Bortezomib‐ and thalidomide‐induced peripheral neuropathy in multiple myeloma: clinical and molecular analyses of a phase 3 study

Abstract

A subanalysis of the GIMEMA-MMY-3006 trial was performed to characterize treatment-emergent peripheral neuropathy (PN) in patients randomized to thalidomide-dexamethasone (TD) or bortezomib-TD (VTD) before and after double autologous transplantation (ASCT) for multiple myeloma (MM). A total of 236 patients randomized to VTD and 238 to TD were stratified according to the emergence of grade 2 PN. Gene expression profiles (GEP) of CD1381 plasma cells were analyzed in 120 VTD-treated patients. The incidence of grade 2 PN was 35% in the VTD arm and 10% in the TD arm (P < 0.001). PN resolved in 88 and 95% of patients in VTD and TD groups, respectively. Rates of complete/near complete response, progression-free and overall survival were not adversely affected by emergence of grade 2 PN. Baseline characteristics were not risk factors for PN, while GEP analysis revealed the deregulated expression of genes implicated in cytoskeleton rearrangement, neurogenesis, and axonal guidance. In conclusion, in comparison with TD, incorporation of VTD into ASCT was associated with a higher incidence of PN which, however, was reversible in most of the patients and did not adversely affect their outcomes nor their ability to subsequently receive ASCT. GEP analysis suggests an interaction between myeloma genetic profiles and development of VTDinduced PN.

VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial

“…[9][10][11] Peripheral neuropathy, which can be irreversible and may impair the quality of life of a patient, is an important issue when selecting a specific induction regimen, but the analysis of a large Italian trial that investigated VTD induction followed by ASCT showed that PN induced by this triplet combination may resolve in the majority of the cases or may improve to grade 1 in at least 90% of the patients. 17 Overall, in our trial, the rate of severe AEs was identical in both arms, and the number of patients that could not receive the planned schedule of induction was very low. Importantly, .90% of the patients underwent successful stem cell harvest, and VTD induction was associated with a superior stem cell yield as compared with VCD.…”

Bortezomib-thalidomide-dexamethasone (VTD) is superior to bortezomib-cyclophosphamide-dexamethasone (VCD) as induction therapy prior to autologous stem cell transplantation in multiple myeloma

“…Of the most common grade 3-4 AEs recorded during induction therapy and listed in Table 2, peripheral neuropathy (PN) 7 and skin rash occurred more frequently with VTD compared to VCD(7% vs 2%, p=0.009,and 8% vs 1%, p<0.001, respectively). By the opposite, VCD was associated with a higher probability of severe anemia (7% vs 0%, p=0.003), neutropenia (8% vs 2%, p<0.001) and thrombocytopenia (4% vs <1%, p=0.006) than VTD.…”

How I manage the toxicities of myeloma drugs

“…[27][28][29] It has been suggested that concomitant cyclophosphamide 30 or IMiD 25 treatment could reduce BiPN; however, reliable evidence is lacking. Whereas some genetic risk factors have been defined, 31,32 clinically useful predictors for BiPN and TiPN are not available, although preexisting PN does heighten the risk. Along this line, our patient may have had subclinical diabetic PN.…”