Lenalidomide, doxorubicin, and dexamethasone induction therapy affects bone remodeling and angiogenesis in newly diagnosed multiple myeloma

The efficacy and safety of the triplet combination lenalidomide, doxorubicin, and dexamethasone (RAD) are well known in patients with relapsed/refractory multiple myeloma (MM), however, data are limited for patients with newly diagnosed multiple myeloma (NDMM) who are eligible for autologous stem cell transplantation (ASCT). ¹Lenalidomide has been shown to exert its function through the inhibition of interactions between myeloma and stromal cells, however, the effect of RAD on bone metabolism and angiogenesis is largely unknown. ²

This open-label, non-comparative, non-randomized phase II study ( NCT02471820), conducted by Evangelos Terposand colleagues, aimed to evaluate the efficacy and safety of the RAD regimen as an induction protocol in patients with transplant-eligible symptomatic NDMM, as well as examining the effect on bone metabolism and angiogenic cytokine levels. ³Patients with symptomatic NDMM (n = 45; median age = 56 years; range, 37–69) were treated with a RAD induction regimen (lenalidomide [25 mg daily, days 1–21]; doxorubicin [9 mg/m ², days 1–4]; dexamethasone [40 mg, days 1, 8, 15, and 22]) for four cycles of 28-days each, prior to ASCT. Following ASCT, patients did not receive a consolidation or maintenance regimen. The primary endpoint of the study was overall response rate (ORR) to RAD regimen. Secondary endpoints included progression-free survival (PFS), time to disease progression (TTP), and safety assessment.

Key findings:

Efficacy

• Median duration of treatment: 15.8 weeks (range, 1.8–25.8)
• ORR following RAD induction: 66.7%
  • ORR increased to 84.4% post-ASCT
• Median follow-up: 29.1 months (range, 21.0–34.9)
• Median PFS, TTP, and OS: not yet reached
  • The probability of 2-year PFS and TTP: 60%
• Patients achieved adequate stem cell collection post-RAD induction: 89% (n = 40)
• RAD significantly reduced circulating levels of bone resorption markers CTX ( P= 0.03) and TRACP-5b ( P< 0.01)
• RAD also increased serum levels of bone formation markers bALP ( P= 0.036), P1NP ( P= 0.028), and OC ( P= 0.026)
• Circulating angiogenic cytokines were significantly reduced following RAD induction: VEGF ( P= 0.01), angiogenin ( P= 0.02), bFGF ( P< 0.01)

Safety

• Grade 3 or 4 adverse events occurring in more than one patient include: anemia (n = 4), neutropenia (n = 3), and febrile respiratory infection (n = 2)
• Overall 55% of patients received prophylactic GCSF during the treatment course

In conclusion, the RAD induction regimen prior to ASCT is effective and has a tolerable safety profile in patients with transplant-eligible NDMM. Moreover, RAD reduced bone resorption, increased bone formation and reduced circulating angiogenic cytokines, suggesting an impact on the tumor microenvironment. Further studies are needed to validate the therapeutic effect of this induction regimen on disease status, bone remodeling, and angiogenesis.