Abnormal Serum IgA Kappa / IgA Lambda Ratios at Maximum Response Predict Poor Progression Free Survival in Myeloma Patients.
Authors: Ludwig Heinz , Harding Stephen , Bradley Caroline , Milosavljevich Dejan , Drayson Mark T , Morgan Gareth J , Child J. Anthony , Bradwell Arthur 
Published: October 2019

Abstract
Abstract 4879
For some myeloma patients, co-migration of IgA monoclonal proteins with other proteins can make serum protein electrophoresis (SPE) densitometry inaccurate. Immunofixation (IFE) will identify the monoclonal immunoglobulins, however, it is not quantitative and requires skilful interpretation. Measurement of total IgA can also be used but has limited value when the monoclonal protein level is low. Antibodies which target the heavy and light chains of the immunoglobulin have now been developed, making it possible to quantify IgAk and IgA» in serum and to calculate the IgAk/IgA» ratio. Here we describe 2 patient groups where archived sera have been analysed to evaluate the utility of IgAk/IgA» ratios for monitoring response to treatment in myeloma patients. We also compared progression free survival (PFS) or overall survival (OS) for patients who did / did not achieve a normal IgAk/IgA» ratio at maximum response.
Sequential, archived sera were analysed from 31 patients treated in the UK Myeloma VII trial (21 IgAk /10 IgA») and 27 patients treated at The Centre for Oncology and Haematology, Vienna (14 IgAκ /13 IgA»). Treatments utilised varied from combinations of cyclophosphamide, vincristine, doxorubicin and methylprednisolone with/without high-dose melphalan/stem cell rescue (UK) to VAD, Thalidomide-Dexamethasone, VMCP, DCEP with/without high dose melphalan/stem cell rescue (Vienna). Between 3 and 51 (median=6) sera were available for each patient. Serum IgAk and IgA» measurements were performed on a Siemens Dade-Behring BN™II nephelometer in UK and on a Roche Cobas Integra 800™ immunturbimeter in Vienna. IgAk/IgA» ratios were compared with a normal range derived from measurement of >100 blood donor sera. SPE and IFE were performed on a SEBIA Hydrasys™ electrophoresis system (UK) and on a SEBIA Kapillarys™ capillary electropheresis system and a Helena SPE 2000™(Vienna). IgAk/IgA» results were compared retrospectively to clinical assessment and outcome. Kaplan Meier curves and Cox regression analysis were performed using SPSS v14.0.
For all 31 UK patients, changes in the IgAk/IgA» ratio were in accordance with the clinical assessments. With regard to the detection of residual disease, the IgAk/IgA» ratios remained abnormal beyond the time when SPE results had normalised and appeared approximately equal to IFE in sensitivity. The IgAk/IgA» ratio remained abnormal in all sera from the 13/31 patients who achieved a partial response (PR) or less. In 10/31 patients, SPE densitometry could not accurately quantify the monoclonal protein, either because there was no obvious monoclonal protein (5/10) or the monoclonal protein was obscured by other serum proteins (5/10). 18/31 patients achieved a complete response (CR) but 9/18 still had abnormal IgAk/IgA» ratios at this time and had a shorter progression free survival (PFS; 277 days v 912 days: p=0.01). Similarly, for the 27 Viennese patients, changes in the IgAκ/IgA» ratios were in accordance with overall clinical assessments. In 18/27 patients, where clinically determined maximum response was reached, an abnormal IgAk /IgA» was associated with a shorter overall survival (344 days v 2241 days: p=0.028).
Monoclonal IgA proteins can be difficult to identify and measure using electrophoresis techniques because of their co-migration with other serum proteins. The results from this preliminary study indicate that the use of IgAk/IgA» ratios may offer an alternative technique for monitoring these myeloma patients. Furthermore, the IgAk/IgA» ratio may provide prognostic information at the point of maximum response.

Disclosures
Ludwig: Celgene: Honoraria; Mundipharma: Honoraria; AMGEN: Honoraria; Ortho-Biotech : Honoraria; Janssen-Cilag: Research Funding; Roche: Honoraria. Harding:The Binding Site Group Ltd: Employment. Bradwell:The Binding Site Group Ltd: Shareholder.