Cutaneous Localization In Multiple Myeloma In The Context Of Bortezomib Resistance: How Myeloma Cells Escape From The Bone Marrow To The Skin?

A rare complication of multiple myeloma is a secondary extramedullary involvement, and the skin is one of the possible sites, due to the physiological homing of plasma cells (PCs) into the skin. The article reports a case of a relapsed refractory MM patient, who developed a cutaneous localization after 16 months from the diagnosis under Bortezomib treatment without a leukemic phase. Patient was refractory to Bortezomib. We analyzed the gene expression profiles, the immunophenotypic and immunohistochemistry profiles of MM cells across the course of the disease at the bone marrow and skin localization. Data obtained were further expanded by an immunohistochemistry analysis on selected molecules in a large cohort of MM patients with cutaneous localization. In particular we focused on the expression of chemokines and chemokine receptors involved in the PC skin homing. The mechanisms behind the extramedullary spread and the formation of localizations outside the BM are not completely understood. Several studies investigated the expression profile of myeloma cells in the extramedullary localization by immunohistochemistry without a prospective molecular and immunohistochemistry study across the progression of the disease and consequently the development of extramedullary localization. This case indicates that the skin homing of MM cells could be related to the high CCR10 expression of at the diagnosis and relapse and the loss of CXCR4 surface expression across the progression of the disease in the contest of Bortezomib resistance. This data was further confirmed in a larger series of patients. Moreover, high expression of CD44, together with the down-regulation of CD54 and the lack of expression of CD56 by MM cells in the BM relapse with the re-acquisition of both antigens during the cutaneous relapse may be the mechanism that drives the escape from BM of PCs and their localization into the skin. Our data have identified a possible mechanism that drives the escape from BM of myeloma cells and their localization into the skin. To investigate the genes differentially expressed in malignant plasma cells of a patient with relapsed refractory MM patient, who developed a cutaneous localization, we performed gene expression profiling using Affymetrix GeneChip analysis of plasma cells purified from the bone marrow aspirates at diagnosis and relapse.