Association Of Stringed Response and Immunoparesis Normalization After Bortezomib-Based Therapy Is Related To Better Outcomes In Multiple Myeloma
Authors: Andrade Sr. Marcio M , Murillo-Florez Ilda , Montes-Limon Anel , de Rueda Beatriz , Grasa Jose-Maria , Giraldo Pilar 
Published: October 2019

Abstract

Background
Proteasoma inhibitors have proven to be one of the major advances on multiple myeloma (MM) therapy. Their principal effect in growth inhibition of MM cells is achieved not only through the inhibition of proteasomes but also by preventing the adhesion of myeloma cells to stromal cells, induction of cytokines by the microenvironment, decrease angiogenic activity and a direct apoptotic effect on MM cells. Actually it is part of the first-line standard of care therapy for patients with MM. On the other hand, multiple strategies have been developed for trying to predict response or improve the assessment of response and follow-up of MM patients. Currently, the International Myeloma Working Group (IMWG) criteria of response include immunophenotype and immunoparesis analysis. The HevyLiteTM and FreeLiteTM assays (The Binding Site Ltd. Birminghan. UK) permit a separate quantification of the amount of kappa- and lambda-bound to a given immunoglobulin (HLC) and the free light chains kappa or lambda amount quantification (FLC), both being excellent tools for immunoparesis assessment.

Aims
To analyze the usefulness of immunoparesis analysis by HevyLiteTM and FreeliteTM in patients who receive bortezomib-based therapy in our institution.

Patients and Methods
A retrospective chart review was performed including the patients diagnosed with secretor IgA or IgG MM who received therapy with bortezomib either at relapse or as first-line therapy. General clinical characteristics, therapy schedules, number of cycles, response to therapy according IMWG criteria and relapse were recorded. For the analysis, only patients with at least 4 cycles of bortezomib based regimen and HLC and/or FLC analysis performed between 4-12 weeks after complete therapy were included. Period of study: June 2004 to April 2013.

Results
At the end of study a total of 67 MM patients had received bortezomib-based therapy, 63 of them completed 4 or more cycles and were included in the analysis. Male/Female ratio: 31/32, mean age: 66.9 years old (46-81), therapeutic schedules were: bortezomib-prednisone: 3 (4.7%), bortezomib-dexametasone: 33 (51.6%), bortezomib-melfalan-prednisone: 18 (28.1%), bortezomib-dexametasone-lenalidomide: 8 (12.5%) and bortezomib-talidomide-dexametasone: 1 (1.6%). 55% of patients received at least 6 cycles of therapy. Immunoglobulin Myeloma subtype: IgAL: 13 (20.4%) patients, IgAK: 10 (15.6%) patients, IgGK: 32 (50.8%) patients and IgGL: 8 (14.1%) patients. A total of 46 (73%) patients showed an abnormal HLC ratio at diagnosis and 48 (76,2%) had immunoparesis before therapy; a total of 47 (74.6%) registered an abnormal FLC ratio at diagnosis. The response to therapy was: 15 (23.8%) of cases achieved a stringent complete response (SR), 3 (4.8%) a very good partial response (VGPR), 36 (57.1%) obtained a partial response (PR) and 9 (14.3%) patients had not-response/progressive-disease. At the time of post-therapy evaluation, 26 (37%) of patients had normalized FLC-ratio, 15 (23.8%) maintain the SR, 1 (1,6%) patient in VGPR and 5 (11.1%) in PR and 1 (1.6%) of non-responder patients. Normalization of HLC-ratio was only observed in patients with SR and VGPR: 13 (20.6%). Regarding the immunoparesis analysis, only 15 (23.8%) of patients with immunoparesis recovered the immune restitution (IR) at the end of therapy, of which 8 (11.7%) were SR patients, 2 VGPR and 5 PR patients. At the end of the study 47(71.4%) patients relapsed, 5 (11.11%) are on maintenance therapy and 11(17.4%) after a median follow-up of 29 months (9-94) without therapy not-relapsed; the association of SR with IR was related to a less tendency to relapse and need of therapy, 7/8 patients who achieved this status are not-relapsed.

Conclusion
In our cohort, patients who achieved a SR with a normalization of immunoparesis shows a clear tendency to less incidence of relapse; probably reflecting a better response with not only an undetectable monoclonal protein but also the recovery of the immune function. Even in small cohorts, the immunoparesis recovery analysis through HLC quantifications seems to be an useful tool to determine a new level of response. More investigations on this field are warranted.
This work has been partially supported by a grant from Fundación para el Estudio de la Hematología y hemoterapia en Aragón (FEHHA)

Disclosures:
No relevant conflicts of interest to declare.