In an important recent study by Dr. Antonio Palumbo and colleagues,¹ reviewed in this issue of The ASCO Post (page 128), 273 patients aged ≤ 65 years were randomly assigned to early transplant or consolidation therapy using MPR (melphalan, prednisone, and lenalidomide [Revlimid]) after successful induction with lenalidomide and dexamethasone, with a further 251 patients assigned to lenalidomide maintenance or no maintenance treatment. This study is of considerable interest in terms of guiding principles but also has certain limitations in the context of application to U.S. practice in particular.

Short Follow-up

First, the median follow-up period of 51.2 months is relatively short in this setting. That being said, both progression-free survival and overall survival proved longer with high-dose melphalan compared to MPR, with the difference in median progression-free survival being particularly in favor of early transplant.

Encouragingly, in the same study, median progression-free survival proved significantly longer with lenalidomide maintenance, with almost a doubling of clinical benefit seen with lenalidomide maintenance given until either time of progression or intolerance. With relatively short follow-up, 3-year overall survival was not significantly prolonged, although a trend in favor of lenalidomide maintenance is noted, and with longer follow-up, this may indeed achieve significance, consistent with other studies in this setting.

Interestingly, the clinical benefit associated with lenalidomide maintenance was independent of the consolidation regimen. Specifically, response rates improved during maintenance therapy in both the high-dose melphalan and MPR groups. As compared with no maintenance, low-dose lenalidomide maintenance until progression delayed relapse by approximately 2 years at the time of this analysis.

As the authors comment, longer follow-up clearly will be needed to better evaluate the benefit of a delayed clinical relapse and the risk of chemoresistance after maintenance therapy. Moreover, the benefit of maintenance therapy was seen in all subgroups except those with high-risk disease by International Staging System assessment, where additional agents as part of maintenance may be needed.

Toxicity Considerations

In terms of toxicities, transplant was clearly associated with more frequent hematologic and nonhematologic adverse events, but toxicity proved manageable and did not affect the rate of early death, treatment discontinuation, or patients’ ability to proceed to the maintenance phase. One major limitation is that only 63% of patients in the MPR group at the time of relapse were able to go on to stem cell transplantation. The reasons for this require greater explanation, but obviously the availability of effective salvage regimens and their timely use are key in making any comparison of early vs late stem cell transplant.

In terms of the side effects of maintenance treatment with lenalidomide, more frequent grade 3 or 4 adverse events including neutropenia and infections were seen with lenalidomide than without. Encouragingly, however, the rate of secondary primary cancers was low, and no between-group differences were seen.

Other Strengths and Weaknesses

This study has strengths and weaknesses. Importantly, with initial induction treatment, only two-thirds of the enrolled patients were eligible to undergo first randomization. This was primarily because of disease progression or patient decision to choose an alternative therapy because of a suboptimal response after induction, presumably as the doublet of lenalidomide-dexamethasone proved ­inadequate.

As the authors acknowledge, the absence of bortezomib (Velcade)-based induction and consolidation regimens in this setting is a substantial limitation. Bortezomib-based induction and consolidation regimens in combination with both alkylating and/or immunomodulatory agents have been associated with unprecedented rates of high-quality response and clinical benefit both in terms of progression-free and overall survival. These benefits have been seen not only in the setting of stem cell transplant but also in non–transplant eligible patients. Therefore, this critical aspect of both induction and consolidation requires further evaluation.

Unanswered Questions

In aggregate, the principles from this study of novel therapy induction and maintenance contributing to clinical benefit are clear, but in the absence of proteasome inhibition, the question of actual benefit and best timing of transplantation as we help guide choices for our patients going forward are not yet answered. Although the maintenance-until-progression data are encouraging, the relatively short follow-up limits their interpretability, and again the absence of a proteasome inhibitor in consolidation leaves the question of early vs late transplantation open.

With that in mind, various ongoing studies will hopefully address these key questions both in North America and Europe. The geographic distinction is critical, not least because differing salvage regimens can impact upon both the feasibility and efficacy of salvage. Furthermore, differences in the duration of maintenance are being assessed as part of these ongoing trials, and that, too, will be very helpful in assessing the impact of continuous therapy on clinical benefit.

Practical Implications

From the standpoint of the practicing oncologist, participation of patients in randomized, ongoing, prospective clinical trials is a top priority. In the absence of the availability of a clinical trial, a personalized approach to induction treatment followed by consolidation is justified, with the use of transplantation early in the course supported by these data, but subject to the important caveats already ­outlined.

Specifically, a one-size-fits-all approach to initial treatment and consolidation with the mandatory use of stem cell transplantation is very difficult to support. Once again, the priority of participation in prospective clinical trials remains of the utmost importance going forward. ■

Disclosure: Dr. Richardson reported no potential conflicts of interest.

Reference

1. Palumbo A, Cavallo F, Gay F, et al: Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 371:895-905, 2014.

Dr. Richardson is Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, and the R.J. Corman Professor of Medicine, Harvard Medical School, Boston.