Extramedullary disease in multiple myeloma: clinical and biological features with a comparative analysis of phenotypic differences

Abstract

Introduction Extramedullary disease (EMD) is a clinical manifestation of multiple myeloma (MM), characterized by a plasma cell (PC) proliferation outside of the bone marrow. The expression modulation of adhesion molecules, including CD44 and CD56, involved in bone marrow (BM) homing, supports clonal PCs migration through the bloodstream. CD38 is a multifunctional transmembrane glycoprotein, expressed by PCs, which also plays a role as adhesion molecule. CD38 is considered a hallmark of MM cells and a therapeutic target for anti-CD38 antibody-based approach, however its expression by extramedullary PCs is still unknown. Aims To analyze the clinical and cytogenetic features of EMD patients (pts). To perform a comparative analysis of phenotypic differences, including CD38, CD56, CD44, between BM PCs and EMD PCs in order to disclose antigenic changes that may contribute to EMD onset. Methods We investigated 22 pts (median age at diagnosis 67 years, range 47 – 76), affected by plasma cell dyscrasia (20 MM and 2 primary plasma cell leukemia, p-PCL) and presenting a biopsy proven soft tissue EMD. Clinical data included type of disease, age at the time of diagnosis and at the time of EMD, myeloma type, ISS stage, cytogenetic abnormalities. The immunostains from BM and EMD biopsies were scored using a semiquantitative evaluation of the percentage of CD38, CD44, CD56 on tumor cells on a 5-tiered scale (score 0, < 5% positive tumor cells; score 1, 5% to 24% positive tumor cells; score 2, 25% to 49% positive tumor cells; score 3, 50% to 75% positive tumor cells; score 4, > 75% positive tumor cells). Results Four pts presented EMD at diagnosis while 18 patients presented EMD at relapse. The median time to extramedullary disease appearance during relapse phase was 29 months (range 9-201 months). The most frequent MM subtype was light chain MM (41%) followed by IgG and IgA. IgM and IgD subtypes were absent. 46% of the patients presented a high stage (ISS III) a median LDH value, was slightly elevated and equal to 517 (normal value < 500 U/L). Overall 14 of 19 (79%) patients with available FISH at any time point considered, showed two or more cytogenetic alterations suggesting and high clonal heterogeneity in this subgroup of MM patients. Fourteen of 19 (73%) patients were included in a high risk prognostic group. The abnormalities of chromosome arm 1q21, including gain (53%, 10 patients) and amplification (21%, 4 patients), were the most frequent cytogenetic alterations reported (74%). The most common sites were soft tissue (muscle, subcutaneous fat) and liver/spleen which represented the 42%, of the total extramedullary localizations, 21% and 21% respectively, followed by lymph nodes (15%). CD38 had a high immunohistochemical score (3-4) in 15 of 19 BM samples (79%) and two patients were negative (score 0). CD38 was absent (score 0) in 3 out of 22 (14%) EMD samples and showed a low score (1-2) in 5 of 22 (23%) patients. Discordant CD38 expression was observed in 26% of samples with a down-regulation of CD38 in the EMD samples compared to BM. CD56 showed a high score (3-4) in 5 of 22 (23%) EMD samples and was absent (score 0) in 14 of 22 (64%) pts. Three out of 13 patients with discordant CD56 expression (18%) showed a strong down-regulation of CD56 in the EMD samples compared to BM. CD44 showed a high score (3-4) in 16 of 20 (80%) EMD samples and was absent (score 0) in 3 out of 20 (10%). Five pts with discordant CD44 expression (27%) showed an up-regulation of CD44 in the EMD samples compared to BM.

Conclusions Our data indicates that discordant expression of CD56, CD44 and CD38 may occur in EMD lesions compared to BM. The down-regulation or lack of CD38 in EMD should be considered for a possible impact on the therapeutic options.