lenalidomide (Len) maintenance therapy (MT) to prolong remission. Due to frequent and severe side effects, Len MT dosing is often reduced, yet the dose-response relationship of Len MT has not been fully described.

Roland Fenk and colleagues from Germany have recently published the results from their multicenter phase III trial (NCT00891384), in which patients were randomized to receive high- or low-dose Len MT. The study, published in Cancer Research, aimed to assess the efficacy and tolerability of two extreme Len doses, and share experience-based recommendations for the optimal MT with Len.¹

Study design

Patients were 18–75 years old, diagnosed with MM, and treated with ≤ 6 cycles of induction (not with Len), up to 2 cycles for mobilization, and auto-HSCT (between 90–120 days) before trial entry. Patient randomization was stratified by International Staging System (ISS) stage, age at diagnosis, and response after high-dose chemotherapy. All enrolled patients received Len at a dose of 25 mg/day for 21 days, every 28 days for 6 months (Len6), and then continued with their assigned dose: the high-dose arm moved onto Len MT at a dose of 25 mg/day, and the low-dose arm began Len MT at 5 mg/day. Maintenance therapy was prescribed until disease progression or limiting toxicity (Figure 1).

The primary outcome of the study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), response rates, adverse events (AE), and incidence of secondary primary malignancies.

Figure 1. Study design¹

auto, autologous; HSCT, hematopoietic stem cell transplant; Len, lenalidomide; MT, maintenance therapy.

Results

• The study enrolled 194 patients.
• 188 patients were randomized to high dose Len MT (n = 94) or low dose Len MT (n = 94).
• There was no significant difference in patient characteristics between arms (Table 1).

Table 1. Patient characteristics

• After a median follow-up of 46.7 months, median PFS in the high-dose arm was 44.8 months vs 33.0 months in the low-dose arm (HR, 0.65; 95% CI, 0.44–0.97; p = 0.032).
• Longer PFS was seen in patients < 66 years, with revised ISS stages II and III at diagnosis, and with ≤ PR after auto-HSCT.
• The median duration of treatment was significantly longer in the high-dose Len MT arm (26.8 vs 22.9 months, p = 0.01).
• Median OS was not reached in either arm.
• Stringent complete response (sCR) rates increased from 6% at randomization to 23% after the initial 6 months with Len in the high-dose arm, and from 9% to 19% in the low-dose arm. Improvement in the remission status in the following years was less frequent at each time point but was still observed until 3.5 years after randomization (Table 2).

Table 2. Response rates in treatment arms over the study course. All values are % unless otherwise specified¹

• The median exposure in the high-dose arm until disease progression was 14.5 mg/day, following various dose adjustments.
• Dose reductions needed throughout the study were distributed as follows (% over the total dose reductions):
  • Len6: 53%
  • High-dose Len MT: 39%, although it did not translate into higher discontinuations
  • Low-dose Len MT: 8%
  • 55.5% of dose reductions were due to neutropenia.
• There were more Grade ≥ 3 AEs in the high-dose arm (87.5%) than the low-dose arm (64.6%).
• Grade ≥ 3 neutropenia and thrombocytopenia were the main adverse events during Len6 (39.0% high-dose arm, 8.9% low-dose arm).
• Grade ≥ 3 neutropenia incidence reduced over the 1–3 years of Len MT in the high-dose arm (34.6% in Year 1, 24.3% in Year 2, and 12.8% in Year 3), but remained constant in the low-dose arm (9%).
• Grade ≥ 3 infections were experienced by 12% of patients during Len6 and reduced during MT (from 12.3% to 7.7% after 3 years, in the high-dose arm).

Conclusions

The research team concluded that their data demonstrate an enhanced PFS (of approximately 1 year) with a high-dose Len MT, and that there is a trend towards improved OS, but that this comes with increased hematological toxicities. The investigators also highlighted that although dose reductions were frequent in the high-dose arm, AEs resulting in discontinuation of treatment were similar in both groups, and the high-dose arm had a significantly longer duration of treatment. They state that the maximum tolerated dose varies and should be up-/down-titrated on a case by case basis. The recommended guidelines to optimize Len maintenance therapy are given at the start of this article, see above.