Molecular profiling of immunoglobulin heavy-chain gene rearrangements unveils new potential prognostic markers for multiple myeloma patients

Abstract

Multiple myeloma is a heterogeneous disease whose pathogenesis has not been completely elucidated. Although B-cell receptors play a crucial role in myeloma pathogenesis, the impact of clonal immunoglobulin heavy-chain features in the outcome has not been extensively explored. Here we present the characterization of complete heavychain gene rearrangements in 413 myeloma patients treated in Spanish trials, including 113 patients characterized by next-generation sequencing. Compared to the normal B-cell repertoire, gene selection was biased in myeloma, with significant overrepresentation of IGHV3, IGHD2 and IGHD3, as well as IGHJ4 gene groups. Hypermutation was high in our patients (median: 8.8%). Interestingly, regarding patients who are not candidates for transplantation, a high hypermutation rate (≥7%) and the use of IGHD2 and IGHD3 groups were associated with improved prognostic features and longer survival rates in the univariate analyses. Multivariate analysis revealed prolonged progression-free survival rates for patients using IGHD2/IGHD3 groups (HR: 0.552, 95% CI: 0.361−0.845, p = 0.006), as well as prolonged overall survival rates for patients with hypermutation ≥7% (HR: 0.291, 95% CI: 0.137−0.618, p = 0.001). Our results provide new insights into the molecular characterization of multiple myeloma, highlighting the need to evaluate some of these clonal rearrangement characteristics as new potential prognostic markers.

Immunoglobulin gene rearrangement in Koreans with multiple myeloma: Clonality assessment and repertoire analysis using next-generation sequencing

“…Neither IGHJ1 nor IGHJ2 was reported in our patients. The IGHJ distribution in our study was similar to that observed in the previous Western studies [7,8,24]…”

“…Twenty IGHV genes were identified (Table 3); among them, IGHV3-23 and IGHV3-9 (each of which was observed in 11.63% of the total samples) were the most frequently reported, followed by IGHV3-30 and IGHV4-31 (each of which was observed in 9.30% of the total samples). Comparing IGHV usage between our study and 3 previously published Western studies [7,8,24] showed that even though the distribution of the IGHV gene group in our study was similar to that of Western studies (S1 S1 File). Particularly, IGHV3-9 (11.63%) and IGHV4-31 (9.30%) were significantly more frequent in our study than in that of Ferrero et al (4.64%, P = 0.004 and 2.03%, P = 0.024, respectively) [7] and of Medina et al (4.14%, P < 0.001 and 1.38%, P = 0.009, respectively) [24].…”

“…Comparing IGHV usage between our study and 3 previously published Western studies [7,8,24] showed that even though the distribution of the IGHV gene group in our study was similar to that of Western studies (S1 S1 File). Particularly, IGHV3-9 (11.63%) and IGHV4-31 (9.30%) were significantly more frequent in our study than in that of Ferrero et al (4.64%, P = 0.004 and 2.03%, P = 0.024, respectively) [7] and of Medina et al (4.14%, P < 0.001 and 1.38%, P = 0.009, respectively) [24]. The overall frequencies of other genes were not significantly different across all 4 studies (including ours).…”

“…Twenty-seven IGHD genes were identified (Table 4), the most frequently occurring of which were IGHD3-10 and IGHD3-3 (13.95% each). A comparison of IGHD usage between our study and 3 previously published Western studies [7,8,24] showed that even though the distribution of the IGHV gene group was similar (S4…”

“…A comparison between our study and a previous Western analysis [24] showed that a lack of IGK rearrangement was significantly more frequent among our patients (21.57% vs. 7.06%, P = 0.017), particularly in kappa-restricted MM (34.48% vs. 0.00%, P < 0.001) (S6 IGKV1 was the most frequently observed IGKV gene group (32.94%), followed by IGKV2 (22.35%), and IGKV3 (12.94%). IGKV4, IGKV5, and IGKV7 were observed in a minority of the series (5.56%, 2.78%, and 2.78%, respectively).…”