Response: Free light chain assay and stringent complete remission in multiple myeloma: more questions than answers

We appreciated the comments by Kröger et al on our article and we have read with interest their experience with free light chain (FLC) measurements in 52 patients with multiple myeloma (MM) in complete remission (CR) after allogeneic stem cell transplantation (Allo-SCT; n = 45), autologous stem cell transplantation (ASCT; n = 3) or conventional bortezomib- or lenalidomide-based therapy (n = 4). The high rate of stringent CR (sCR), with 51 of 52 (98) of the patients achieving a normal FLC κ/λ ratio, is surprising. Moreover, none of their 13 patients with oligoclonal bands had an abnormal FLC κ/λ ratio, which contrasts with our results.¹ 

The differences between the 2 studies may be explained by the nature of the treatments and the timing of light chain measurement. In the series by Kröger et al, 87% of the patients had achieved CR after Allo-SCT, whereas in our study 76.5% were in CR after ASCT. It is very likely that the immune reconstitution could be different and more delayed after the allogeneic procedure. Of note, in Kröger’s study, the free light chains were measured in patients who had been in stable CR for a minimum of only 3 months and at least 6 weeks from the first negative immunofixation electrophoresis. On the contrary, in our series, median duration of the CR was 5 years (range, 1-23.2 years), and median time of oligoclonal band appearance after allogeneic or autologous SCT was 6 months (range, 2-53 months). It is conceivable, therefore, that in those patients with long-lasting responses after high-dose therapy/SCT the robust immune reconstitution would result in the presence of oligoclonal bands and an abnormal FLC ratio, due to a kappa light chain overproduction. In fact, there is a general thought that these oligoclonal bands are transient.²  However, in our 14 patients the duration of oligoclonal bands ranged from 0.7 to 9.4 years and persisted in all of them except in the only one who relapsed, in keeping with a recent report by Mark et al.³ 

There are still many important unsolved issues concerning FLC measurements and sCR in MM. (1) At what time could the FLC assay be more informative (early or after a certain duration of the CR)? (2) Does the frequency of sCR vary depending on the type of treatment? (3) Is the meaning of sCR different after conventional chemotherapy, ASCT, or Allo-SCT? (4) What is the significance of an abnormal FLC ratio in patients with oligoclonal bands? (5) Is sCR of real prognostic value and, if so, in what population of patients?

Finally, we agree completely with Kröger et al that, with the current therapeutic approaches for MM as well as the availability of novel laboratory technologies, the achievement of serologic CR should no longer be the ultimate endpoint. The recent results on the prognostic impact of minimal residual disease studies by multiparameter flow cytometry⁴  and by molecular quantitative reverse transcription–polymerase chain reaction⁵  are important steps forward that can be crucial to determining for how long beyond serologic CR additional treatment is needed.