Association between Immunoglobulin Isotypes and Cytogenetic Risk Groups in Multiple Myeloma

Introduction:

Cytogenetic abnormalities (CAs) in multiple myeloma (MM) have prognostic significance and predict the risk of clonal evolution, disease progression, and response to treatment. The Revised International Scoring System (R-ISS) was recently updated to incorporate high risk CAs, including del(17p), t(14:16), and t(14:20), the presence of which confer a poorer prognosis. Prior studies have demonstrated the prognostic value of specific CAs and MM immunoglobulin isotypes, for example, non-IgG isotypes having been associated with poorer prognosis. However, data showing a link between cytogenetic risk groups and MM isotypes are limited. Thus, we determined whether a relationship exists between higher-risk CAs and MM isotypes, as well as the degree of malignant plasma cell infiltration of the bone marrow (BM).

Methods:

We performed a retrospective analysis of a multi-institutional commercial pathology repository of 442 MM patients identified according to the International Myeloma Working Group criteria that included assessment of BM infiltration (BM%), MM isotype, CA, and cytogenetic risk group. The study protocol was approved in accordance with IRB standards. As per the R-ISS, the high risk CAs included del(17p), t(14:16), and t(14:20), intermediate risk CAs included t(4;14), del(13q), dup(1q), and hypodiploidy, and standard risk CAs included t(6;14), t(11;14), and hyperdiploidy. Patients with CAs that included more than one risk group were considered to be in the higher risk category. Associations between categorical variables were made using the chi-squared test or Fisher's exact test. The Mann-Whitney test was used to compare groups (MM isoytpe, CAs, or cytogenetic risk group). Statistical significance was considered at p<0.05. Analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC).

Results:

Among the 442 MM patients, isotype groups included 42% IgG, 16% IgA and 42% light chain-only (LCO). There were 184 patients (42%) who had CAs associated with known MM cytogenetic risk groups, of which 34% were standard-risk, 61% were intermediate-risk, and 5% were high-risk. The median BM% of clonal plasma cells was 50% (range 1-95%). When examining the relationship between any CA and BM%, del(13q14), dup(1p32), dup(1q21), t(4;14), trisomy(11q13), and monosomy(16q23) were associated with a significantly higher BM% than patients who were lacking those respective CAs. For example, the median BM% for patients with t(4;14) was 60% compared with 15% in patients lacking this translocation (p<0.0001). LCO isotype was associated with a lower BM% (p<0.04), however there was no significant correlation between IgG/IgA isotypes and BM%. There was a higher median BM% seen in the intermediate risk group (50%, p<0.0001) compared to standard risk group (20%, p<0.04). The high risk group was not significantly associated with BM%. When comparing isotypes to cytogenetic risk groups, IgA isotype was significantly associated with intermediate risk cytogenetics (p<0.03). Conversely, there was a significantly lower rate of standard risk CAs among IgA isotypes (p<0.01). There was no significant correlation between IgG/LCO and cytogenetic risk. IgA isotype correlated with specific CAs, including del(13q) (p<0.02) and del(16q23) (p<0.04). There was a higher rate of t(11:14) in the non-IgA isotype groups. Additionally, IgG isotype was associated with a trisomy(11q13) (p<0.03). LCO isotype also corresponded with a higher rate of del(17p) (p<0.03), t(11:14) (p<0.03), and a lower rate of t(4:14) (p<0.04) and trisomy (11q13) (p<0.01).

Conclusions:

In MM, CAs are valuable in risk stratifying patients and predicting treatment responses. In this study, data suggest that the IgA isotype is significantly associated with intermediate-risk cytogenetics, including del(13q) and hypodiploidy, and LCO disease correlates with high risk cytogenetics, including del(17p). When taken together this may explain the previously known association of these isotypes with poorer prognosis, and suggests divergent clonal evolution among MM isotypes. Associations between clinical parameters and disease responses remain ongoing.