AL amyloidosis is caused by clonal light chains (LC) exerting systemic proteotoxicity and forming amyloid deposits in target organs. The aim of treatment is to rapidly restore organ function, thus improving survival. Early and accurate diagnosis, including unequivocal amyloid typing, is the keystone of effective therapy. The combined measurement of amyloid LC and biomarkers of cardiac and renal dysfunction are essential in the management of this disease. Severe heart involvement represents an unmet need.

Dr. Merlini will discuss current chemotherapy approaches aimed at suppressing the production of the amyloid LC using a risk-adapted approach. Novel agents, including those that specifically target amyloid deposits and proteotoxicity will be presented, and the potential for their use in an integrated, more effective, and less toxic treatment strategy that may also benefit high-risk patients. Genomic sequencing has revealed a high prevalence of MYD88 and CXCR4 somatic mutations in patients with Waldenstrom’s Macroglobulinemia (WM). MYD88L265P-mutated WM cells show enhanced IRAK, BTK, and PI3K signaling, and sensitivity to agents that block these pathways. Over thirty types of CXCR4 WHIM-like somatic mutations have been revealed in WM patients. MYD88 and CXCR4 mutation status can impact disease presentation and survival, as well as response to targeted therapeutics.

Dr. Treon will discuss current strategies aimed at targeting MYD88 and CXCR4 signaling in WM. The impact of MYD88 and CXCR4 mutations on novel drug development, including ibrutinib which was recently approved for the treatment of symptomatic WM patients, will also be discussed in this session.