Dissecting non-transformed B cell responses in chronic lymphocytic leukaemia and multiple myeloma

Chronic lymphocytic leukaemia(CLL) and multiple myeloma(MM) are related mature B cell malignancies associated with secondary immunodeficiency. Advances in therapy have improved survival of CLL and MM patients, but infections remain a major cause of morbidity and mortality, accounting for an estimated 60% and 45% of deaths in CLL and MM, respectively. Unlike in other cohorts, in which immunodeficiency in the B cell compartment is observed, including elderly individuals, the non-transformed B cell composition and activation landscape that underlies dysregulated or deficient B cell responses in CLL and MM remains uncharacterized. Furthermore, CLL and MM patients have higher risk of severe COVID-19 and display impaired generation of protective antibodies and as such the pandemic has highlighted that antigen-specific B cell differentiation pathways are also unknown in these B cell haematological malignancies. Utilising our expertise in clinical haemato-oncology and B cell immunology, as well as the unique access to well-characterised CLL and MM patient cohorts, we will dissect non-malignant B cell activation pathways, their interplay with the malignant clone and the dynamics of antigen-specific B cell response to SARS-CoV-2 vaccination to address this knowledge gap. We will further assess how these B cell pathways relate to demographic, prognostic (e.g. CD38 for CLL and CD117 for MM), clinical (e.g. duration of disease) parameters and received therapy in CLL and MM patients.