Multiple Myeloma Cytogenetics: Insights on Genetic Abnormalities

Multiple myeloma is a hematologic cancer marked by uncontrolled plasma cell proliferation in the bone marrow. Genetic abnormalities play a crucial role in disease development, progression, and treatment response. Cytogenetic analysis has identified distinct genetic alterations that influence prognosis and therapeutic strategies.

Key Translocations

Chromosomal translocations are key genetic abnormalities in multiple myeloma, shaping disease behavior and prognosis. These rearrangements often involve the immunoglobulin heavy chain (IGH) locus on chromosome 14q32, a central player in plasma cell function. When IGH translocates, it frequently fuses with oncogenes, leading to dysregulated gene expression that drives myeloma. Common translocations include t(4;14), t(11;14), t(14;16), and t(14;20), each with distinct clinical implications.

The t(4;14)(p16;q32) translocation results in WHSC1 (MMSET) and FGFR3 overexpression. WHSC1 encodes a histone methyltransferase that alters chromatin structure, promoting epigenetic dysregulation. FGFR3, a tyrosine kinase receptor, enhances tumor cell survival in some cases. Patients with t(4;14) typically experience more aggressive disease and poorer prognosis. The IFM 2005-01 trial showed reduced overall survival in this subgroup despite intensive therapy.

The t(11;14)(q13;q32) translocation leads to CCND1 overexpression, encoding cyclin D1, which regulates cell cycle progression. Unlike other translocations, t(11;14) is not inherently high-risk but has unique therapeutic implications. Myeloma cells with this translocation often rely on BCL-2, making them particularly responsive to BCL-2 inhibitors like venetoclax. The BELLINI study demonstrated promising responses in t(11;14)-positive patients treated with venetoclax-based regimens.

The t(14;16)(q32;q23) translocation results in MAF overexpression, a transcription factor that enhances tumor adhesion, angiogenesis, and proliferation. Initially considered high-risk, its prognostic impact may depend on co-occurring genetic alterations. Similarly, t(14;20)(q32;q12) upregulates MAFB, another oncogenic transcription factor. Both MAF and MAFB translocations increase adhesion molecule expression, potentially contributing to disease dissemination and therapy resistance.

Deletions, Gains, And Complex Abnormalities

Structural chromosomal alterations, including deletions, gains, and complex abnormalities, significantly affect multiple myeloma’s biological behavior and prognosis. These changes disrupt key regulatory pathways, influencing tumor growth, treatment response, and disease progression.

A well-characterized deletion is the loss of 13q (del(13q)), affecting RB1 and DIS3, which regulate the cell cycle and RNA processing. Historically linked to poor prognosis, its adverse impact is now attributed to frequent co-occurrence with high-risk translocations like t(4;14). A more prognostically significant deletion is del(17p), involving TP53, a key regulator of genomic stability and apoptosis. Patients with del(17p) respond poorly to standard therapies and have shorter survival. A Blood (2018) meta-analysis found that del(17p)-positive patients had a median overall survival of less than three years despite aggressive treatment.

Chromosomal gains also play a role in disease pathogenesis, with hyperdiploidy being a common feature. This condition involves extra copies of odd-numbered chromosomes such as 3, 5, 7, 9, 11, 15, 19, and 21, leading to increased expression of genes that enhance cell survival. Unlike high-risk deletions and translocations, hyperdiploidy is generally associated with a more favorable prognosis, with prolonged survival in affected patients. The overexpression of pro-survival factors may contribute to better responsiveness to immunomodulatory drugs and proteasome inhibitors.

Beyond simple deletions and gains, multiple myeloma often involves complex chromosomal abnormalities. Chromothripsis, a phenomenon of massive chromosome shattering and rearrangement, has been identified in a subset of patients and is linked to aggressive disease. This catastrophic event creates extensive genomic instability, promoting additional mutations that drive therapy resistance. A Nature Communications (2020) study found that patients with chromothripsis had higher relapse rates and worse outcomes. Similarly, complex karyotypes involving multiple structural abnormalities often indicate advanced disease, reflecting an increased mutational burden that complicates treatment.

Laboratory Detection Approaches

Accurate detection of cytogenetic abnormalities in multiple myeloma relies on advanced laboratory techniques. Conventional karyotyping, historically used, has limitations due to the low proliferative capacity of myeloma cells in vitro, often missing key abnormalities. More refined molecular methods are now standard.

Fluorescence in situ hybridization (FISH) is widely used in clinical practice, providing a targeted approach to detect common translocations, deletions, and amplifications. Using fluorescently labeled DNA probes, FISH can visualize chromosomal rearrangements even in non-dividing cells, making it valuable for identifying high-risk abnormalities like t(4;14) or del(17p). The European Myeloma Network recommends FISH for risk stratification, as it provides prognostically relevant data that guide treatment. However, FISH is probe-dependent and cannot offer a comprehensive genomic overview.

To address these limitations, next-generation sequencing (NGS) and single nucleotide polymorphism (SNP) arrays have gained prominence. NGS enables deep genome sequencing, identifying structural alterations, point mutations, and copy number variations that influence disease progression. This approach has uncovered key mutations in TP53, KRAS, and NRAS, refining prognostic assessment. SNP arrays provide high-resolution detection of chromosomal gains and losses across the entire genome, making them particularly useful for identifying hyperdiploidy or complex karyotypic abnormalities.

Genetic Sub-Types

Multiple myeloma exhibits significant genetic heterogeneity, with distinct sub-types based on chromosomal and molecular alterations. These genetic differences shape disease progression, treatment responses, and outcomes, making classification essential for patient management.

Broadly, multiple myeloma falls into hyperdiploid and non-hyperdiploid categories. Hyperdiploid cases, nearly half of all diagnoses, have extra copies of odd-numbered chromosomes. This subtype generally follows a more indolent course and responds well to immunomodulatory therapies, likely due to the overexpression of genes that enhance plasma cell survival while maintaining treatment sensitivity.

Non-hyperdiploid cases are more often driven by primary translocations involving the IGH locus. These translocations create distinct molecular subgroups, each shaped by the oncogene involved. The cyclin D group includes t(11;14), marked by cyclin D1 overexpression, while the MAF and MAFB subgroups arise from t(14;16) and t(14;20), respectively, promoting tumor proliferation and adhesion. These distinctions have direct therapeutic implications, as certain molecular subtypes show differential sensitivity to targeted agents, proteasome inhibitors, and BCL-2 antagonists.