Clinical Features of Bone Complications and Prognostic Value of Bone Lesions Detected by X-ray Skeletal Survey in Previously Untreated Patients with Multiple Myeloma

Multiple myeloma is usually associated with the presence of lytic bone lesions. We reviewed the clinical and laboratory features of patients with newly diagnosed myeloma bone disease and evaluated the prognostic significance of different X-ray image patterns in symptomatic MM patients. We retrospectively reviewed 260 patients with newly diagnosed MM. X-ray image patterns of patients were correlated with hematologic parameters, therapeutic reaction and patient survival. Patients with the X-ray imaging pattern of grade 2–4 had significantly higher marrow plasma cells levels, marrow CD138⁺ D38⁺ cell percentage, ECOG performance score, and serum IL-6 level than grade 0–1. Univariate analysis demonstrated that skeletal lytic changes associated with rapid progression. There is a high incidence of myeloma bone disease (MBD) in patients of MM in China. Patients of extensive bone lesions have more severe alterations in hematologic parameters than do those without bone lesions and severe bone lesions is an important adverse prognostic factor associated with a short TTP.     

IgM multiple myeloma: Disease definition,prognosis, and differentiation from Waldenstrom's macroglobulinemia

IgM multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) are two distinct hematologic entities with the common finding of an IgM monoclonal gammopathy. Distinguishing these two diagnoses is critical as the approach to therapy is different. A priori, we defined IgM MM as a symptomatic clonal plasma cell proliferative disorder characterized by an IgM monoclonal protein (regardless of size), 10% or more plasma cells on bone marrow biopsy, plus the presence of lytic bone lesions and/or translocation t(11;14). Twenty‐one patients met this definition of IgM MM. All 21 patients had lytic bone lesions. Of the 16 evaluated with FISH, 6 (38%) demonstrated t(11;14). Median overall survival was 30 months, which is similar to non‐IgM myeloma patients treated during this period and shorter than what would be expected for WM. In this, the largest series of patients with IgM MM, we describe the clinical features and prognosis of patient with IgM MM using a strict definition for the disease. The subset of patients without lytic lesions or t(11;14) but with immunophenotypic features suggestive of MM need further study. Am. J. Hematol., 2010. © 2010 Wiley‐Liss, Inc.     

Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma

Objectives: Lytic bone disease is a hallmark of multiple myeloma (MM) and is caused by osteoclast activation and osteoblast inhibition. Secretion of Dickkopf (DKK)‐1 by myeloma cells is a major factor which causes inhibition of osteoblast precursors. So far, there is no study showing a significant difference in serum DKK‐1 levels in MM patients with or without lytic bone lesions. Methods: DKK‐1 serum levels were quantified in 184 untreated MM patients and 33 monoclonal gammopathy of undetermined significance (MGUS) patients by ELISA, using a monoclonal anti‐DKK‐1 antibody. Results: Serum DKK‐1 was elevated in MM as compared with MGUS (mean 11 963 pg/mL vs. 1993 pg/mL; P < 0.05). Serum DKK‐1 levels significantly correlated with myeloma stage according to Durie and Salmon (mean 2223 pg/mL vs. 15 209 pg/mL in stage I and II/III, respectively; P = 0.005). Importantly, myeloma patients without lytic lesions in conventional radiography had significantly lower DKK‐1 levels than patients with lytic bone disease (mean 3114 pg/mL vs. 17 915 pg/mL; P = 0.003). Of interest, serum DKK‐1 correlated with the number of bone lesions (0 vs. 1–3 vs. >3 lesions: 3114 pg/mL vs. 3559 pg/mL vs. 24 068 pg/mL; P = 0.002). Conclusion: Using a large series of myeloma patients, we could show for the first time a correlation between DKK‐1 serum concentration and the amount of lytic bone disease, indicating that DKK‐1 is an important factor for the extent of bone disease and supporting the hypothesis of DKK‐1 as a therapeutic target in myeloma bone disease.     

Bone lesions in elderly multiple myeloma

We investigated the incidence of bone lesions in elderly cases of multiple myeloma (MM) and the course of those lesions, and also evaluated the relationships of skeletal symptoms with prognostic factors, and prognosis. The subjects were 146 patients, aged 65 years or more (median age 74, range 65-97 year), who were admitted to 11 institutions between January, 1988 and December, 1997. They consisted of 64 men and 82 women. The disease type was IgG type in 88 patients, IgA type in 37 patients, Bence-Jones (BJ) type in 17 patients, IgD type in three patients, and non-secretory type in one patient. Bone lesions in elderly MM patients were compared with those in 65 non-elderly MM patients. Skeletal symptoms were noted in 104 patients, and bone pain in 75 patients at the time of diagnosis. The bone lesions were evaluated as only osteolytic lesions in 26 patients, osteolytic lesions + osteoporosis in 23 patients, only osteoporosis in 2 patients and pathologic bone fractures in 53 patients. The occurrence rate of osteoporosis plus osteolytic lesion was higher in elderly patients (63.5%) than that in non-elderly patients (NE-MM group) (28.3%) (p < 0.0001). The bone lesions were most often observed in lumbar vertebrae (58.7%), cranial bone (56.7%), thoracic vertebrae (40.4%) and ribs (27.9%). The occurrence rate of bone lesion in lumbar vertebrae was higher in elderly patients (58.7%) than that in non-elderly patients (22.6%) (p < 0.0001). The life activities were limited in 71 patients because of the bone lesions. The relationship between the prognostic factors of MM and bone lesions was evaluated. There was a significant difference in the serum Ca level between patients with and without bone pain (P < 0.0001) and between those with and without pathologic bone fracture (P < 0.01). There was a significant difference in the appearance rate of plasma cells in the bone marrow between the patients with and without bone lesions (P < 0.05), between those with and without bone pain (P < 0.01), and between those with and without pathologic fracture (P < 0.05). There was a significant difference in the serum beta 2-microglobulin level between the patients with and without bone pain, and between those with and without pathologic fracture. There were no significant differences in survival times between elderly MM patients with and without bone lesions, bone pain and pathological bone fractures, while significant differences of survival times were found between non-elderly MM patients with and without bone lesions, bone pain and pathological bone fractures (P < 0.05, each). These data suggest that there are some differences in bone lesions between elderly and non-elderly MM patients.     

Biochemical markers of bone disease in asymptomatic early stage multiple myeloma. A study on their role in identifying high risk patients

BACKGROUND AND OBJECTIVES: Skeletal involvement is typical of multiple myeloma (MM) and its occurrence increases with the progression of the disease. We performed a study to evaluate the clinical importance of osteocalcin (bone gla-protein, BGP) and bone alkaline phosphatase (b-AP) as indices of osteoblastic activity, and deoxypyridoline (DPD) as a marker of bone resorption. DESIGN AND METHODS: Fifty-two MM patients, 39 patients with monoclonal gammopathy of undetermined significance (MGUS), and 30 normal controls entered the study. Of the 52 MM patients, 10 showed lytic lesions at standard X-rays and 42 did not; 21 were untreated and 31 had been treated with chemotherapy (combined with bisphophonates in 15). Of these last, 12 had progressive disease and 19 were in plateau phase. RESULTS: DPD levels were higher in MM patients than in patients with MGUS or healthy controls (p = 0.0001 and p = 0.0008, respectively). No statistical differences were seen between patients with MGUS and healthy controls. BGP serum levels were significantly lower in MM patients than in MGUS patients (p = 0.001) or healthy controls (p = 0.001). b-AP was significantly higher in MGUS patients than in MM patients (p = 0.04). Biochemical parameters were analyzed in a continuous fashion and after dichotomization into low and high values with respect to normal ones. Abnormal high values of DPD showed statistically significant correlations with presence of osteolysis (p = 0.008), advanced stage (p = 0.03) and abnormal beta2-microglobulin (beta2M) values (p = 0.03), while DPD as a continuous variable correlated significantly only with the presence of osteolysis (p = 0.02). In contrast, neither BGP nor b-AP showed statistical correlations with the presence of lytic lesions, or with other clinical or laboratory parameters. In 15 patients followed with serial controls, modifications of DPD levels reflected bone disease status well. Of the 42 patients without radiologic evidence of skeletal lesions, 15 had abnormal DPD values. Spinal magnetic resonance imaging (MRI) showed initial lytic lesions in 10 of them. INTERPRETATION AND CONCLUSIONS: Biochemical markers of bone metabolism are useful in evaluating and monitoring skeletal involvement in MM patients. They may help clinicians to identify: 1) from among patients without radiologic evidence of lytic lesions, those who deserve more accurate radiologic examinations (namely MRI); 2) from among asymptomatic patients, and in association with spinal MRI, those patients at higher risk of progression who might benefit from early treatment.     

Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)-1alpha and MIP-1beta correlates with lytic bone lesions in patients with multiple myeloma

Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta have been identified as candidates for multiple myeloma (MM)-derived bone-resorbing factors. To validate the clinical relevance of these observations, we investigated correlations between the ability of MM cells to secrete these chemokines and the extent of MM bone lesions as well as levels of biochemical bone markers in patients with MM. Patients with multiple bone lesions exhibited higher MIP-1alpha and MIP-1beta secretion from MM cells along with elevated urinary deoxypyridinoline (Dpd), without significant elevation of serum bone-specific alkaline phosphatase (BALP) or osteocalcin compared with those with minimal bone lesions. MIP-1alpha and MIP-1beta levels correlated positively with urinary Dpd and serum BALP but not with serum osteocalcin. These results provide further evidence for a causal role of MIP-1alpha and MIP-1beta in the development of lytic bone lesions, and suggest that MM cells suppress osteoblastic bone formation to cause an imbalance of bone turnover and development of destructive bone lesions.     

Bone remodelation markers are useful in the management of monoclonal gammopathies

The evaluation of bone disease in multiple myeloma (MM) by conventional radiology has low reproducibility. In the last decade, several serum and urine biochemical parameters, for evaluation of bone turnover, have become available. The present study was designed to explore the value of six bone remodelation markers. It was studied in a series of 176 newly diagnosed patients with monoclonal gammopathies (107 MM and 69 monoclonal gammopathies of unknown significance (MGUS)). As control groups we used 25 patients with benign osteoporosis (BO) and 32 healthy individuals (HI). The bone markers analyzed included: bone resorption markers (BRM) (total pyridinoline, total deoxypyridinoline, free deoxypyridinoline and C-terminal telopeptide of collagen I) and bone formation markers (BFM) (bone alkaline phosphatase (bAP) and osteocalcin (OC)). Serum or urinary levels of BRM were significantly higher in MM patients than in MGUS patients, BO patients or HI (P < 0.001, respectively). BRM were higher in MM patients with lytic lesions. However, only C-terminal telopeptide discriminated MM patients without bone lesions from MGUS patients. BFM did not show significant differences in the aforementioned comparisons, although a trend toward higher values of OC and lower values of bAP in patients with early bone affectation was observed. Ratios BRM/BFM that contained bAP exhibited differences that were most significant between the MM group and other entities, as well as between the different MM subgroups. In fact, the ratios BRM/bAP provided discrimination between the MM subgroup without lyses and MGUS group (P < 0.01). BRM and BFM, especially the ratios, are useful in the evaluation of bone lesions in patients with monoclonal gammopathies.     

Osteoblast stimulation in multiple myeloma lacking lytic bone lesions

The reasons why some patients with multiple myeloma (MM) do not develop severe bone loss, or even develop sclerotic bone lesions, remain unclear. In order to answer this question at the cellular and tissue level, we evaluated the histological bone condition of 10 patients with MM who never developed lytic bone lesions during the course of their disease (including two patients with sclerotic MM). Myeloma-induced bone changes in the close vicinity of myeloma cells were evaluated by quantitative histology (bone histomorphometry). All 10 patients presented a significantly increased osteoblastic activity. This was associated with an increased bone resorption in seven of the 10 cases. Three patients had a pure osteoblastic presentation. These features were the reverse of the pattern observed in seven patients with lytic bone lesions: increased bone resorption with decreased bone formation. Almost all of these 10 patients showing excessive osteoblastic activity had increased serum bone gla protein levels, a specific marker of bone formation. Finally, 90% of these patients were lambda MM (70% of them were IgG lambda MM), an immunoglobulin subtype previously associated with the sclerotic MM variants. In conclusion, a subset of patients with MM never develop severe bone loss because of the stimulation of osteoblastic activity. These patients belong to the same family as osteosclerotic MM, presenting more frequently the IgG type and lambda subtype.     

Smoldering multiple myeloma: natural history and recognition of an evolving type

Patients with smoldering multiple myeloma (SMM) meet the diagnostic criteria of multiple myeloma (MM) but are asymptomatic. Between January 1978 and July 2001, 53 patients (median age 63 years) were diagnosed with SMM. The median serum M-protein and proportion of bone marrow plasma cells were 36 g/l and 27% respectively. Two subsets of SMM were identified: (i) evolving SMM (n = 22), characterized by a progressive increase in serum M-protein, a previously recognized monoclonal gammopathy of undetermined significance (MGUS) and a significant higher proportion of IgA type and (ii) non-evolving SMM (n = 26) with stable M-protein that abruptly increases when symptomatic MM develops. Thirty-four patients developed symptomatic MM. The median time to progression in the overall series was 3.2 years and the only feature associated with a shorter time to progression was the evolving versus non-evolving type (1.3 vs. 3.9 years respectively, P = 0.007). The pattern of progression consisted of anaemia, lytic bone lesions or both, without renal failure, hypercalcaemia or extramedullary plasmacytomas. Fifty-seven per cent of patients that required chemotherapy showed no or minimal response. The median survival from diagnosis and from progression was 8.2 and 3.5 years respectively.     

Multiple myeloma patients with CKS1B gene amplification have a shorter progression-free survival post-autologous stem cell transplantation

The prevalence and prognostic relevance of recurrent gains of CKS1B (cyclin kinase subunit 1B) gene at chromosome 1q21 region was investigated by interphase fluorescence in situ hybridisation in a cohort of 99 multiple myeloma (MM) patients treated with intensive chemotherapy followed by autologous stem cell transplantation. CKS1B amplification (3-8 CKS1B signals) was detected in 31of 99 (31%) patients and was associated with deletions of p53 (P = 0.003) and 13q (P = 0.039) but not with translocation t(11;14) or t(4;14). CKS1B amplification was associated with bone marrow plasmacytosis (P = 0.02), but there was no correlation with patient age, gender, disease stage, lytic bone lesions, albumin, creatinine, C-reactive protein or beta-2 microglobulin levels. Patients with CKS1B amplification had a significantly shorter progression-free survival than those without such amplification (18.5 vs. 25.7 months, P = 0.035). Likewise, a shorter overall survival (44.8 months vs. not reached) was observed; however, the difference did not reach statistical significance (P = 0.20). Seven patients had paired bone marrows obtained at diagnosis and at relapse, the percentage of cells with CKS1B amplification and the level of amplification were significantly increased in the relapse marrows. In this cohort of patients, CKS1B was frequently amplified in MM and may represent genetic instability associated with disease progression.     

Prognostic variables and clinical staging in multiple myeloma

To evaluate the most important factors in the prognosis and staging of multiple myeloma (MM), the presenting clinical features of 163 previously untreated patients with MM were correlated with survival duration using univariate and multivariate regression analyses. The univariate proportional hazard analysis ranked the parameters in the following order of importance: platelet count, hemoglobin level (Hb), tumor cell mass stage, lytic bone lesions, creatinine, and age. When the individual contribution of each variable was assessed by multivariate regression analysis, platelet count was confirmed to be the dominant feature for prognosis and clinical stage provided additional information. The introduction of platelet count could then be used to improve the reliability of the Durie and Salmon staging, by allowing to separate the high-risk group (stages II and III) into a smaller subgroup (22%) of thrombocytopenic patients (less than 150 x 10(9) platelets/L) whose risk of death was actually very high (median survival, 9 months) and a larger subgroup (46%) of patients with normal platelet count and intermediate or standard risk (median survival, 48 months). This simple change in the prognostic system gave rise to markedly different survival curves also after the exclusion of patients with renal failure and applied successfully to both old and young patients (greater than and less than 50 years, respectively). Finally, platelet count, Hb, and lytic bone lesions could be combined simply to stratify patients with normal renal function into three risk groups: (1) low (39% of cases; median survival, 79 months), (2) intermediate (53% of cases; median survival, 48 months), and (3) high (8% of cases; median survival, 19 months).     

多发性骨髓瘤骨病患者骨代谢及调节因子水平及其意义

目的 研究多发性骨髓瘤(MM)患者血清Dickkopf-1(DKK-1)、可溶性核因子κB配体受体激活剂(sRANKL)、护骨素(OPG)和骨代谢因子[碱性磷酸酶(ALP)、抗酒石酸酸性磷酸酶(TRACP-5b)]水平及其与MM分期、溶骨性病变的关系,探讨骨代谢及调节因子DKK-1和sRANKL在MM骨病中的临床意义.方法 采用双抗体夹心ELISA检测30例初诊MM患者和20例健康人血清DKK-1、sRANKL、OPG、ALP、TRACP-5b等骨代谢因子及调节因子的水平.结果 MM患者血清DKK-1、sRANKL、OPG和TRACP水平均显著高于健康人,分别为42.96μg/L比5.33 μg/L,1.83pmol/L比0.79 pmol/L,1799.30 pmol/L比822.40 pmol/L,5.81 U/L比0.28 U/L,P值均＜0.05.国际分期系统(ISS)分期Ⅲ期患者血清DKK-1水平(46.33 μg/L)和sRANKL(2.26 pmol/L)水平显著高于Ⅰ/Ⅱ期患者(37.91μgL和1.19 pmol/L,P值均＜0.05).3处以上与1～3处溶骨病变患者相比,血清DKK-1、sRANKL和TRACP-5b水平显著升高(46.30μg/L比31.98μg/L,2.18 pmol/L比0.69 pmol/L,6.02 U/L比5.13 U/L,P值均＜0.05).结论 MM患者血清DKK-1、sRANKL、OPG和TRACP-5b水平均显著高于健康人;血清DKK-1、sRANKL水平与MM分期及溶骨病变程度相关.

Abstract：

Objective To detect serum concentrations of Dickkopf-1(DKK-1) and soluble receptor activator of nuclear factor-κB ligand (sRANKL) in patients with multiple myeloma (MM) and to investigate its clinical significance. Methods Serum DKK-1, sRANKL, osteoporotegerin(OPG) and tartrate-resistant acid phosphatase 5b (TRACP-5b) levels were quantified in 30 newly diagnosed MM patients and 20 healthy control subjects by using sandwich ELISA. Results The serum DKK-1, sRANKL,OPG and TRACP-5b levels were significantly higher than those in the healthy controls (42.96 μg/L vs 5.33 μg/L, 1.83 pmol/Lvs 0. 79 pmol/L, 1799. 30 pmol/L vs 822.40 pmol/L, 5.81 U/L vs 0. 28 U/L, respectively; all P＜0. 05). Serum levels of DKK-1 were positively correlated with sRANKL and TRACP-5b, respectively.Serum concentrations of DKK-1 and sRANKL were significantly elevated in stage Ⅲvs stages Ⅰ and Ⅱaccording to International Staging System (ISS) (46. 33 μg/L vs 37.91 μg/L, 2.26 pmol/L vs 1.19pmol/L, respectively, all P ＜0.05). Serum concentrations of DKK-1 , sRANKL and TRACP-5b were significantly higher in patients with more than 3 lytic bone lesions than those with only 1-3 lytic bone lesions (46. 30 μg/L vs 31.98 μg/L, 2. 18 pmol/L vs 0. 69 pmol/L, 6.02 U/L vs 5. 13 U/L, all P ＜ 0.05).Conclusions MM patients have increased serum DKK-1, sRANKL, OPG and TRACP-5b levels as compared with the healthy controls. Serum concentrations of DKK-1 and sRANKL have close relationship with MM stage and lytic bone disease.     

Bone lesions in elderly patients with multiple myeloma: a multicenter study by the Society for Geriatric Hematology

Background: Bone lesions in multiple myeloma (MM) have a significant impact on the quality of life of elderly patients, but they have not been extensively investigated in the elderly. Methods: The subjects were 146 elderly MM patients (aged ≥ 65 years, median age 74) admitted to 11 institutions. Bone lesions were compared with those in 65 non‐elderly MM patients. Results: At the time of diagnosis, skeletal symptoms were present in 104 cases and bone pain in 75. Mixed type occurred more often in elderly patients (63.5%) than in controls (28.3%) (P < 0.0001). Lumbar vertebral lesions were more common in elderly than non‐elderly patients (P < 0.0001). Bone lesions restricted physical activity in 71 elderly patients (48.6%). There was a significant difference between elderly patients with and without bone lesions in the rate of detection of plasma cells in bone marrow. Significant differences were detected in serum calcium concentration, the rate of detection of plasma cells in bone marrow, and serum β2‐microglobulin concentration between patients with and without bone pain, and between those with and without fractures. No significant differences were detected in survival time between elderly patients with and without bone lesions, with and without bone pain, or with and without fractures, whereas a significant difference was seen between these subgroups of non‐elderly patients. Conclusion: Although there were no significant differences in the incidence of bone lesions between elderly and non‐elderly patients, the mixed type of bone lesions occurred more often in the elderly than in controls. Lumbar vertebral lesions were more common in elderly than non‐elderly patients. There was no significant difference in prognosis between elderly patients with and those without bone lesions so the treatment strategy for bone lesions in the elderly should be aimed at improving quality of life through direct treatment of the bone lesions, with subsequent improvement of the related symptoms.     

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

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.     

p53 gene deletion detected by fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation

We investigated the relevance of p53 deletions to the clinical outcome of patients with multiple myeloma (MM) treated with high-dose chemotherapy and autologous stem cell transplantation. Hemizygous p53 gene deletions were detected by fluorescence in situ hybridization in 10 of 105 (9.5%) patients studied. p53 deletions were associated with higher serum calcium (P = .0062) and creatinine (P = .013) levels, but there were no association with patient age, gender, beta2-microglobulin, C-reactive protein, hemoglobin, albumin or bone lytic lesions, or immunoglobulin isotype. There were no associations of p53 deletions with 13q deletions or translocations t(11;14) or t(4;14). Patients with p53 deletions had significantly shorter progression-free (median, 7.9 versus 25.7 months, P = .0324) and overall survival (median, 14.7 versus 48.1 months, P = .0008) than patients without a p53 deletion. A multivariate analysis confirmed p53 deletion was an independent prognostic factor predicting shortened progression-free (P = .0009) or overall survival (P = .0002) in patients with MM after high-dose chemotherapy and autologous stem cell transplantation.     

Macrophage inflammatory protein-1 alpha is produced by human multiple myeloma (MM) cells and its expression correlates with bone lesions in patients with MM

Macrophage inflammatory protein-1 alpha (MIP-1alpha) is a chemokine primarily associated with bone absorption. We examined whether MIP-1alpha was produced by purified fresh tumour cells isolated from bone marrow samples from 31 multiple myeloma (MM) patients. High levels of MIP-1alpha were found in supernatants of myeloma cell cultures. Immunohistochemical staining showed MIP-1alpha in the cytoplasm of myeloma cells. MIP-1alpha mRNA expression was detected in 18 of 31 patients. Bone lesions were seen in 16 of the 18 MIP-1alpha-positive patients but only in six of the 13 MIP-1alpha-negative patients (P = 0.0097,chi2-test). The data indicate that MIP-1alpha is produced by myeloma cells and possibly plays a role in the pathogenesis of bone lesions in MM patients.     

Soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index

Interaction between receptor activator of nuclear factor kappaB ligand (RANKL) and RANK/osteoprotegerin (OPG) plays a dominant role in osteoclast activation and possibly in plasma cell survival in multiple myeloma (MM). We measured soluble RANKL (sRANKL), OPG, and bone remodeling markers in 121 patients with newly diagnosed MM to evaluate their role in bone disease and survival. Serum levels of sRANKL were elevated in patients with MM and correlated with bone disease. The sRANKL/OPG ratio was also increased and correlated with markers of bone resorption, osteolytic lesions, and markers of disease activity. The sRANKL/OPG ratio, C-reactive protein (CRP), and beta2-microglobulin were the only independent prognostic factors predicting survival in multivariate analysis. We generated a prognostic index based on these factors that divided our patients into 3 risk groups. The low-risk group had a 96% probability of survival at 5 years, whereas the intermediate-risk and the high-risk groups had probabilities of survival of 52% and 0%, respectively. Not only do these results confirm for the first time in humans the importance of sRANKL/OPG in the development of bone disease, they also highlight the role of this pathway in the biology of plasma cell growth as reflected by its influence on survival.     

Molecular imaging in myeloma precursor disease

Multiple myeloma (MM) is consistently preceded by its pre-malignant states, monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). By definition, precursor conditions do not exhibit end-organ disease (anemia, hypercalcemia, renal failure, skeletal lytic lesions, or a combination of these). However, new imaging methods are demonstrating that some patients in the MGUS or SMM category are exhibiting early signs of MM. Although MGUS/SMM patients are currently defined as low-risk versus high-risk based on clinical markers, we currently lack the ability to predict the individual patient's risk of progression from MGUS/SMM to MM. Given that the presence of gross lytic bone lesions is a hallmark of MM, it is reasonable to believe that less severe bone changes defined by more sensitive imaging may be predictive of MM progression. Indeed, since bone disease is such an essential aspect of MM, imaging techniques directed at the detection of early bone lesions, have the potential to become increasingly more useful in the setting of MGUS/SMM. Current guidelines for the radiological assessment of MM still recommend the traditional skeletal survey, although its limitations are well documented, especially in early phases of the disease when radiographs can significantly underestimate the extent of bone lesions and bone marrow involvement. Newer, more advanced imaging modalities, with higher sensitivities, including whole-body low-dose computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) are being employed. Also various imaging techniques have been used to provide an assessment of bone involvement and identify extra-osseous disease. This review emphasizes the current state of the art and emerging imaging methods, which may help to better define high-risk versus low-risk MGUS/SMM. Ultimately, improved imaging could allow more tailored clinical management, and, most likely play an important role in the development of future treatment strategies for high-risk precursor disease.     

Bone disease from monoclonal gammopathy of undetermined significance to multiple myeloma: pathogenesis, interventions, and future opportunities

Manifestations of bone disease-osteopenia, osteolytic lesions, and fractures-are the hallmark of multiple myeloma (MM) and occur clinically in the vast majority of patients. These abnormalities can have devastating clinical effects by increasing both the morbidity and mortality of patients. Bone disease is usually found when patients are diagnosed with active MM; however, recent data suggest that it is present in early myelomagenesis, including patients with myeloma precursor disease, monoclonal gammopathy of undetermined significance (MGUS). The primary mechanisms of abnormal bone remodeling are increased osteoclastic activity, which occurs in close proximity to active myeloma cells, and decreased activity of the surrounding osteoblasts. Better understanding of the pathogenesis of bone disease in MM will allow us to enhance our current therapeutic options in the treatment of bone disease. In patients with active MM and at least one lytic lesion, intravenous bisphosphonates have been shown to decrease skeletal-related events and pain, improve performance status, and maintain quality of life. Emerging evidence suggests that intervention at earlier stages of disease may prevent skeletal-related events at time of progression, but there is no evidence that bisphosphonates in this setting change the natural history of the disease.