Impact of Cytogenetics on Multiple Myeloma Prognosis and Further Insights
Multiple Myeloma (MM), a type of cancer that affects plasma cells - a kind of immune cell, is characterized by various cytogenetic mutations that influence its progression, prognosis, and treatment responses.
Primary Cytogenetic Mutations
The common primary cytogenetic mutations in MM involve the immunoglobulin heavy chain (IgH) locus at 14q32 and hyperdiploidy. These mutations divide MM into two main genetic subtypes:
- Hyperdiploid Multiple Myeloma: Characterized by trisomies of odd-numbered chromosomes, this subtype is generally associated with a better prognosis.
- Non-hyperdiploid Multiple Myeloma: Often characterized by IgH translocations involving partner genes such as t(11;14), t(4;14), t(14;16), and others. Some of these translocations, like t(4;14) and t(14;16), are associated with poorer prognosis.
Secondary Cytogenetic Mutations
Secondary cytogenetic mutations, such as del(17p), involving TP53 loss, gains (e.g., 1q21), and mutations in genes like RAS and NF-kB pathway components, affect disease progression and prognosis and often contribute to treatment resistance.
Impact on Prognosis and Treatment
Cytogenetics plays a crucial role in prognosis assessment and therapy choices for MM. High-risk patients, such as those with t(4;14) or del(17p), might receive more aggressive treatment approaches, including proteasome inhibitors like bortezomib, immunomodulators, and consideration for early stem cell transplantation.
Risk stratification based on cytogenetics helps inform therapy selection. For instance, emerging therapeutic targets like epigenetic regulators (e.g., EZH2) and immune checkpoint molecules (e.g., CD200) can influence response to therapies such as Daratumumab (anti-CD38 monoclonal antibody).
Influence on Prognosis
Favorable prognosis is associated with hyperdiploidy and t(11;14) translocation, with patients typically responding better to standard therapies and having longer survival. On the other hand, translocations like t(4;14) and t(14;16), deletion 17p (TP53), and gain of 1q21 are linked to poor prognosis, more aggressive disease, and shorter survival.
Clinical Implications
Cytogenetic testing is recommended for the initial diagnosis and relapse of MM. Clinical trials have shown that people with different cytogenetic mutations show varied responses to treatments and therapies. For example, some individuals with a deletion on chromosome 17 responded well to treatment with pomalidomide and dexamethasone.
Primary mutations occur during the monoclonal gammopathy of undetermined significance (MGUS) stage and can cause parts of a chromosome to break away and reattach to a different chromosome (translocation mutations). Secondary mutations occur later in the disease or during its progression and can develop in any MM subtypes.
Conclusion
In summary, cytogenetics plays a significant role in understanding the development, progression, and treatment of MM. Primary cytogenetic mutations mainly involve IgH translocations and hyperdiploidy, which define disease subtypes and baseline prognosis, while secondary mutations like del(17p) and 1q21 gain contribute to progression and worse outcomes. Cytogenetics guides prognosis assessment and therapy choices, with new treatments targeting associated molecular pathways gaining importance.
- The immunoglobulin heavy chain (IgH) locus at 14q32 and hyperdiploidy are common primary cytogenetic mutations in Multiple Myeloma, dividing it into two main genetic subtypes: hyperdiploid and non-hyperdiploid.
- Non-hyperdiploid Multiple Myeloma is frequently characterized by IgH translocations that involve partner genes such as t(11;14), t(4;14), t(14;16), and others, some of which, like t(4;14) and t(14;16), are associated with poorer prognosis and shorter survival.
- Secondary cytogenetic mutations, including del(17p) and gains in genes like RAS and NF-kB pathway components, affect disease progression and prognosis, often contributing to treatment resistance and more aggressive disease.
- Cytogenetics plays a crucial role in prognosis assessment and therapy choices for Multiple Myeloma, as high-risk patients might receive more aggressive treatment approaches, including proteasome inhibitors like bortezomib, immunomodulators, and consideration for early stem cell transplantation.
- In clinical practice, cytogenetic testing is recommended for the initial diagnosis and relapse of Multiple Myeloma, as people with different cytogenetic mutations have varied responses to treatments and therapies, such as some individuals with a deletion on chromosome 17 responding well to treatment with pomalidomide and dexamethasone.
