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La inestabilidad genómica (IG) es una característica observada en casi todas las neoplasias y se define como una tendencia aumentada del genoma a adquirir diferentes tipos de cambios. El mieloma múltiple (MM) se caracteriza por una heterogeneidad genética importante evidenciada por numerosas alteraciones cromosómicas numéricas y estructurales recurrentes, primarias y secundarias, presentes al diagnóstico o adquiridas durante la evolución de la enfermedad, que sustentan una importante IG en la patología. Existen diferentes formas de IG que abarcan: inestabilidad cromosómica (IC), de microsatélites (IMS) y nucleotídica (IN). La IC constituye la forma más común en cáncer humano y se caracteriza por la existencia de una tasa acelerada de alteraciones cromosómicas durante las sucesivas divisiones celulares. Existen diferentes mecanismos relacionados al desarrollo de IC, entre ellos: rupturas del ADN a nivel de 1q12 asociada a la presencia de translocaciones “jumping”, cromotripsis, cromoplexia e inserciones con cambio de templado. A estas alteraciones corresponde agregar el acortamiento telomérico y la asincronía de replicación. La IMS ha sido poco estudiada en MM. En cuanto a la IN, se caracteriza por sustituciones de base y pequeñas inserciones/deleciones (indels) que involucran tanto el genoma codificante como el no-codificante, generando firmas mutacionales distintivas que pueden afectar diferentes caminos de señalización. Entre ellas las más relevantes son: desaminación de metilcitosinas, APOBEC, actividad aberrante de AID y kataegis. Su presencia se asocia a progresión de la enfermedad y resistencia al tratamiento. Finalmente, cabe destacar la importancia de las alteraciones epigenéticas: metilación del ADN, modificaciones de histonas y expresión de ARNs no-codificantes, que presentan también un rol importante en el desarrollo neoplásico. Sin duda, el estudio de estos mecanismos de IG en el MM permitirá ahondar en el conocimiento de las características biológicas de la patología, pudiendo constituir un aporte en la generación de nuevas estrategias terapéuticas.
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