Effect of induction therapy with lenalidomide, doxorubicin and dexamethasone on bone remodeling and angiogenesis in newly diagnosed multiple myeloma

Abstract

There is limited data regarding the efficacy and safety of lenalidomide, adriamycin and dexamethasone (RAD) combination on newly diagnosed multiple myeloma (NDMM) patients. There is also scarce information about the effect of lenalidomide on bone metabolism and angiogenesis in NDMM. Thus, we conducted a Phase 2 study to evaluate the efficacy and safety of RAD regimen as induction in transplant‐eligible NDMM patients and we studied the effects on bone metabolism and angiogenesis. A total of 45 patients were enrolled. Following four cycles of RAD, the overall response rate was 66.7% and after a median follow up of 29.1 months (range 21.0–34.9), the median survival outcomes have not been reached yet. RAD had a favorable toxicity profile and did not impair stem cell collection. RAD significantly reduced bone resorption markers CTX (p = 0.03) and TRACP‐5b (p < 0.01). Interestingly, RAD also increased bone formation markers bone‐specific alkaline phosphatase (p = 0.036), procollagen type 1 amino‐terminal propeptide (p = 0.028) and osteocalcin (p = 0.026), which has not been described before with lenalidomide‐containing regimens in the absence of bortezomib coadministration. Furthermore, the angiogenic cytokines VEGF (p = 0.01), angiogenin (p = 0.02) and bFGF (p < 0.01) were significantly reduced post‐RAD induction. Our results suggest that RAD is an effective induction regimen before autologous stem cell transplantation with beneficial effects on bone metabolism and angiogenesis.

Metabolic Disorders in Multiple Myeloma

“…Parathyroid hormone-related protein (PTHrP) is usually within normal limits in contrary with solid tumors and myeloma patients usually respond rapidly to corticosteroids administration, due to rapid control of the disease. Interestingly, anti-myeloma treatment seems to restore bone metabolism [ 95 , 96 , 97 , 98 , 99 ], whereas anti-resorptive treatment such as bisphosphonates and anti-RANKL agents reverse myeloma-induced hypercalcemia [ 90 , 96 ].…”

Daratumumab Improves Bone Turnover in Relapsed/Refractory Multiple Myeloma; Phase 2 Study “REBUILD”

“…Bisphosphonates, especially zoledronic acid, and denosumab, a monoclonal antibody binding to the receptor activator of nuclear factor kappa-Β ligand (RANKL), are the mainstay of treatment for MM-related bone disease [ 3 ]. Furthermore, anti-myeloma drugs, such as the proteasome inhibitors bortezomib and carfilzomib, have shown a positive effect on bone health [ 4 , 5 , 6 , 7 , 8 ]. Consequently, research into agents that combine anti-myeloma activity with positive effects on bone metabolism is of high importance [ 9 , 10 ].…”

Comparison of efficacy, safety, patients’ quality of life, and doctors’ occupational stress between lenalidomide‐based and bortezomib‐based induction in patients with newly diagnosed multiple myeloma

“…The high failure rate of stem cell mobilization in the RAD group also led to difficulty with ASCT and hematopoietic reconstitution, which was the major reason for treatment interruption. However, in the study by Terpos et al, 9 89% of patients successfully mobilized stem cells after four courses of RAD induction, and the average number of CD34+ cells collected was 8.94 × 10 6 /kg. In addition, Baz et al 8 reported that in 31 T A B L E 4 Stem cell mobilization, transplantation, and hematopoietic reconstruction patients with MM induced by the RAD regimen for four to eight courses, the number of stem cells collected from all of the patients was ≥2 × 10 6 /kg.…”

“…Baz et al 8 reported that the RAD regimen resulted in a 77.2% overall response rate (ORR) in NDMM patients. In addition, Terpos et al 9 found that the ORR was 66.7% after four cycles of RAD induction. However, all of these trials were single‐arm phase II trials, and the regimens were not compared with other induction regimens.…”