Together for better?

In this issue of Blood, Mateos et al report that bortezomib plus melphalan and prednisone (VMP) and lenalidomide plus low-dose dexamethasone (Rd) administered in a sequential or an alternating scheme were equally active and induced comparable toxicities in elderly myeloma patients.¹ 

The treatment paradigm of multiple myeloma (MM) has evolved rapidly over the last years and still continues to change. Following the first novel agents thalidomide, bortezomib, and lenalidomide, more potent next-generation proteasome inhibitors (PIs), like carfilzomib and ixazomib, and immunoderivative (IMiD) agents, such as pomalidomide, have been developed. More recently, new classes of drugs, including histone deacetylase inhibitors (HDACi) and monoclonal antibodies (mAbs) directed against proteins expressed on the surface of myeloma cells, in addition to molecularly targeted therapies, immune checkpoint inhibitors, and modulators of cellular antitumor immune surveillance, have been successfully introduced to the expanded therapeutic armamentarium of MM.²  Among these new agents, panobinostat, an HDACi, the first oral PI ixazomib, and the anti-CD38 and -SLAMF7 mAbs daratumumab and elotuzumab have been granted recent approval by the US Food and Drug Administration or the European Medicines Agency (EMA) for the treatment of relapsed and/or refractory MM. In patients with newly diagnosed MM (NDMM) who are not candidates to receive an autotransplantation (ASCT), incorporation of an IMiD or bortezomib into newer up-front therapies, more frequently built on the backbone of melphalan-prednisone (MP), resulted in improved clinical outcomes compared with standard MP.^3-5  Therefore, regimens like MP-thalidomide (MPT) or VMP, each of them usually administered for a fixed number of cycles, have been traditionally considered the standard therapy in this setting, particularly in European countries. More recently, based on the superior progression-free survival (PFS) and overall survival (OS) reported with continuous Rd in comparison with MPT and Rd given for 12 and 18 cycles, respectively, Rd until progression has been approved by the EMA and is likely to become a new standard of care for elderly or ASCT-ineligible patients with NDMM.⁶ 

Mateos et al report on the results of a phase 2 study designed to investigate the feasibility and efficacy of VMP and Rd given either sequentially (eg, 9 cycles of VMP followed by 9 cycles of Rd) or in an alternating scheme (eg, 1 cycle of VMP followed by 1 cycle of Rd, and so on, up to 18 cycles) in NDMM patients who were not candidates for ASCT (see figure). No difference in the 18-month probability of PFS, which was the primary study end point, was seen between patients randomly assigned to receive the sequential vs the alternating administration of the 2 regimens (75% vs 80%, respectively). The 2 schemes were also comparable with respect to the toxicity profile, which was a coprimary end point. Moreover, secondary efficacy measurements did not differ between the sequential and alternating treatment arms. Indeed, the probability of best complete response (CR) or higher was 42% vs 40%. With a median follow-up of 30 months, median PFS was 32 vs 34 months, whereas the 3-year OS estimate was 72% vs 74%. Remarkably, patients ≥75 years of age had a significantly poorer outcome in comparison with those <75 years of age.

Bortezomib and lenalidomide have different, but at the same time overlapping, mechanisms of action that include activation of apoptosis mediated by caspase-9 and/or caspase-8 and inhibition of nuclear factor-κB signaling. Additionally, lenalidomide sensitizes MM cells to both bortezomib and dexamethasone, whereas the anti-MM activity of dexamethasone is enhanced by both bortezomib and lenalidomide. These preclinical findings supported the use of these 2 drugs combined with dexamethasone in MM patients. More recently, new insights into the biology of MM have provided a better understanding of the evolutionary landscape of the disease, which is composed of an array of multiple clones that compete with each other and are potentially associated with different biological characteristics and sensitivity to various drugs.⁷  Intraclonal heterogeneity and clonal evolution are well-known mechanisms leading to treatment resistance. Therefore, the best choice of, and the optimal combination or sequence in which, different classes of drugs are administered represent an area of current research and may affect our future approach to MM therapy.

To avoid the anticipated unacceptable toxicity related to a 5-drug therapy combining the triplet VMP and the doublet Rd, Mateos et al aimed to administer these 2 standard regimens either in 2 sequential blocks of 9 cycles each or in alternating cycles for a total of 18 courses. The alternating scheme was supposed by the authors to be more active than the sequential one due to the enhanced killing of subclones with potentially different sensitivity to an IMiD and to a PI combined with an alkylator. Additionally, the opposite effects of bortezomib and lenalidomide on host anti-MM immunity, in particular T cells and natural killer cells, provided further support to the alternating use of these agents. The hypothesis of the higher activity and lesser toxicity of the alternating vs the sequential scheme was not confirmed by the results. Nevertheless, the efficacy of both these treatments was remarkable. Although cross-trial comparisons are inadequate and potentially biased by many factors, the rate of CR or higher, including the negativity of minimal residual disease detection by flow cytometry, and the duration of PFS yielded by the sequential and alternating schemes of VMP and Rd were among the best results reported thus far in elderly or ASCT-ineligible NDMM patients.^3-6,8,9  In contrast, OS duration was unlikely to differ from the figure reported with a similar follow-up in the original Velcade as Initial Standard Therapy in Multiple Myeloma study comprising 9 cycles of VMP.⁴  On one hand, these findings suggest that the efficacy in terms of depth and durability of response of a fixed-duration therapy including 2 different regimens like VMP and Rd was superior to that expected by administering each of these regimens for a fixed number of cycles, even when the planned treatment duration was the same.^4,6  Notably, the median PFS afforded by VMP and Rd was comparable to values reported with a more complex treatment program comprising 6 to 9 cycles of VMP or VMP plus thalidomide induction, followed by maintenance therapy with combined bortezomib and thalidomide for 2 to 3 years.^8,9  On the other hand, it might be hypothesized that the continuous or alternating exposure to lenalidomide and bortezomib combined with an alkylating agent might influence the choice and activity of salvage therapy at the time of progression, possibly exerting a (different) selection pressure driving (different) dynamics of clonal tiding. These questions were not addressed in the article by Mateos et al, possibly due to the relatively short follow-up at the time the analysis was performed, and therefore remain unanswered. To rule out the possible negative effect of VMP and Rd on the efficacy of second-line therapy, PFS2 (eg, the time from initial randomization to the date of progression or death from any cause after second-line therapy) warrants careful evaluation in the 2 treatment arms. Data from this analysis, along with evaluation of additional time-to-event measures, such as treatment-free interval and time to next therapy, and positive results hopefully confirmed with a longer follow-up will help to better clarify the benefits of this new treatment incorporating an alkylator-based triplet and an alkylator-free doublet for NDMM patients aged 65 to 75 years. In older individuals, this therapeutic approach needs further investigation to avoid any detrimental overtreatment of an often frail patient population.