Eliminating the complete response penalty from myeloma response criteria

To the editor:

Lonial and Gertz raise important concerns about the definition of disease progression used in patients who are in complete response following therapy for myeloma.¹  They also correctly highlight the limitation of using immunofixation to categorize complete response (CR), and call for reporting combined CR plus very good partial response (VGPR) rates instead. We agree. The new International Myeloma Working Group (IMWG) uniform response criteria has now rectified these important concerns.²  In the new criteria, patients achieving CR will be considered to have progressive disease for purposes of estimating time to progression (TTP) or progression-free survival (PFS) only if there is an increase in M protein level to that required for all other response categories. A positive immunofixation will not be adequate to classify patients as having progressive disease in estimating TTP or PFS. The criteria also specifically define VGPR, and we agree that trials should report combined CR plus VGPR rates as the primary metric of depth of response.³ 

The IMWG criteria including the above changes have been endorsed by a recent American Society of Hematology (ASH)/Food and Drug Administration (FDA) panel on regulatory endpoints in myeloma.⁴  Both the Eastern Cooperative Oncology Group (ECOG) and the Southwest Oncology Group (SWOG) have incorporated the IMWG criteria in all new trials, including all currently accruing phase 3 trials. Other myeloma groups are doing the same. Thus in the future we will have trials reporting results as suggested by Lonial and Gertz. The trials presented at the recent ASH meeting used older response criteria. For such trials that have already been completed and analyzed, it is often difficult to accurately recalculate TTP or PFS using the new definitions because once patients were considered to have disease progression they were typically taken off-study and often treated with nonprotocol therapy. Thus one may not be able to determine the correct time point at which they would have met the revised definition of progressive disease had they stayed on the trial. But in some cases with careful review it may be possible to do this, and we agree that when possible authors should adopt the revised definition of progressive disease and report corrected TTP and PFS estimates.

Finally, we would like to also point out that it is important to distinguish TTP and PFS, and report both endpoints in clinical trials. They cannot be used interchangeably. Although both use the same definition of disease progression, in TTP (the favorite end point in many industry-sponsored myeloma trials), deaths not due to disease progression (such as toxic deaths) are censored and not counted as progression events.