Cytogenetic abnormalities in multiple myeloma: association with disease characteristics and treatment response

Nadine Abdallah,Leif Bergsagel,Mustaqeem Siddiqui,Martha Q Lacy,Robert A Kyle,Nelson Leung,Linda B Baughn,David Dingli,Suzanne R Hayman,Francis K Buadi,Prashant Kapoor,Morie A Gertz,Angela Dispenzieri,Taxiarchis Kourelis,Rhett P Ketterling ,Ronald S Go,John A Lust ,Yi Lin,S Vincent Rajkumar,Patricia T Greipp ,Miriam Hobbs,Yi L Hwa,Amie Fonder,Rahma Warsame,Shaji Kumar

doi:10.1038/s41408-020-00348-5

Nadine Abdallah, Leif Bergsagel + Show 23 more

Open Access

https://doi.org/10.1038/s41408-020-00348-5

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Abstract

Cytogenetic abnormalities are found in most multiple myeloma (MM) patients. Although their prognostic value has been well studied, there are limited data on the association of primary cytogenetic abnormalities with disease characteristics and treatment response. This study was designed to evaluate these associations. This is a retrospective study including 2027 Mayo Clinic patients diagnosed with MM between February 2004 and February 2018 who had cytogenetic testing by FISH at diagnosis. Translocations t(4;14), t(14;16), t(6;14), and t(14;20) were associated with anemia, beta2microglobulin >5.5 µg/ml and ≥50% bone marrow plasma cells; t(4;14) was associated with higher serum monoclonal protein and plasma cell proliferation. Overall response rate to proteasome inhibitor (PI)-based treatment was higher for IgH translocations compared to trisomies (83% vs. 71%, P = 0.002), but was higher for trisomies with immunomodulatory drug (IMiD)-based treatment (87% vs. 75%, P < 0.001). Time to next treatment was longer with trisomies than IgH translocation with IMiD-based (32.1 vs. 18.4 months, P < 0.001) and PI + IMiD-based (44.0 vs. 27.4 months, P = 0.003) treatments. Outcomes were superior with PI + IMiD combinations in all groups. Our results show that t(4;14), t(14;16), t(6;14), and t(14;20) are associated with high-risk disease characteristics, and IgH translocations and trisomies may be associated with better responses to PIs and IMiDs, respectively.

Highlights

Multiple myeloma (MM) is a clonal plasma cell disorder accounting for 1.8% of all malignancies in the US, 18% of hematologic malignancies, and 2% of all cancer-deaths[1]
Statistical analysis We focused the analysis on primary cytogenetic abnormalities, grouping patients into those with an immunoglobulin heavy chain gene (IgH) translocation and those with trisomies of at least 1 chromosome in the absence of an IgH translocation
Consistent with previous studies, IgH translocations and trisomies were detected in a large subset of patients (46% and 57%, respectively) with newly diagnosed MM12,15,16, and IgH translocations were more frequent in non-hyperdiploid myeloma[17]

Summary

Introduction

Multiple myeloma (MM) is a clonal plasma cell disorder accounting for 1.8% of all malignancies in the US, 18% of hematologic malignancies, and 2% of all cancer-deaths[1]. It is characterized by significant heterogeneity in clinical characteristics, spectrum of genetic abnormalities and treatment outcomes. The use of interphase fluorescence in situ hybridization (FISH), which has greater sensitivity (IgH) locus and trisomies of odd numbered chromosomes are considered primary cytogenetic abnormalities, occurring at the early premalignant stages and potentially involved in disease pathogenesis[4]. Amongst all prognostic factors described in MM, FISH abnormalities have been found to be the most predictive of outcomes[5].

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