Time to Improve Bortezomib and Lenalidomide Lines of Therapy

Background. Thalidomide, part of the MPT regimen upfront for eNDMM, e.g. elderly newly diagnosed myeloma, remains one of the most prescribed regimens. It is then often followed by either bortezomib-based at first relapse then lenalidomide-based regimens at the subsequent relapse. This sequence of treatment is challenged by a start with Bortezomib, primarily as VMP as first line, then uniquely followed by lenalidomide-based regimens at first relapse. In the latter, it is likely that patients would not receive thalidomide throughout the disease course of myeloma. We sought to analyse the 2 types of sequence, and demonstrate that patients not exposed to thalidomide upfront, and that were solely exposed to bortezomib-based and lenalidomide-based regimens would have a similar survival than patients exposed to all 3 drugs, e.g. thalidomide, lenalidomide and bortezomib.

Method. A total of 145 patients were recruited in this multicentric study, 46,2% were in the thalidomide upfront exposed arm and 53,8% had never been exposed to thalidomide. Patients were required to be aged ≥65 years, NDMM treated with either thalidomide upfront or never been exposed to thalidomide. If not exposed to thalidomide, the patients were to have received bortezomib upfront and lenalidomide first relapse or vice versa. MPT was given as published. In the non-exposed thalidomide group, all patients had bortezomib upfront, either Vd, VCd or VMP. Lenalidomide and dexamethasone was given as published.

Results. Overall, the median age was 73 years (range, 65 - 85), with 35% aged >75. The M/F ratio was 1.1, 38% were ISS 3, the median b2m was 5.5mg/L, 26% had an ECOG score ≥ 2, 42% had renal insufficiency, 11% had elevated LDH, 8% presence of plasmacytoma, and 14% had adverse FISH (del17p, t(4;14) and or t(14;16)). There was no difference in patients' characteristics across studied groups, according to exposure or not to thalidomide. With a median follow-up of 5 years, 60% have died overall; 69% in the thalidomide exposed group versus 52% in the thalidomide non-exposed group (p=0.027). The median OS of thalidomide exposed patients was 55.7 months (46;65) versus 44 months (35;53) in the thalidomide non exposed patients (p=0.079). In the thalidomide exposed group, the median PFS of the thalidomide, bortezomib then lenalidomide sequences were 27 months (24;30), 11 months (8;13) and 13 months (10;15). In the thalidomide non-exposed group, the median PFS of bortezomib then lenalidomide lines were 17 months (13;21) and 13 months (6;20). We then studied the survival of patients from onset of first relapse in the thalidomide exposed group, e.g. upon treatment with bortezomib, followed by lenalidomide at subsequent relapse, 22.5 months (10;34) compared to patients in the thalidomide non-exposed group that received bortezomib upfront and lenalidomide at first relapse, 44 months (35;53), p=0.005.

Conclusion. Overall, thalidomide exposed versus non exposed groups had similar OS, while OS was significantly lower in the thalidomide exposed patients at first relapse onset versus in the thalidomide non exposed patients from diagnosis. This data seems to spare the thalidomide but for this it is necessary to optimize the first and second sequences of treatment based on bortezomib and lenalidomide which justifies the use of triplet.