Perils of Ignoring Overall Survival in Interpreting the Myeloma Literature

Abstract

Richardson et al 1 and D'Souza et al 2 explored the phase III TOURMALINE MM-3 trial that compared ixazomib-lenalidomide-dexamethasone with placebolenalidomide-dexamethasone for relapsed and/or refractory multiple myeloma. We wish to highlight the importance of postprotocol therapies and our interpretation of this study.

Reply to G. R. Mohyuddin et al and A. Garfall et al

“…Demonstrating an OS benefit in phase III trials in the newly diagnosed and early-relapse settings is increasingly challenging, 3,4 but its analysis-and that of postprotocol therapies-should not be neglected. 1 OS remains an important end point for confirming no adverse impact of novel therapies or a differential benefit across subgroups, 3 as shown in several trials. A phase III trial of lenalidomide plus high-or low-dose dexamethasone demonstrated an initial clinical benefit with lenalidomide plus high-dose dexamethasone; however, OS was poorer versus the low-dose dexamethasone regimen because of toxicity.…”

“…We thank Mohyuddin et al 1 and Garfall et al 2 for their comments on our manuscript reporting the final overall survival (OS) analysis of the TOURMALINE-MM1 phase III trial 3 and associated editorial. 4 We agree that OS remains an important end point for patients and on the need for optimal sequencing of therapies.…”

“…This is particularly true in first-line or early-relapse settings, given the potential exposure to multiple additional lines of therapy, particularly including highly active agents such as daratumumab. 11 Although, as noted by Mohyuddin et al, 1 OS remains important in determining whether combining drugs is better than simply sequencing them, studies are usually not designed to investigate this because subsequent lines are not controlled per protocol. Conversely, OS may remain a practical end point in advanced disease patients, who may not be expected to receive extensive subsequent lines.…”

“…Conversely, OS may remain a practical end point in advanced disease patients, who may not be expected to receive extensive subsequent lines. 1 Optimal treatment sequencing is very important, but in multiple myeloma, both the disease and patients are highly heterogeneous. Thus, several factors affect subsequent therapy choice beyond the clinical-trial setting.…”

“…Conversely, OS may remain a practical end point in advanced disease patients, who may not be expected to receive extensive subsequent lines. 1…”