Atypical Serum Immunofixation Pattern (ASIP) Development during Induction Therapy with BiRD for Newly Diagnosed Multiple Myeloma Correlates with a High Rate of Complete Remission.
Authors: Mark Tomer , Jayabalan David , Pearse Roger N. , Wang Y. Lynn , Lent Richard , Christos Paul J. , Lee Joong W. , Agrawal Yashpal P. , Matthews Susan , Ely Scott , Mazumdar Madhu , Cesarman Ethel , Rambo April , Leonard John P. , Coleman Morton , Chen-Kiang Selina , Niesvizky Ruben 
Published: October 2019

Abstract
The excess production of monoclonal immunoglobulin is the hallmark of multiple myeloma (MM) diagnosis and is an essential element of the determination of disease response to therapy. The development of new monoclonal immunoglobulins that are distinct from the baseline diagnostic paraprotein during the course of MM therapy can therefore pose a challenge in assessing disease response or potential relapse. There are prior reports of the development of abnormal protein banding (APB) after autologous stem cell transplantation for MM comprised of transient non-myeloma related mono- or oligoclonal protein bands that have been correlated with higher rates of event-free and overall survival. We now report the development of atypical serum immunofixation patterns (ASIPs) for the first time outside of the setting of stem cell transplant during the course of MM induction therapy with the BiRD (Biaxin® [clarithromycin], Revlimid® [lenalidomide], Dexamethasone) regimen. 72 patients with newly diagnosed Stage II and III MM (Salmon-Durie Criteria) were treated in a phase 2 clinical study of BiRD. The BiRD treatment regimen was given in 28-day cycles as follows: Clarithromycin 500mg po BID for days 1 – 28, Lenalidomide 25mg po daily for days 1 – 21, and Dexamethasone 40mg po weekly on days 1, 8, 15, and 21. The median age of the patients was 63 (range 36–83), and the baseline monoclonal immunoglobulins detected on serum immunofixation were as follows: 61% IgG, 22% IgA, 17% light chain only. 24 patients (33%) developed one or more ASIPs with either a mono- or oligoclonal banding pattern during the course of BiRD therapy. The new protein bandsvaried widely in duration of appearance (range 26–315 days) as well as isotype with IgM-κ, IgM-λ, IgG-κ, IgG-λ, IgA-λ, free λ light chain, and free IgM heavy chain all observed in one or more instances. The extent of therapy prior to first ASIP development was variable as well, (range 27– 724 days, median of 178 days). Patients with ASIPs had significantly better response to BiRD vs. non-ASIP patients (p = .00002), with CR+sCR rate of 71% vs. 23%, and a VGPR or better rate of 96% vs. 61%. The extent of BiRD therapy prior to development of first ASIP did not correlate with response rate (p = .7284). Bone marrow examination by histology, karyotype, FISH, and PCR IgH / IgK clonality analysis confirmed the disease response and furthermore showed no evidence for newly emergent plasma cell or other B-cell malignancy to account for ASIP generation suggesting molecular remission in some of the patients. Peripheral blood analysis by flow cytometry also showed no evidence for a circulating B-cell neoplasm to account for the new immunoglobulin production. We propose that ASIP development during myeloma therapy with a lenalidomide-based regimen heralds a robust tumor reduction with a hitherto unprecedented rate of complete remission. The immune phenomena that contribute to ASIP generation are unclear at present, however it is neither due to a new clonal B-cell population or transformation of the original MM plasma cell clone.