GMMG-MM5 | Response-adapted lenalidomide maintenance in newly diagnosed multiple myeloma

Lenalidomide (Len) maintenance therapy is the standard of care in newly diagnosed multiple myeloma (NDMM) following high-dose melphalan (HDM; 200 mg/m²) and autologous stem cell transplantation (ASCT) and was approved by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) in 2017.¹ At the International Myeloma Workshop (IMW) in Boston, US, the Multiple Myeloma (MM) Hub reported from a debate regarding continuous vs definitive Len maintenance therapy (which can be found here) and a Twitter poll conducted by the MM Hub found that 60% of voters felt that Len maintenance should be given indefinitely.

Hartmut Goldschmidt and Elias Mai, University Hospital Heidelberg, Heidelberg, DE, and colleagues from the German-Speaking Myeloma Multicenter Group (GMMG) have recently published the findings from their phase III MM5 trial (2010-019173-16), which assessed whether Len maintenance therapy should be continued beyond the achievement of complete response (CR).¹

Study design

In patients with NDMM who were eligible for transplantation, the study aimed to demonstrate that induction therapy with bortezomib, doxorubicin, and dexamethasone (PAd) was non-inferior to bortezomib, cyclophosphamide, and dexamethasone (VCD) in relation to very good partial response (VGPR) rate, published previously², and to determine which of the following four treatment strategies was most beneficial in terms of progression-free survival (PFS):

• A1: PAd plus Len for 2 years (Len-2Y)
• B1: PAd plus Len until CR (Len-CR)
• A2: VCD plus Len-2Y
• B2: VCD plus Len-CR

All treatment strategies included three cycles of induction therapy, plus HDM and ASCT, and Len consolidation therapy prior to maintenance therapy with Len-2Y or Len-CR. For patients in < CR following ASCT, tandem HDM/ASCT was recommended. The dose of melphalan was adjusted according to renal function but not age.

CR was determined by a negative serum/urine immunofixation and the assessment of cytology of bone marrow. Secondary endpoints included overall survival (OS), response rates, and toxicities.

Results

Patient numbers throughout the study are detailed in Table 1. In the patients included in arms B1 and B2, Len maintenance was not initiated if CR was achieved during consolidation (n = 31 and n = 29, respectively). Additionally, Len maintenance was stopped early due to CR in 15 and 13 patients in arms B1 and B2, respectively. Full Len maintenance of two years was administered to 44, 18, 44, and 22 patients in arms A1, B1, A2, and B2, respectively.

Mean Len treatment durations were 17.6 vs 9.5 months (p < 0.001) in the Len-2Y vs Len-CR groups, and of those who achieved CR before or during Len maintenance, mean Len maintenance treatment duration was 17.8 vs 3.1 months (p < 0.001), respectively. There was no significant difference in Len maintenance treatment duration in those patients who did not achieve CR.

Table 1. Patient numbers¹

There was no significant difference in PFS between the treatment arms at a median follow-up of 59.4 months (95% CI, 58.2–61.0), with median PFS of 43.2, 35.9, 40.9, and 35.7 months for A1, B1, A2, and B2, respectively (p = 0.60). OS was not significantly different between the four study arms at a median follow-up of 60.1 months (95% CI, 59.2–61.9), but was significantly shorter for B1 vs A1 (p = 0.047), with 36-month OS rates of 75.1% and 82.9%, respectively. Between the Len-2Y and Len-CR arms, there was no significant difference in PFS (HR 1.15 [95% CI, 0.93–1.44]; p = 0.20), however OS favored Len-2Y (HR 1.42 [95% CI, 1.04–1.93]; p = 0.03).

On multivariate analysis, the Len maintenance strategy (Len-CR vs Len-2Y) had a significant impact on OS (HR 1.71; p = 0.003) but not PFS (HR 1.23; p = 0.10). OS after first relapse/progression was also analyzed, and Len-2Y was favored, though therapies used at first relapse/progression differed significantly between the Len maintenance groups (p = 0.04).

Adverse events (AEs) are detailed in Table 2. There was at least one AE in 87.3% vs 79.5% vs 91.3% vs 77.4% of patients in arms A1, B1, A2, and B2, respectively, and there was a significant difference in the number of AEs between the LEN-2Y and LEN-CR groups (77.6% vs 58.2%, respectively; p < 0.001). This was no longer significant when adjusting for the number of years of Len exposure. There was no significant difference in the rate of second primary malignancy (5.6% vs 6.1%) between the Len-2Y and Len-CR groups, respectively (p = 0.85).

Table 2. AEs according to maintenance strategy¹

In patients with high-risk cytogenetic aberrations (CA; defined as either deletion of 17p13 subclonal in > 10% of nucleated, CD138-purified cells, and/or translocation t(4;14), and/or gain > 3 copies 1q21), the CR-adapted withdrawal Len maintenance therapy strategy was associated with a decreased PFS and OS (Len-CR, high-risk CA yes vs no — PFS: HR 1.93 [95% CI, 1.34–2.77], p < 0.001; OS: HR 2.96 [95% CI, 1.91–4.61], p < 0.001).

Conclusion

Goldschmidt and Mai concluded that stopping Len maintenance therapy at CR was associated with a reduced OS and a shortened PFS, and the use of continuous Len maintenance therapy was particularly important in patients with high-risk CA. The team felt that the toxicities of Len maintenance beyond CR were manageable and would enable a continuous Len maintenance strategy.