Rationale and design of the German-Speaking Myeloma Multicenter Group (GMMG) trial ReLApsE: a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma

With an incidence rate of 5-6/100.000, multiple myeloma (MM) accounts for 13 % of hematologic cancers and 1 % of all neoplastic diseases in Western countries [1]. In first-line treatment of MM, high-dose chemotherapy (HDCT) with subsequent autologous stem-cell transplantation (ASCT) has become the standard of care in eligible patients [1‐3]. In recent years patient outcomes have been further improved by the introduction of novel agents, namely immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) into first-line therapy. Nevertheless, MM remains largely incurable and almost all patients eventually relapse. Therapeutic options in the setting of relapsed MM (RMM) include salvage HDCT/ASCT, novel agents (IMiDs, PIs, agents under clinical investigation), chemotherapy, corticosteroids, and allogeneic stem cell transplantation [4]. In the absence of an established standard of care the selection of a suitable treatment regimen for RMM patients is usually based on disease- and patient-specific factors such as regimens employed in and response to prior lines of therapy. Again, the introduction of IMIDs and proteasome inhibitors into the treatment of RMM has led to a major increase in survival rates of this patient population [4‐11].

Lenalidomide is an orally administered IMiD and a derivative of the structurally related thalidomide [12]. The mechanism of action of lenalidomide is multifaceted [13, 14] including apoptosis induction, alteration of the interaction of myeloma cells with bone marrow stroma [15], antiangiogenesis [16, 17], and immunomodulation [18, 19]. More recently, anti-myeloma activity of lenalidomide has been shown to depend on interaction with cereblon, a protein involved in the teratogenicity of thalidomide [20‐22]. Two pivotal phase III trials (MM-009 and MM-010) have demonstrated highly significant improvement of response rates with lenalidomide/dexamethasone compared with placebo/dexamethasone in a total of 704 RMM patients and subsequently led to regulatory approval of lenalidomide in the USA and the EU. All patients in these pivotal trials received 40 mg dexamethasone on days 1–4, 9–12 and 17–20 and either 25 mg lenalidomide or placebo on days 1–21 of 28-day cycles. After completion of the 4^th cycle, dexamethasone was limited to days 1–4 [8, 9]. Pooled analysis of both registration studies revealed superior overall response rate (ORR; 60.6 % vs. 21.9 %), time to progression (TTP; 13.4 vs. 4.6 months) and median OS (38.0 vs. 31.6 months) of the lenalidomide-containing regimen, but also significantly more adverse events (AEs), especially grade 3–4 neutropenia (35.4 % vs. 3.4 %) and thromboembolic events (15.9 % vs. 5.4 %) [23]. Dexamethasone dosing was subject of investigation in a phase III trial in NDMM patients. In combination with lenalidomide, high-dose dexamethasone (480 mg/cycle; 40 mg on days 1–4, 9–12 and 17–20) led to significantly increased ORR (79 % vs. 68 %), but low dose-dexamethasone (160 mg/cycle; 40 mg on days 1, 8, 15, 22) showed significantly increased OS after 1 and 2 years (96 % vs. 87 % and 87 % vs. 75 %, respectively). This was related to a significantly lower incidence of AEs including infectious and thromboembolic events and deaths in the low-dose dexamethasone arm [24]. A subgroup analysis of RMM patients from MM-009 and MM-010 with dexamethasone dose reduction confirmed these results [25]. Furthermore, lenalidomide maintenance treatment has been evaluated in four phase III trials in NDMM patients [26‐29]. While PFS after lenalidomide maintenance was markedly prolonged in all four trials, OS was significantly superior in only one trial [30]. Despite the finding of an increased incidence of second primary malignancies in the maintenance arm, the odds for lower mortality are in favor of lenalidomide maintenance treatment [31].

Available data on HDCT/ASCT in RMM patients largely comes from retrospective, non-randomized, single-center or registry-based studies [32‐45] and few prospective trials of early (i.e. first-line) vs. delayed (i.e. second-line) HDCT/ASCT [46, 47]. These studies suggest that salvage HDCT/ASCT is feasible in RMM patients considered eligible based on sufficient general condition and absence of prohibitive comorbidities. However, reported outcomes vary due to small and/or heterogeneous patient populations and differing salvage regimens. A recently published review of 19 retrospective studies of salvage HDCT/ASCT in patients treated with first-line HDCT/ASCT reported median ORR of 64.3 % (range 27.3 to 97.4 %), median PFS of 12.3 months (range 6 to 36 months), median OS of 32.4 months (range 8 to 79.1 months) and median transplantation associated mortality (TRM) of 4.1 % (range 0 to 22 %). TTP after first-line HDCT/ASCT of ≥ 19.8 months (range 6 to 36 months) was identified as the major predictive factor for a beneficial outcome after salvage HDCT/ASCT. Furthermore, the quality of response after first-line HDCT/ASCT and the number of prior lines of therapy were suggested as predictive factors [48]. A similar, retrospective study from our center involving 200 patients treated between 1995 and 2010 with salvage HDCT/ASCT at relapse after first-line HDCT/ASCT yielded comparable results with median ORR of 80.4 %, median PFS of 15.4 months, median OS of 42.3 months and TRM of 3 %. An overall survival advantage for patients treated with bortezomib or lenalidomide during reinduction suggested that salvage HDCT/ASCT and novel agents are complementary treatment approaches. Moreover, a favorable cytogenetic status (i.e. absence of +1q21, del(17p13) and t(4;14)) was associated with significantly prolonged PFS (25.6 vs. 13.2 months) [41]. Recently, results from the first prospective, randomized trial on salvage HDCT/ASCT in patients with a previous HDCT/ASCT have been published [49]. At first relapse at least 18 months (later reduced to 12 months) after previous HDCT/ASCT, 293 patients were treated with bortezomib/doxorubicin/dexamethasone (PAD) reinduction therapy and underwent stem cell mobilization and harvesting if applicable. Subsequently, 174 eligible patients were randomized on a 1:1 basis to receive either HDCT (melphalan 200 mg/m²) and ASCT or cyclophosphamide (400 mg/m² per week for 12 weeks) consolidation therapy. ORR in the HDCT/ASCT arm was 83 % compared with 75 % in the cyclophosphamide arm with significantly more very good partial remissions or better after HDCT/ASCT (60 % vs. 47 %). The primary endpoint of median TTP was significantly prolonged (19 vs. 11 months). OS did not differ significantly with median OS not having been reached at the cut off date for the final analysis and 3-year OS of 80.3 % vs. 62.9 %. TRM was 1 % in the HDCT/ASCT arm. A subgroup with an unfavorable cytogenetic status (i.e. t(4;14), t(14;16) and/or del(17p13)) did not benefit from HDCT/ASCT (hazard ratio (HR) 2.41). However, the low proportion of patients with available cytogenetic data (51 % of patients undergoing randomization) and the low number of patients with an unfavorable cytogenetic status (n = 13; 15 %) limit the interpretation of this finding.

Existing evidence suggests both feasibility and benefit of salvage HDCT/ASCT in eligible RMM patients. Moreover, novel agent based regimens and HDCT/ASCT seem to be complementary salvage treatment approaches. The ReLApsE trial is designed to analyze the benefit of salvage HDCT/ASCT incorporated into the widely used and novel agent based salvage treatment lenalidomide/dexamethasone (Rd) in a prospective, randomized setting.

For RMM patients no universal therapeutic standard exists. Novel agents, especially lenalidomide in combination with dexamethasone are well evaluated [8, 9] and widely used in RMM patients. However, prospective data on salvage HDCT/ASCT are limited [49] and no prospective, randomized trial evaluating the benefit of salvage HDCT/ASCT versus continued novel agent-based salvage treatment has been published. In the ReLApsE trial, HDCT/ASCT is integrated into and compared against the widely used Rd salvage regimen. Due to the fact that patients randomized into the continued Rd arm are recommended to receive salvage HDCT/ASCT for their next relapse, comparison of early versus late salvage HDCT/ASCT will be possible. Additionally, cytogenetic bone marrow analysis by iFISH is integrated into the diagnostic workup at trial screening which will allow for evaluation of the prognostic relevance of recurrent cytogenetic aberrations in the context of salvage HDCT/ASCT. The ReLApsE trial is therefore expected to generate clinically relevant information to help guide decision-making in the RMM setting.