Unusual Association between Increased Bone Resorption and Presence of Paroxysmal Nocturnal Hemoglobinuria Phenotype in Multiple Myeloma

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) clones deficient in glycosylphosphatidylinositol-anchored molecules, including CD55 and CD59, have been previously described in patients with multiple myeloma (MM). The aim of this study was to investigate the possible association between existence of the PNH phenotype and myeloma bone disease. Forty-three patients with newly diagnosed MM were the subjects of the study. Radiographic evaluation of the skeleton was performed in all patients at diagnosis. The following biochemical markers were measured: bone resorption markers (tartrate-resistant acid phosphatase isoform 5b [TRACP-5b]and N-terminal cross-linking telopeptide of type-I collagen [NTX]), bone formation markers (bone alkaline phosphatase [bALP] and osteocalcin [OC]), osteoprotegerin (OPG), soluble receptor activator of nuclear factor KB ligand (sRANKL), and interleukin 6 (IL-6). Detection of CD55- and/or CD59-deficient red cell populations was performed after diagnosis. Patients with MM had elevated mean baseline NTX, TRACP-5b, sRANKL, and IL-6 levels compared with controls, whereas the mean values of bALP, OC, and OPG were significantly decreased. Four patients had no osteolytic lesions, whereas 8 patients had 1 to 3 lytic lesions, and 31 patients had more than 3 lytic lesions and/or pathologic fractures in the skeletal survey. CD55- and/or CD59-deficient red cell populations were observed in 56% of patients with MM. There was a strong correlation between the presence of PNH-like erythrocytes and increased bone resorption, as measured by NTX, TRACP-5b, and sRANKL/OPG ratio (P < .03, P < .02, and P < .02, respectively). There was also a significant correlation between PNH phenotype and severe bone disease (P < .02). These results suggest that there is a possible link between PNH phenotype and increased osteoclastic activity in MM owing to a potential effect of myeloma microenvironment on a preexisting PNH clone. Further studies are required for clarifying this phenomenon and investigating possible mechanisms of this unusual association.

Significance of the detection of paroxysmal nocturnal hemoglobinuria clones in patients with multiple myeloma undergoing autologous stem cell transplantation

“…15 Despite this finding, no correlation was found between the presence of clones and Durie-Salmon disease stage, where Scale 3 bone disease was enough to characterize MM as Stage III. 29 Response to either induction chemotherapy or ASCT was not correlated with the presence of the clones.…”

“…However, these reports were based on demonstration of CD55/CD59-deficient populations in erythrocytes only; an obsolete method was applied in the previous studies. 14,15,18 In this study, we applied the current guidelines for detecting PNH clones, wherein we performed flow cytometric analysis on neutrophils and monocytes as well, requiring the presence of CD55/CD59-deficient populations in at least two different cell lines before accepting a ''PNH positive'' result.…”

“…11,12 There have also been reports regarding the presence of clones in patients with lymphoproliferative disorders and plasma cell dyscrasias. [13][14][15] These observations were based on obsolete technology for clone detection. 16,17 ; however, a recent work published after we commenced our study identified CD55 À RBC by flow cytometry (FC) in multiple myeloma (MM) patients.…”

Thrombotic risk in paroxysmal nocturnal hemoglobinuria-like (PNH-like) phenotype

“…No correlation was found between the infiltration of plasma cells in bone marrow, the stage or isotype of MM, the presence of anemia, the levels of paraprotein and β2-microglobulin in MM patients with the PNH phenotype. Instead, in another paper from Terpos E. et al, has been observed an association between existence of the PNH phenotype and myeloma bone disease [54]. These results suggest that there is a possible link between PNH phenotype and increased osteoclastic activity in MM owing to a potential effect of myeloma microenvironment.…”

Clinical conditions responsible for hyperviscosity and skin ulcers complications

“…In addition, an alternative hypothesis may be explained by the presence of a paroxysmal nocturnal hemoglobinuria-like defect in the erythrocyte membrane of MM subject group [19,64,94,100].…”