Multiple myeloma (MM) progression is dependent on its interaction with the bone marrow microenvironment and the immune system and is mediated by key surface antigens. Some antigens promote adhesion to the bone marrow matrix and stromal cells, while others are involved in intercellular interactions that result in differentiation of B-cells to plasma cells (PC). These interactions are also involved in malignant transformation of the normal PC to MM PC as well as disease progression.
1. Introduction
Multiple myeloma (MM) is a neoplastic disease of plasma cells (PC) causing painful destructive bony lesions, anemia, hypercalcemia, kidney injury, and immune dysfunction [1]. The disease is precedented by monoclonal gammopathy of unknown significance (MGUS), a very common pre-malignant condition, characterized by a small PC clone secreting a monoclonal protein [1,2]. Though many of the abnormal properties of the PC including major chromosomal events are already present at the MGUS state, additional molecular events are needed for progression from MGUS to MM, and only a minority of MGUS patients will eventually progress to MM [1,2]. Great efforts have been undertaken to understand the pathogenesis of the evolution from a normal PC to MGUS and then MM and to understand the mechanism of MM PC survival, proliferation, and resistance to therapies [3,4,5,6,7]. Multiple myeloma (MM) is a neoplastic disease of plasma cells (PC) causing painful destructive bony lesions, anemia, hypercalcemia, kidney injury, and immune dysfunction [1]. The disease is precedented by monoclonal gammopathy of unknown significance (MGUS), a very common pre-malignant condition, characterized by a small PC clone secreting a monoclonal protein [1][2]. Though many of the abnormal properties of the PC including major chromosomal events are already present at the MGUS state, additional molecular events are needed for progression from MGUS to MM, and only a minority of MGUS patients will eventually progress to MM [1][2]. Great efforts have been undertaken to understand the pathogenesis of the evolution from a normal PC to MGUS and then MM and to understand the mechanism of MM PC survival, proliferation, and resistance to therapies [3][4][5][6][7].
2. Bioactivity and Prognostic Implication of Commonly Used Surface Antigens in Multiple Myeloma
CD38 is a surface protein which is expressed at high levels on normal and malignant PC as compared with the rest of the BM [18]. Consequently, it is utilized mostly for identification of PC, and not for discrimination between normal and malignant PC, although malignant cells can express a lower level of CD38 than normal PCs. CD38 expression is common to all hematopoietic cells but its levels are usually lower in mature myeloid cells and lymphoid lineage cells and negative on red cells and platelets. Activated hematopoietic cells upregulate CD38 expression to high levels, although not as high as PC [19]. This upregulation is due to binding to CD31 (present on the endothelium) and/or hyaluronan, which mediates CD38 adhesion to the BM ECM [8,18]. In addition, CD38 has an enzymatic activity: it can catalyze the generation of potent messengers that regulate intracellular calcium levels [20], which overall promotes proliferation. CD38-dependent adenosin production causes immune suppression.
Daratumumab, a full humanized anti-CD38 antibody, was the first anti-CD38 therapy that was investigated, followed by isatuximab [19,20]. The mechanism of both drugs involves complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), induction of apoptosis, and modulation of CD38 enzyme activities [23]. Both daratumumab and isatuximab have shown unprecedented efficacy, and thus paved their way to act as the backbone of treatment of relapsed and refractory MM, in various combinations. In addition to many other advantages, the rationale for anti-CD38 combinations is the ability of some anti-myeloma therapies to increase the density of CD38 molecules on the MM cells [21].
CD38 is a surface protein which is expressed at high levels on normal and malignant PC as compared with the rest of the BM [8]. Consequently, it is utilized mostly for identification of PC, and not for discrimination between normal and malignant PC, although malignant cells can express a lower level of CD38 than normal PCs. CD38 expression is common to all hematopoietic cells but its levels are usually lower in mature myeloid cells and lymphoid lineage cells and negative on red cells and platelets. Activated hematopoietic cells upregulate CD38 expression to high levels, although not as high as PC [9]. This upregulation is due to binding to CD31 (present on the endothelium) and/or hyaluronan, which mediates CD38 adhesion to the BM ECM [8][10]. In addition, CD38 has an enzymatic activity: it can catalyze the generation of potent messengers that regulate intracellular calcium levels [11], which overall promotes proliferation. CD38-dependent adenosin production causes immune suppression.
Daratumumab, a full humanized anti-CD38 antibody, was the first anti-CD38 therapy that was investigated, followed by isatuximab [9][11]. The mechanism of both drugs involves complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), induction of apoptosis, and modulation of CD38 enzyme activities [12]. Both daratumumab and isatuximab have shown unprecedented efficacy, and thus paved their way to act as the backbone of treatment of relapsed and refractory MM, in various combinations. In addition to many other advantages, the rationale for anti-CD38 combinations is the ability of some anti-myeloma therapies to increase the density of CD38 molecules on the MM cells [13].
CD138 (syndecan-1) is a large glycoprotein expressed on pre-B-cells, lost during B-cell maturation and re-expressed on PC [28], where it is one of the most abundant surface molecules [29]. Consequently, similar to CD38, its role in diagnosis is mainly for the identification of PC and not the discrimination between normal and malignant PC. Carrying heparan sulphate chains, CD138 interacts directly with ECM proteins such as fibronectin, promoting cell adhesion [8]. Moreover, CD138 plays a critical role in the ability of heparan sulphate-binding cytokines and chemokines to interact with the MM cell and promote its proliferation and survival [30].
Recently, CD138
CD138 (syndecan-1) is a large glycoprotein expressed on pre-B-cells, lost during B-cell maturation and re-expressed on PC [14], where it is one of the most abundant surface molecules [15]. Consequently, similar to CD38, its role in diagnosis is mainly for the identification of PC and not the discrimination between normal and malignant PC. Carrying heparan sulphate chains, CD138 interacts directly with ECM proteins such as fibronectin, promoting cell adhesion [10]. Moreover, CD138 plays a critical role in the ability of heparan sulphate-binding cytokines and chemokines to interact with the MM cell and promote its proliferation and survival [16].
Recently, CD138 MM cells were characterized by a proliferative but static phenotype, as opposed to CD138
low MM cells which were more motile and disseminative [29]. Junctional Adhesion Molecule-C was described as a key regulator in the switch between these two states [32]. These recent findings may explain earlier reports of CD138 shedding into the plasma [33], and correlating high plasma levels of soluble CD138 with a dismal prognosis [34].
MM cells which were more motile and disseminative [15]. Junctional Adhesion Molecule-C was described as a key regulator in the switch between these two states [17]. These recent findings may explain earlier reports of CD138 shedding into the plasma [18], and correlating high plasma levels of soluble CD138 with a dismal prognosis [19].
CD45 expression is ubiquitous on nucleated hematopoietic cells, and is thought to be a regulator of antigen-mediated T- and B-lymphocyte activation [38,39]. In normal BM, there appears to be a balance between the number of early PC, that express CD45, and terminally differentiated PC, that are CD45-negative [38]. In MM, the PC population is skewed toward CD45+ cells, that appear to be more proliferative compared to CD45− cells, co-express other different surface molecules, and respond differently to inhibitory and activating stimuli [38,40,41,42,43,44,45].
In daratumumab-treated patients, an increase in CD45 expression is associated with a very aggressive and resistant disease [47]. A small clone expressing high levels of CD45 may imply the existence of MRD that at relapse will become aggressive. In contrast, others reported worse prognosis in CD45− disease [48].
CD45 expression is ubiquitous on nucleated hematopoietic cells, and is thought to be a regulator of antigen-mediated T- and B-lymphocyte activation [20][21]. In normal BM, there appears to be a balance between the number of early PC, that express CD45, and terminally differentiated PC, that are CD45-negative [20]. In MM, the PC population is skewed toward CD45+ cells, that appear to be more proliferative compared to CD45− cells, co-express other different surface molecules, and respond differently to inhibitory and activating stimuli [20][22][23][24][25][26][27].
In daratumumab-treated patients, an increase in CD45 expression is associated with a very aggressive and resistant disease [28]. A small clone expressing high levels of CD45 may imply the existence of MRD that at relapse will become aggressive. In contrast, others reported worse prognosis in CD45− disease [29].
CD19 is a B-lineage lymphocyte antigen expressed on the surface of most B-cells. Its expression appears during immunoglobulin gene rearrangement, which coincides with B-lineage commitment at the hematopoietic stem cell stage and its expression progressively increases in concentration along B-cell maturation and terminal differentiation to PC. Throughout development, the surface density of CD19 is highly regulated, with the more mature B-cells expressing higher levels of CD19 [49].
CD19 has a dual role. The first role is as part of the B-cell receptor (BCR) complex, allowing B-cell differentiation and the antigen-dependent maturation processes, which the cell survival is dependent on [51,52]. In the second role, it interacts with CD21 to activate the BCR, and is essential for B-cell functionality by decreasing the threshold of the BCR activation [53]. It also interacts with other ligands such as complement (C3d) receptor, CD81, and CD225 [49,54].
CD19 has been utilized as a target for B-cell leukemia immunotherapies with antibodies or bi-specific antibodies, and as the main antigen used for chimeric antigen receptors (CAR)-T-cell therapy in B-cell lymphoma treatment [60,61]. The latter modality has been tested in MM patients based on the MM stem cell theory. A published case report described a deep response to CD19 CAR-T in MM patients, despite the absence of CD19 expression in 99.95% of the patient’s neoplastic PC [62]. This led to a recently reported exploration of autologous transplantation followed by CD19 CAR-T-cell therapy in MM patients [63], and moreover to the future construction of a dual anti-BCMA and anti-CD19 CAR-T strategy [64].
CD19 is a B-lineage lymphocyte antigen expressed on the surface of most B-cells. Its expression appears during immunoglobulin gene rearrangement, which coincides with B-lineage commitment at the hematopoietic stem cell stage and its expression progressively increases in concentration along B-cell maturation and terminal differentiation to PC. Throughout development, the surface density of CD19 is highly regulated, with the more mature B-cells expressing higher levels of CD19 [30].
CD19 has a dual role. The first role is as part of the B-cell receptor (BCR) complex, allowing B-cell differentiation and the antigen-dependent maturation processes, which the cell survival is dependent on [31][32]. In the second role, it interacts with CD21 to activate the BCR, and is essential for B-cell functionality by decreasing the threshold of the BCR activation [33]. It also interacts with other ligands such as complement (C3d) receptor, CD81, and CD225 [30][34].
CD19 has been utilized as a target for B-cell leukemia immunotherapies with antibodies or bi-specific antibodies, and as the main antigen used for chimeric antigen receptors (CAR)-T-cell therapy in B-cell lymphoma treatment [35][36]. The latter modality has been tested in MM patients based on the MM stem cell theory. A published case report described a deep response to CD19 CAR-T in MM patients, despite the absence of CD19 expression in 99.95% of the patient’s neoplastic PC [37]. This led to a recently reported exploration of autologous transplantation followed by CD19 CAR-T-cell therapy in MM patients [38], and moreover to the future construction of a dual anti-BCMA and anti-CD19 CAR-T strategy [39].
CD117 (c-kit) is a tyrosine kinase receptor involved in cell differentiation and proliferation [65,66]. It is essential for the survival of CD34+ myeloid precursors, and is also strongly expressed on mast cells and some sub-populations of natural killer (NK) cells and early T-cell precursors [67]. Some cancers are also characterized by CD117 expression, including gastrointestinal stromal tumor (GIST) and lymphoproliferative and myeloproliferative neoplasms [65,67].
About a third of MM PC express CD117, as opposed to almost none of normal PC [67,68]. Interestingly, it was found that CD117 expression is frequently lost at disease relapse [65]. Similar to other malignancies, following activation by its ligand stem cell factor (SCF), CD117 promotes cell proliferation in MM [65]. Compared to CD117−, CD117+ MM patients were found to have more hyper-diploid karyotype cases, less 14 chromosome translocations, and overall, a better prognosis [65,67,68,69,70], but not in all reports [71]. C-kit inhibition was not successful as a treatment for MM [72].
CD117 (c-kit) is a tyrosine kinase receptor involved in cell differentiation and proliferation [40][41]. It is essential for the survival of CD34+ myeloid precursors, and is also strongly expressed on mast cells and some sub-populations of natural killer (NK) cells and early T-cell precursors [42]. Some cancers are also characterized by CD117 expression, including gastrointestinal stromal tumor (GIST) and lymphoproliferative and myeloproliferative neoplasms [40][42].
About a third of MM PC express CD117, as opposed to almost none of normal PC [42][43]. Interestingly, it was found that CD117 expression is frequently lost at disease relapse [40]. Similar to other malignancies, following activation by its ligand stem cell factor (SCF), CD117 promotes cell proliferation in MM [40]. Compared to CD117−, CD117+ MM patients were found to have more hyper-diploid karyotype cases, less 14 chromosome translocations, and overall, a better prognosis [40][42][43][44][45], but not in all reports [46]. C-kit inhibition was not successful as a treatment for MM [47].
CD56, or neural cell adhesion molecule (NCAM), is a membrane glycoprotein and is a member of the immunoglobulin superfamily. CD56 is expressed on neural cells, muscle tissues, and various lymphoid cells. It is expressed on a small percent of normal PC but overexpressed in about 65–80% of malignant PC dyscrasias, especially MM [73,74,75]. Overexpression of CD56 promotes the transcription of CREB1 targets, the anti-apoptotic genes BCL2 and MCL1, resulting in a robust anti-apoptotic effect [76].
CD56 positivity in MM correlates with greater osteolytic burden, and is associated with well-differentiated neoplastic PC and a lower frequency of standard risk features, such as the presence of t(11;14) [76]. In another study, CD56 absence was associated with unfavorable prognostic parameters, such as elevated lactate dehydrogenase (LDH) and β2-microglobulin levels, advanced stage, and BM plasmacytosis of above 60%, however none of these factors effected patients’ OS [79]. Others have shown that CD56 absence may be associated with extramedullary involvement, plasma-blastic morphology, a plasma cell leukemia (PCL) state, non-hyper-diploid chromosomal abnormalities, and eventually worse PFS [65,77,80,81]. Okura et al. also reported on worse OS for CD56-negative MM [82]. In conclusion, CD56 may indeed be associated with prognosis and remains as one of the leading MM markers [83].
CD56, or neural cell adhesion molecule (NCAM), is a membrane glycoprotein and is a member of the immunoglobulin superfamily. CD56 is expressed on neural cells, muscle tissues, and various lymphoid cells. It is expressed on a small percent of normal PC but overexpressed in about 65–80% of malignant PC dyscrasias, especially MM [48][49][50]. Overexpression of CD56 promotes the transcription of CREB1 targets, the anti-apoptotic genes BCL2 and MCL1, resulting in a robust anti-apoptotic effect [51].
CD56 positivity in MM correlates with greater osteolytic burden, and is associated with well-differentiated neoplastic PC and a lower frequency of standard risk features, such as the presence of t(11;14) [51]. In another study, CD56 absence was associated with unfavorable prognostic parameters, such as elevated lactate dehydrogenase (LDH) and β2-microglobulin levels, advanced stage, and BM plasmacytosis of above 60%, however none of these factors effected patients’ OS [52]. Others have shown that CD56 absence may be associated with extramedullary involvement, plasma-blastic morphology, a plasma cell leukemia (PCL) state, non-hyper-diploid chromosomal abnormalities, and eventually worse PFS [40][53][54][55]. Okura et al. also reported on worse OS for CD56-negative MM [56]. In conclusion, CD56 may indeed be associated with prognosis and remains as one of the leading MM markers [57].
CD81 is a transmembrane protein of the tetraspanin family, which is expressed on normal B-cells and plays a critical role in the regulation of B-cell receptor activation [84], and as mentioned before, trafficking and expression of CD19 [85,86,87]. In vitro studies identified an anti-tumorigenic effect of CD81 in MM cells, including reduced proliferation and invasion potential [88], as well as enhanced protein synthesis with activation of unfolded protein response (UPR) [89], causing autophagic MM cell death. CD81 has a bright expression on normal PC, and is usually dim on abnormal PC, with up to a 40–45% detection rate in MM [90,91]. Paiva et al. of the PETHEMA group reported on a cohort of 233 newly diagnosed MM patients, with CD81+ MM patients having a significantly shorter PFS (3-year rates of 26% vs. 52%, in CD81+ vs. CD81−, respectively), which translated to a significantly shorter OS [90]. This group further showed, in a larger cohort, that MM cases expressing the combination of CD38
CD81 is a transmembrane protein of the tetraspanin family, which is expressed on normal B-cells and plays a critical role in the regulation of B-cell receptor activation [58], and as mentioned before, trafficking and expression of CD19 [59][60][61]. In vitro studies identified an anti-tumorigenic effect of CD81 in MM cells, including reduced proliferation and invasion potential [62], as well as enhanced protein synthesis with activation of unfolded protein response (UPR) [63], causing autophagic MM cell death. CD81 has a bright expression on normal PC, and is usually dim on abnormal PC, with up to a 40–45% detection rate in MM [64][65]. Paiva et al. of the PETHEMA group reported on a cohort of 233 newly diagnosed MM patients, with CD81+ MM patients having a significantly shorter PFS (3-year rates of 26% vs. 52%, in CD81+ vs. CD81−, respectively), which translated to a significantly shorter OS [64]. This group further showed, in a larger cohort, that MM cases expressing the combination of CD38 low, CD81+, and CD117− had the strongest correlation with an inferior outcome [92]. The significance of the CD81+ and CD117− expression pattern as a strong adverse prognostic marker was further reported by Chen et al. [68]. CD81 expression in smoldering MM (SMM) is correlated with shorter time to progression to active MM [90]. CD81 was also demonstrated as one of the most useful markers to detect different sub-clones. Interestingly, progression from MGUS to MM is characterized by reduced sub-clones’ variability with the appearance of a dominant clone. The immunophenotype profile was similar between MGUS and MM, however loss of CD27 and an increase in CD81 was noted in the dominant clone of relapsed patients [93].
, CD81+, and CD117− had the strongest correlation with an inferior outcome [66]. The significance of the CD81+ and CD117− expression pattern as a strong adverse prognostic marker was further reported by Chen et al. [43]. CD81 expression in smoldering MM (SMM) is correlated with shorter time to progression to active MM [64]. CD81 was also demonstrated as one of the most useful markers to detect different sub-clones. Interestingly, progression from MGUS to MM is characterized by reduced sub-clones’ variability with the appearance of a dominant clone. The immunophenotype profile was similar between MGUS and MM, however loss of CD27 and an increase in CD81 was noted in the dominant clone of relapsed patients [67].
CD27 is a membrane glycoprotein of the tumor necrosis factor (TNF) superfamily, which is expressed on the surface of most peripheral T-cells and certain sub-populations of B-cells [95], specifically memory B-cells and PC [96]. CD27 expression on T-cells acts as a co-stimulatory receptor, while binding of CD70 to CD27 on B-cells promotes differentiation to PC [97]. Several studies have shown that loss of CD27 expression characterizes progression to MM and less favorable prognosis [93,98,99]. Chu et al. investigated the significance of CD27 expression in newly diagnosed MM patients and found that CD27-negative disease had higher adverse risk characteristics, including higher PC burden and advanced stage. Furthermore, PFS was significantly shorter in the CD27-negative group [100]. Counterintuitively, the tumor cells in PCL displayed a high expression of CD27, which was shown to be protective of dexamethasone-induced apoptosis [101]. The difference between MM and PCL regarding CD27 expression is still not well understood.
CD27 is a membrane glycoprotein of the tumor necrosis factor (TNF) superfamily, which is expressed on the surface of most peripheral T-cells and certain sub-populations of B-cells [68], specifically memory B-cells and PC [69]. CD27 expression on T-cells acts as a co-stimulatory receptor, while binding of CD70 to CD27 on B-cells promotes differentiation to PC [70]. Several studies have shown that loss of CD27 expression characterizes progression to MM and less favorable prognosis [67][71][72]. Chu et al. investigated the significance of CD27 expression in newly diagnosed MM patients and found that CD27-negative disease had higher adverse risk characteristics, including higher PC burden and advanced stage. Furthermore, PFS was significantly shorter in the CD27-negative group [73]. Counterintuitively, the tumor cells in PCL displayed a high expression of CD27, which was shown to be protective of dexamethasone-induced apoptosis [74]. The difference between MM and PCL regarding CD27 expression is still not well understood.
CD28 is expressed on T-cells and acts as a co-stimulatory receptor with the T-cell receptor, resulting in enhanced proliferation and cytokine secretion [102,103]. CD28 expression is highly specific for MM PC, as it is not expressed on normal PC. Moreover, CD28 expression is correlated with disease progression, reaching up to 93% and 100% expression on relapsed extra-medullary MM and PCL, respectively [104]. T-cell activation is mediated by the binding of CD80 and CD86, expressed on antigen-presenting cells, to CD28 on MM PC. Data suggests that CD80/86 binding to CD28 on MM PCs generates a crosstalk between the stromal and MM PC. This promotes secretion of IL-6 by the stromal cells, which in turn supports survival of MM cells and ameliorates the anti-proliferative effects of dexamethasone [105]. In addition, activation of CD28 also induces activation of PI3 kinase signaling in MM PC, with downstream nuclear factor kappa B (NFkB) activation causing a pro-survival effect, which further strengthens the role of CD28 in the stroma–myeloma cell interaction [106].
CD28 is expressed on T-cells and acts as a co-stimulatory receptor with the T-cell receptor, resulting in enhanced proliferation and cytokine secretion [75][76]. CD28 expression is highly specific for MM PC, as it is not expressed on normal PC. Moreover, CD28 expression is correlated with disease progression, reaching up to 93% and 100% expression on relapsed extra-medullary MM and PCL, respectively [77]. T-cell activation is mediated by the binding of CD80 and CD86, expressed on antigen-presenting cells, to CD28 on MM PC. Data suggests that CD80/86 binding to CD28 on MM PCs generates a crosstalk between the stromal and MM PC. This promotes secretion of IL-6 by the stromal cells, which in turn supports survival of MM cells and ameliorates the anti-proliferative effects of dexamethasone [78]. In addition, activation of CD28 also induces activation of PI3 kinase signaling in MM PC, with downstream nuclear factor kappa B (NFkB) activation causing a pro-survival effect, which further strengthens the role of CD28 in the stroma–myeloma cell interaction [79].
CD24 is a highly glycosylated protein expressed on the surface of most B-lymphocytes, neutrophils, and its precursor myelocytes and differentiating neuroblasts. CD24 is expressed on pre-B-lymphocytes, remains expressed on mature resting B-cells, and becomes downregulated during the maturation process to PC [107,108]. A lack of CD24 results in a decrease in maturation of B-cells in mice [109]. CD24 overexpression has been found in many solid cancers and has been correlated with worse prognosis and presence of metastasis [110,111,112]. In MM PC, CD24 mRNA has been shown to be downregulated, correlated to worse OS [12]. The decreased tumorigenicity correlated with a “more normal” PC immunophenotype in patients with MM and correlated with CD45 expression [113]. Furthermore, following immunophenotype analysis in 124 MM patients treated with bortezomib, cyclophosphamide, and dexamethasone, we found that elevated CD24 expression on PC at diagnosis correlated significantly with longer PFS and OS (Gross Even-Zohar N, et al., submitted). Indeed, among CD19, CD45, CD117, CD56, and CD24, the latter was the only marker that retained its prognostic impact on PFS and OS. In light of these results, we believe that the addition of CD24 to the immunophenotype panel of MM at diagnosis should be considered. Its expression during the course of the disease is being studied.
CD24 is a highly glycosylated protein expressed on the surface of most B-lymphocytes, neutrophils, and its precursor myelocytes and differentiating neuroblasts. CD24 is expressed on pre-B-lymphocytes, remains expressed on mature resting B-cells, and becomes downregulated during the maturation process to PC [80][81]. A lack of CD24 results in a decrease in maturation of B-cells in mice [82]. CD24 overexpression has been found in many solid cancers and has been correlated with worse prognosis and presence of metastasis [83][84][85]. In MM PC, CD24 mRNA has been shown to be downregulated, correlated to worse OS [86]. The decreased tumorigenicity correlated with a “more normal” PC immunophenotype in patients with MM and correlated with CD45 expression [87]. Furthermore, following immunophenotype analysis in 124 MM patients treated with bortezomib, cyclophosphamide, and dexamethasone, the researchers found that elevated CD24 expression on PC at diagnosis correlated significantly with longer PFS and OS (Gross Even-Zohar N, et al., submitted). Indeed, among CD19, CD45, CD117, CD56, and CD24, the latter was the only marker that retained its prognostic impact on PFS and OS. In light of these results, the researchers believe that the addition of CD24 to the immunophenotype panel of MM at diagnosis should be considered. Its expression during the course of the disease is being studied.
