Immunoparesis Defined By Heavy/Light Chain Pair Suppression in Smoldering Multiple Myeloma Patients Shows Isotype Specificity
Authors: Isola Ignacio , Moreno David , Moga Esther , Mena Mari-Pau , Tovar Natalia , Rodríguez-Lobato Luis Gerardo , Cibeira M. Teresa , Rosinol Laura , Bladé Joan , Fernandez de Larrea Carlos 
Published: November 2020

BACKGROUND
Smoldering multiple myeloma (SMM) is an asymptomatic and biologically heterogeneous clonal plasma cell disorder. Prognostic factors to identify patients at higher risk of progression have been described, including the suppression of uninvolved polyclonal immunoglobulins (Ig) or immunoparesis (IP). Novel serum assays allow the quantification of each isotype-specific heavy and light chain pair (HLC), enabling the study of a new type of IP: the suppression of the uninvolved light chain counter part of the same heavy-chain Ig isotype (isotype matched immunoparesis).
AIM:
To prospectively characterize the prevalence and severity of immunoparesis as determined by HLC measurements, its association with other risk factors for progression and its prognostic significance, in patients with SMM diagnosed at a single institution.
METHODS:
Fifty-four patients newly diagnosed with SMM from January 2014 through March 2019 were prospectively included. Serum samples obtained at baseline and during follow-up were tested for M-protein level, free light chain (FLC) and HLC concentrations (all three isotype pairs at baseline, involved isotype pair at follow up visits).
Isotype matched immunoparesis (IMI) was defined by the HLC assay, based on the levels of the Ig with the same heavy chain of the monoclonal isotype but of the alternative light chain (e.g. IgG-kappa suppression in a patient with IgG-lambda SMM). Aditionally, HLC immunoparesis (IP) was defined by suppression of any Ig with a heavy chain different to the M-protein (e.g. IgA kappa/lambda pair suppression in a patient with IgG-lambda SMM). Severe immunoparesis was defined by Ig values suppressed by 50% or greater below the lower limit of normal (LLN).
RESULTS:
Median age at diagnosis was 73 years, with the following heavy chain isotype distribution: 31 IgG, 20 IgA, 2 biclonal IgG-IgA and 1 light-chain only SMM. Median follow up for the series was 2.5 years.
Isotype specificity of immunoparesis was reflected in the greater prevalence of IMI vs. noninvolved isotype IP (Figure 1, A). HLC measurements identified IMI in 42 out of the 53 patients with IgG, IgA or biclonal SMM (82%), with severe IMI observed in 27 patients (53%). Suppression of at least one HLC pair of an uninvolved isotype was present in 37 patients (72%), with severe suppression observed in 20 patients (38%). Eleven patients presented severe IMI without severe IP of uninvolved isotypes. On the other hand, only one out of the 37 patients with IP of uninvolved isotypes presented without IMI. In the case of the 12 patients that showed IP of any IgM HLC pair, they all had concomitant severe IMI and IP of the other uninvolved heavy chain isotype.
Analysis of other risk factors for progression between groups of patients with i) no severe immunoparesis (n=22), ii) severe IMI without severe IP of uninvolved isotypes (n=11) and iii) severe IMI and severe IP of one or more HLC pairs of uninvolved isotypes (n=18), showed significantly different FLC ratios and lower % of normal plasma cells in bone marrow (Figure 1, B). There was a trend, although statistically not significant, towards higher M-protein levels.
Progression to malignant symptomatic gammopathy was observed in 12 patients. The suppression of any IgM HLC pair was associated with a shorter time to progression (p=0.007; HR=4.2; 95% CI, 0.84-21) (Figure 1, C). Severe IMI alone or severe IMI plus severe IP of a different isotype were associated only with a statistically not significant trend towards a shorter time to progression.
Eight patients demonstrated an evolving behavior (≥ 10% increase in the involved HLC pair in 3 or more consecutive determinations from diagnosis), 7 of which presented with severe IMI at diagnosis. Of the five evolving patients that progressed, four had severe IMI and the remaining one developed severe IMI during follow up. Patients with severe IMI at diagnosis maintained the same level of HLC suppression throughout the follow up period.
CONCLUSION:
The significantly greater incidence of IMI over IP of uninvolved isotypes pairs supports an isotype specificity of early Ig suppression mechanisms in the case of IgG and IgA SMM. That would be of special interest at the time of initial evaluation of patients with SMM using HLC pairs. Both IMI and IP of uninvolved isotypes are associated with other recognized risk factors for progression, but the later appears to develop with more advanced disease and associate with a higher risk of progression.

Disclosures
Cibeira: Amgen: Honoraria, Other: Educational lectures; Celgene: Honoraria, Other: Educational lectures; Akcea Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational lectures. Bladé:Oncopeptides: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria.