Kenneth C. Anderson, MD
Dr. Anderson has served on Celgene’s advisory board.
Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366:1759-1769.
McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770-1781.
Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791.
Three recently published studies support the use of lenalidomide maintenance therapy in multiple myeloma (MM). The first, a clinical trial from Palumbo and colleagues compared melphalan prednisone (MP) versus MP lenalidomide (MPR) versus MPR plus R maintenance therapy. At a median follow-up of 30 months, progression-free survival (PFS) was significantly prolonged after MPR-R (31 months) versus MPR (14 months, p < 0.001) or MP (13 months, p < 0.001). Importantly, the PFS benefit occurred in patients 65 to 75 years old, but not in older patients. To date, there is no overall survival (OS) difference. Landmark analysis showed a 66 percent reduction in progressive disease after MPR-R treatment. The incidence of secondary cancers at three years was 7 percent in patients receiving MPR-R, 7 percent for those receiving MPR, and 3 percent for those receiving MP. The other two studies evaluated lenalidomide maintenance post high-dose therapy supported by autologous stem cell rescue. The study by McCarthy et al. was unblinded when an interim analysis revealed that 20 percent of patients on lenalidomide versus 44 percent of patients on placebo (p < 0.001) treatment died or had progressive disease. Moreover, 86 of 128 patients receiving placebo who had not yet progressed then elected to begin lenalidomide maintenance. In spite of this high percentage of crossover, the median time to progression, post-transplant, was 46 months with lenalidomide maintenance versus 27 months in the placebo group (p < 0.001). Additionally, more deaths were noted in the placebo arm (53, 23%) compared with the lenalidomide arm (35, 15%) (p = 0.03). Secondary cancers were noted in 18 (8%) and six (3%) of patients who received lenalidomide and placebo maintenance, respectively. The third trial by Attal and colleagues in the Intergroupe Francophone du Myelome (IFM) also evaluated lenalidomide maintenance therapy post-transplant. PFS was 41 months and 23 months with lenalidomide and placebo maintenance, respectively (p < 0.001), but there was no significant difference in OS. The incidence of secondary malignancies was 3.1 versus 1.2 per 100 patient-years in the lenalidomide and placebo maintenance cohorts, respectively (p = 0.002). Moreover, median event-free survival, including secondary cancers, was prolonged in the lenalidomide cohort at 40 months compared with 23 months in the placebo cohort (p < 0.001).
These three studies provide a strong rationale for the use of lenalidomide as maintenance therapy in MM. For many years, there have been efforts to identify effective maintenance therapies to prolong response to initial treatment in MM. Although a interferon prolonged responses by several months, its toxic adverse effect profile precluded broad clinical use. Corticosteroids were also explored in early trials, but efficacy was unconfirmed. In the era of novel therapies, low-dose thalidomide has been evaluated in both patients ineligible for transplant and those undergoing transplant. Benefit was observed in both groups, but neuropathy attendant to prolonged use of even low-dose thalidomide limits its utility. Intravenous bortezomib at several doses and schedules has also shown activity in prolonging PFS and even OS in both patients ineligible for transplant and patients who are post-transplant. Further evaluation of proteasome inhibitor therapy as a maintenance strategy is warranted as bortezomib given subcutaneously has the advantage of ease of administration and better tolerability compared with the intravenous form, and next-generation, oral proteasome inhibitors promise an even more patient-friendly delivery system. At present, however, the three randomized trials cited above provide the strongest evidence for use of lenalidomide maintenance treatment to prolong response in MM.
What have we learned? In all three studies, the PFS was markedly prolonged with use of lenalidomide maintenance. For many years we have understood the heterogeneity of MM, and recent studies have confirmed its genetic complexity at diagnosis as well as the molecular mechanisms that underlie treatment failure due to drug resistance. Although relapsed MM may be effectively treated with novel agents, it is not curable. Therefore, current strategies include combinations of targeted and conventional therapies to address heterogeneity at diagnosis, followed by maintenance therapy to short-circuit mechanisms of relapse as they evolve. The prolongation of PFS associated with use of lenalidomide maintenance in all these studies validates this strategy and identifies a critically important target for continued basic and clinical investigation.
At the time of analysis, the OS was significantly prolonged only in the McCarthy et al. posttransplant study. This outcome is remarkable given that the majority of patients crossed over from placebo to lenalidomide treatment after unblinding the study. Although prolongation of OS is the ultimate goal of maintenance therapy, it is currently difficult to design trials to show this result, given the necessary crossover option and the lack of uniform treatment approaches when the disease progresses while on maintenance treatments. In the Palumbo et al. trial, there was a trend for an OS advantage in patients 65 to 75 years old who were being treated with lenalidomide. Moreover, many of the randomized IFM transplant trials, such as those comparing single versus double stem cell transplantation in MM, show survival differences only after prolonged follow-up. Therefore, it will be of great interest to carefully monitor the lenalidomide maintenance trials for survival differences as they mature.
What about secondary cancers? In all three trials there was a small but statistically significant increase in the incidence of secondary cancers. In addition to lenalidomide, careful analysis has identified other factors associated with secondary cancer risk, including prior exposure to an alkylating agent, advanced-stage disease, and male sex. Most importantly, however, is the overwhelming risk of progressive disease and death from MM relative to the small but real risk of secondary cancer. Ongoing studies of the relationship of secondary cancer development and lenalidomide maintenance therapy are further examining MM biology, clinical parameters, and duration of lenalidomide therapy in order to further exploit the benefit of lenalidomide maintenance while minimizing the attendant risk.
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