Frontline treatment for transplant‐eligible multiple myeloma: A 6474 patients network meta‐analysis

Abstract

Autologous transplantation continues to be the cornerstone of younger and fit multiple myeloma patients. It is known that frontline induction therapy before transplantation can influence post-transplant results. Therefore, best frontline treatment for transplant-eligible patients should be based on best available evidence to guide therapy. Furthermore, until now due to data scarcity, it was not possible to thoroughly compare lenalidomide to other regimens in this setting. We performed a systematic review and network (mixed treatment comparison) meta-analysis of 21 clinical trial publications, enrolling 6474 patients and comparing 11 different treatment frontline setting regimens regarding survival, response, and safety outcomes. OS analysis showed superiority of CRD (cyclophosphamide-lenalidomide-dexamethasone) over TD-based (thalidomide-dexamethasone, HR = 0.76,0.62-0.90), VAD-based (HR = 0.71,0.52-0.90), and Z-Dex (idarubicin-dexamethasone, HR = 0.37,0.17-0.76) regimens. Concerning PFS, VTD (bortezomib-thalidomide-dexametasone) showed superior results when compared with TD-based (HR = 0.66,0.51-0.84), VAD-based (HR = 0.61,0.46-0.82), Z-Dex (HR = 0.42,0.22-0.78), and high dose dexamethasone (Dex, HR = 0.62,0.41-0.90) regimens. Bortezomib/thalidomide regimens were not superior to lenalidomide, considering these outcomes. Also, concerning complete and overall response, VTD ranked first among other regimens, showing clear superiority over thalidomide-only containing protocols. Safety outcome evaluated infectious, cardiac, gastrointestinal, neurological, thrombotic, and hematological grade 3 to 4 adverse events. Risk of thrombotic events was higher with TAD (thalidomide-doxorubicin-dexamethasone), neurological with PAD (bortezomib-doxorubicin-dexamethasone), infectious with Dex, hematological with Z-Dex, gastrointestinal with VTD, and cardiac with PAD regimens. Our study endorses current recommendations on combined immunomodulatory drugs and proteasome inhibitors frontline regimens (in triplets) in transplant-eligible multiple myeloma patients, but also formally demonstrates the favorable performance of lenalidomide in overall and progression-free survival, when compared with bortezomib/thalidomide protocols.

Evolution of diagnostic workup and treatment for multiple myeloma 2013‐2019

“…Recently, network meta‐analysis of results of 21 clinical trial publications endorsed combining IMiDs and proteasome inhibitors (PIs) for frontline regimens in transplant‐eligible MM patients. It also confirmed superiority of lenalidomide over thalidomide in this setting 38 …”

Treatment of Multiple Myeloma and the Role of Melphalan in the Era of Modern Therapies—Current Research and Clinical Approaches

“…Three-drug combinations including a PI with an IMiD and dexamethasone are currently considered as the gold standard regimens [ 48 , 71 ]. The combination of bortezomib, thalidomide, and dexamethasone (VTD) shows superiority over the combinations of the two drugs thalidomide-dexamethasone (TD) and bortezomib-dexamethasone (VD) in terms of response rates and long-term outcomes [ 56 , 72 , 73 ]. Lenalidomide in combination with bortezomib and dexamethasone (RVD) has advantages over lenalidomide-dexamethasone (RD) and is associated with deeper and sustained responses and increased survival [ 74 ].…”

Multiple myeloma: Role of autologous transplantation

“…Induction with the triple combination of first-in-class PI, bortezomib, and IMiD, thalidomide, with dexamethasone (VTD) has shown superiority compared with the two-drug combinations thalidomidedexamethasone (TD) and bortezomib-dexamethasone (VD) in terms of response rates and long-term outcomes [49][50][51][52]. Both a meta-analysis of single-arm studies and a phase 3 clinical trial have also demonstrated the superiority of VTD over the combination of bortezomib-cyclophosphamide-dexamethasone (VCD) regarding the depth of response (VGPR or better rate 66% vs 56%, respectively, p = 0.05), whereas VTD showed a better toxicity profile except for a higher rate of peripheral neuropathy [53,54].…”

“…Induction with VRD has demonstrated high rates of deep responses [16,56,57]; in a phase 3 clinical trial more than one third of transplant-eligible NDMM patients achieved MRD negativity and almost half of the patients with high-risk cytogenetics achieved CR or better [58]. Although lenalidomide-based may be superior to bortezomib-and thalidomide-based regimens [49] and VRD has become the prevalent induction regimen in the United States, VTD or even VCD may be viable options depending on the setting and drug availability [59].…”