Thalidomide (T), bortezomib (V) and lenalidomide, all were initially shown to be efficacious to treat relapsed refractory myeloma, then relapsed myeloma, and now are used routinely to treat newly diagnosed myeloma. In particular, each has been added to melphalan and prednisone (MP) as initial therapy for elderly patients and increased overall and extent of response, as well as PFS and OS, compared to MP alone. Similarly, each has been combined with dexamethasone as initial therapy for transplant-eligible patients and achieved increased overall and extent of response both before and after high-dose melphalan and autotransplantation, setting the stage for ongoing trials evaluating novel therapies with and without transplantation. Finally, each has been examined as maintenance therapy. For example, lenalidomide maintenance therapy has prolonged PFS in both newly diagnosed elderly patients treated with MP lenalidamide, as well as in younger patients who have undergone highdose melphalan and autotransplantation therapy.
In Brief
In the current trial reported by Palumbo et al. from Torino, Italy, two very important questions are asked. First, is a four-drug combination VMPT followed by maintenance-VT better than three-drug VMP without maintenance in terms of both efficacy and toxicity for non-transplant patients with newly diagnosed myeloma? The overall rate and extent of response, as well as progression-free survival (PFS) were superior in patients treated with VMPT-VT (38% vs. 24% CR rate and 56% vs. 41% estimated three-year PFS), but no differences were yet seen in overall survival (89% vs. 87%). Importantly, adverse events were more frequent and severe with VMPT-VT, with 38 percent versus 28 percent ≥ grade 3 neutropenia, 10 percent versus 5 percent cardiologic events, and 5 percent versus 2 percent thromboembolic events, so additional studies are clearly needed prior to recommending four-drug induction combination therapy. The incidence of treatment-related death was similar in both groups (4% vs. 3%). In this study, it is impossible to evaluate the independent value of VT maintenance therapy since there were two variables, four-drug and maintenance VT in one arm, versus three-drug VMP without maintenance in the other cohort. Nonetheless, this study does provide further support to a Spanish trial, which showed that VT maintenance was superior to VP maintenance post VMP therapy.
The second important question of this study is the relative efficacy and toxicity of once- versus twice-weekly bortezomib treatment. Indeed, the most important finding of this study is that bortezomib can be given weekly (three-year PFS of 50% vs. 47% compared to twice weekly), thereby markedly reducing overall and severe adverse events without significantly compromising efficacy. Thus, the therapeutic index of this therapy was greatly improved, with ≥ grade 3 non-hematologic adverse events reduced from 51 percent to 36 percent (p=0.003) and ≥ grade 3 sensory peripheral neuropathy reduced markedly from 16 percent to 3 percent with the once weekly regimen. Other trials such as cytoxan, bortezomib, and dexamethasone now further support these benefits of weekly bortezomib, and additional studies are ongoing. Thus, this study has modified the paradigm to weekly bortezomib treatment, assuring that it can be given to a broader spectrum of patients for longer durations and markedly expanding its therapeutic benefits.
