Abstract
Multiple myeloma (MM) is a plasma cell (PC) neoplasm affecting cells of the final stage of B-cell differentiation while chronic lymphocytic leukemia (CLL) involves mature B-lymphocytes that have not become differentiated PC. The coexistence of MM and CLL in the same patient is rare and raises questions about the clonal relationship between these two hematologic malignancies.
To evaluate whether concomitant MM and monoclonal B-cell lymphocytosis (MBL)/CLL derive from the same B-cell or develop independently.
Bone marrow (BM) and peripheral blood (PB) samples (collected from 06/2014 to 06/2025) of 27 patients with concomitant MM and MBL/CLL (female: 26%, median age: 76 years, range 58-91) were analyzed. NGS-based B-cell receptor (BCR) analysis was performed on PC enriched from BM (CD138+ MACS) for MM and on PB or CD138-depleted fraction for CLL. Copy number variations and IGH translocations were assessed by interphase FISH and mutations by targeted NGS. One selected case was also analyzed by whole-genome sequencing (WGS).
In 17 cases MM and MBL/CLL were diagnosed concurrently, whereas 10 cases were initially diagnosed with MBL/CLL followed by MM 1-13 years later. Median age at diagnosis did not differ between the two groups (both 76 years). 46% of patients had at least one of the unfavorable genetic MM markers del(17p), del(1p), +1q, t(4;14), t(14;16), t(14;20) or TP53mut. For CLL samples, none of the patients exhibited del(17p) (FISH available for 21/27) or TP53mut and 17% showed an unmutated IGHV status.
BCR analysis revealed 16/18 patients analyzed in whom MM and CLL carried different IGH rearrangements, indicating two clonally unrelated and separately developed entities. In one patient, MM and CLL shared IGHV, only the MM sample lost IGHJ and showed somatic hypermutation (SHM), but not the CLL sample. Both fractions had the same IGKV but a kappa deleting element instead of IGKJ, indicating a subsequent IGL rearrangement. This, along with phenotypical findings of a B-cell clone with lambda light chain restriction (LCR), a PC clone with kappa LCR and an IgM kappa paraprotein indicates that IGK of the MM fraction was not properly captured by BCR analysis. In one additional patient MM and CLL shared IGH and IGK rearrangements in the initial NGS analysis. However, WGS from this case using CD138+ MACS exhibited an additional IGH rearrangement that was not identified in the previous BCR analysis which could be confirmed in a subsequent NGS analysis of an additional follow-up sample in complete B-cell depletion after treatment. Consequently, the initial suspicion of clonal relation and derivation from the same B-cell could not be confirmed. The discrepancy between NGS-based and WGS-based BCR analysis is likely attributable to inefficient primer binding due to SHM. Thus, relying just on a single technique for BCR analysis can lead to incorrect conclusions in rare cases. The remaining nine patients had to be excluded due to low DNA quality/PC/B-cell count or cross-contamination. In summary, no evidence for clonal relations was found between MM and CLL according to BCR analysis.
Somatic mutation analysis revealed shared mutations in KRAS and TET2 for one patient and a shared DNMT3A mutation for another patient indicating origin from the same progenitor cell but independent development from different cells during B-cell differentiation. In all other 25/27 patients, MM and CLL exclusively had distinct mutations present in only one of the diseases. In summary, only rare clonal relations according to shared somatic mutations were identified.Conclusion: Both, MM and CLL affect late-stage B-cells and their co-occurrence gives rise to the question about distinct or common clonal origins. While 2/27 patients showed shared somatic mutations, BCR analysis showed an independent development of both malignancies from different B-cells for 17/18 cases investigated and most likely also for the remaining patient. Although we cannot exclude the existence of singular cases with co-occurring MM and CLL that derive from the same B-cell through identical IGH and IGK rearrangements, our data on a relatively large series of 27 patients at least indicate that this would be a rare phenomenon. Our findings may help for future research to unravel the complex landscape of such rare patients with concomitant MM and CLL, with the ultimate goal of identifying optimized treatment strategies and improving patient outcomes.
