Up-Front HDT Consolidation Beneficial in Myeloma With High-Risk Cytogenetics

Patients with multiple myeloma and high-risk cytogenetics may benefit from treatment with high-dose therapy consolidation compared with delaying this approach.

Although the overall survival (OS) benefit of high-dose therapy (HDT) is dependent on cytogenetics, investigators recommend that patients with high-risk multiple myeloma receive this regimen up front as consolidation therapy, according to findings published in Cancer.

After a median follow up ranging from 3.1 to 7.8 years, investigators reported a pooled OS hazard ratio of 0.90 (95% CI, 0.70-1.17) for HDT compared with 0.66 (95% CI, 0.45-0.97) for standard-dose therapy (SDT) consolidation in those with standard- and high-risk disease. Moreover, when assessing OS efficacy with HDT between standard- and high-risk populations, investigators reported that the high-risk group benefited most from the regimen (P = .03). Additionally, the hazard ratios for progression-free survival (PFS) for HDT vs SDT in both cohorts were 0.65 (95% CI, 0.56-0.76) and 0.52 (95% CI, 0.330.83), respectively, with a nonsignificant difference in HDT use across risk groups (P = .25).

“Up-front HDT consolidation, when compared to SDT, continues to offer PFS benefit in newly diagnosed myeloma, with the magnitude of benefit being similar across cytogenetic risk subgroups. However, OS benefit from up-front HDT is derived primarily by cytogenetic high-risk patients despite a high rate of salvage HDT in the control arms. Based on our results, HDT consolidation should not be delayed in cytogenetic high-risk patients outside of well-designed clinical trials. Future [randomized controlled trials] in transplant-eligible high-risk patients investigating up-front novel immunotherapies such as CAR T-cell therapy or T-cell engagers should ensure that fit patients in the control arm are not deprived from up-front HDT,” investigators wrote.

To conduct the systemic review and meta-analysis, investigators searched databases from 2000 to 2021. The primary goal was to examine any differences in efficacy among standard- and high-risk patients treated with HDT. A total of 3305 citations were identified, 42 of which met the inclusion criteria. Of these trials, 6 were randomized controlled trials totaling 2959 patients.

Across the trial populations, 70.3% to 91.7% of patients were evaluable for cytogenetic risk stratification. Patients with high-risk cytogenetics ranged from 17% to 34% and 17% to 29% of those in the HDT and SDT treatment arms, respectively.

Induction regimens in the HDT arm included bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd; n = 1); carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd; n = 1); Rd (n = 2); bortezomib, cyclophosphamide, and dexamethasone (n = 1); and carfilzomib, cyclophosphamide, and dexamethasone (KCd; n = 1). Moreover, in the SDT arm, consolidation regimens included VRd (n = 1); bortezomib, melphalan, and prednisone (n = 1); cyclophosphamide, lenalidomide, and dexamethasone (n = 1); melphalan, prednisone, and lenalidomide (n = 1); KRd (n = 1); and KCd (n = 1).

Patients who underwent treatment with salvage HDT at relapse ranged from 43% to 77% of those included. In another approach to the subgroup analysis, investigators reported a hazard ratio of 0.76 (95% CI, 0.54-1.08) for OS in the high-risk vs standard-risk populations, respectively.

“This is the first systematic review and meta-analysis investigating outcomes of consolidation with up-front HDT vs SDT by cytogenetic risk subgroup in newly diagnosed myeloma. We have demonstrated that the magnitude of PFS benefit with HDT over SDT consolidation was similar across cytogenetic-risk subgroups. However, OS benefit with up-front HDT consolidation was seen only in cytogenetic high-risk patients. Notably, the OS benefit in high-risk patients was seen despite a high incidence of salvage transplants in the SDT group,” investigators concluded.

Reference

Chakraborty R, Siddiqi R, Wilson G, et al. Impact of autologous transplantation on survival in newly diagnosed multiple myeloma patients with high-risk cytogenetics: a meta-analysis of randomized controlled trials. Cancer. Published online April 4, 2022. doi:10.1002/cncr.34211