Assessment of bone involvement in patients with multiple myeloma using bone densitometry

Abstract: To evaluate the use of dual energy X-ray absorptiometry (DXA) in multiple myeloma (MM) we performed a prospective study of 34 patients with newly diagnosed MM. Most patients had advanced disease and all but two patients had osteolytic bone destructions and/or pathological fractures. Bone mineral content (BMC) and bone mineral density (BMD) of the lumbar spine (L₁–L₄) and hip were measured using a Hologic QDR-1000 scanner. Collapsed vertebrae were not excluded from analysis. Data from 289 healthy Danish volunteers aged 21–79 yr were used for calculation of Z-scores. Lumbar spine BMC (Z-score –0.46±0.23, p=0.05) and lumbar spine BMD (Z-score –0.56±0.23, p=0.02) were significantly reduced in MM patients, whereas no reduction was seen in hip BMC or BMD. Collapsed vertebrae had marked reduced BMD (Z-score –1.34±0.22, p<0.001), as had non-fractured vertebrae in the same individuals (Z-score –1.42±0.25, p<0.001). Lumbar spine BMD correlated with radiologically assessed bone morbidity (r –0.37, p=0.03) and stronger with the incidence of vertebral fractures (r –0.64, p<0.001). Thus, osteopenia of the back is common in multiple myeloma and correlates with an increased incidence of fractures. DXA may identify subjects with increased risk of vertebral fractures for more intensive chemotherapeutic or anti-resorptive treatment.     

Occurrence of multiple myeloma in both donor and recipient after bone marrow transplantation

The transplantation of malignant cells during allogeneic transplant is a rare occurrence. 27 months after donating progenitor cells, a diagnosis of multiple myeloma was made in a 6/6 HLA-phenotypically matched unrelated donor. The 42-year-old recipient transplanted for chronic phase chronic myeloid leukemia developed IgA myeloma 40 months after transplantation. Serum electrophoresis and bone marrow investigations established the diagnosis of IgA K multiple myeloma in both. This case illustrates the natural history and biology of multiple myeloma.     

Prognostic value of serum markers of bone metabolism in untreated multiple myeloma patients

Bone involvement is a central feature of multiple myeloma (MM). We investigated whether serum markers of osteoblastic and osteoclastic activity correlate with the presence of bone disease and survival in 313 MM patients enrolled in a phase III trial (E9486). Five markers were measured, including osteocalcin (OC), carboxy-terminal propeptide of type I collagen (PICP), bone alkaline phosphatase (BAP), carboxy-terminal telopeptide of type I collagen (ICTP) and tartrate-resistant acid phosphatase (TRAP). We analysed the relationship between serum levels of these markers and the presence of bone manifestations, and survival. Serum levels of ICTP and BAP correlated significantly with bone pain, lesions and fractures. Serum level of ICTP was also higher in stage II-III compared with stage I disease. The serum level of ICTP was significantly associated with shortened survival in the univariate analysis. The median survival times were 4.1 and 3.5 years for low and high ICTP respectively (P = 0.02). There was a strong relationship between ICTP and beta-2-micrgolobulin (B2M). ICTP stands out as a significant marker of bone disease. Incorporation of these markers into clinical trials assessing the use of bisphosphonates in MM is needed to determine whether they might serve as indicators of effectiveness of these agents.     

Medium-term results of percutaneous vertebroplasty in multiple myeloma

Vertebral compression fractures (VCFs) are common in multiple myeloma (MM). Percutaneous vertebroplasty (PVP) is used to stabilize vertebral collapse and treat the pain. Few studies have been carried out on PVP in MM and follow-up has tended to be short. We have prospectively evaluated the safety and efficacy of PVP in the VCFs resulting from MM or plasmacytomas. Nineteen PVP were performed in 12 consecutive patients. We monitored their pain and functional status using visual analog (VAS) and Eastern Cooperative Oncology Group (ECOG) scale, respectively. For a subjective assessment, every patient was asked about his/her degree of satisfaction. The mean age of the participants was 66 yr. Significant improvement occurred 1 d after PVP according to the VAS score (7.5 pre-PVP to 3.7, P < 0.0001) and ECOG assessment (3.1 to 2.5, P = 0.002). This significant improvement was maintained after 3.2 yr of follow-up. Sixty-three percent of patients were highly satisfied with the result of the PVP and 37% were satisfied. The peri-operative mortality was 0%. Leakage of the cement outside of the vertebral body was noted in 16 of 19 injected vertebrae (84%) but none of the patients developed any clinical or neurological symptoms. At the last follow-up, no further collapse in the treated or neighboring vertebrae was noted. VCFs caused by MM or plasmacytomas can be effectively treated by vertebroplasty. PVP is associated with early clinical improvement of pain and function and can be maintained after a long follow-up without major procedure-related complications.     

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.     

多发性骨髓瘤42例99mTc-MDP骨显像表现特征

目的探讨多发性骨髓瘤(MM)~(99m)Tc-MDP骨显像表现特征及其在MM诊断中的价值。方法对42例MM患者进行~(99m)Tc-MDP骨显像检查,分析其病灶分布、形态等特点。结果 42例MM患者~(99m)Tc-MDP骨显像异常34例(80.5%),病灶均为多发,大部分表现为放射性浓聚区,少部分表现为浓聚合并缺损。受累部位依次为肋骨、胸椎、腰椎、骨盆和四肢肩带,胸骨、颈椎较少见。肋骨大部分表现为圆点状、串珠状放射性浓聚,多条肋骨受累,在腰椎、胸椎上则以扁平横条状放射性浓聚多见,骨盆、脊柱可见"面圈样"改变,颅骨可见"帽状"放射性浓聚。结论 ~(99m)Tc-MDP骨显像在MM中有某些表现特征,可作为探测MM骨损害的常规检查方法。     

Pathophysiology of myeloma bone disease

Multiple myeloma is a tumor of terminally differentiated plasma cells that home to and expand in the bone marrow. It is the second most common hematologic malignancy, with approximately 16,000 new cases per year, and accounts for an estimated 11,000 deaths in the USA. It is the most common cancer to metastasize to bone, with up to 90% of patients developing bone lesions. The bone lesions are purely osteolytic in nature, and up to 60% of patients develop a pathologic fracture over the course of their disease. Bone disease is a hallmark of multiple myeloma, and the bone disease differs from other bone metastasis caused by other tumors. Although both myeloma and other osteolytic metastasis induce increased osteoclastic bone resorption, in contrast to other tumors, osteoblast activity in myeloma is either severely decreased or absent. The basis for this severe imbalance between increased osteoclastic bone resorption and decreased bone formation resulting from suppressed osteoblastic activity has been a topic of extensive investigation during the last several years. The clinical consequences of this extensive accelerated and imbalanced bone destruction process include bone pain, pathologic fractures, hypercalcemia and spinal cord compression syndromes, which can be devastating for patients and significantly impact overall quality of life and expected survival. In this chapter, we will discuss the pathophysiology underlying bone disease in myeloma. This results from the uncoupling of bone remodeling and is characterized by markedly increased activity of osteoclasts and profound decreased activity of osteoblasts. In addition, we also review the emerging data on novel targeted therapies aimed at ameliorating myeloma bone disease.     

Diverse niches within multiple myeloma bone marrow aspirates affect plasma cell enumeration

A basic criterion for the diagnosis of multiple myeloma is plasma cell enumeration within the bone marrow (BM). This report showed that flow cytometry under-estimated the number of plasma cells in BM aspirates by an average of 60%, compared with morphological evaluation. The discrepancy was partially because BM smears contain cells associated with the lipid-enriched spicules. In contrast, flow cytometry is performed on the BM fluid, which is depleted of the lipid-adhesive plasma cells. This discrepancy may point to different plasma cell subpopulations associated with diverse niches within the BM.     

Non-invasive markers of bone turnover and plasma cytokines differ in osteoporotic patients with multiple myeloma and monoclonal gammopathies of undetermined significance

Abstract Aims: To determine whether various markers of bone turnover and/or plasma cytokines differ in patients with multiple myeloma (MM) compared with patients with monoclonal gammopathies of undetermined significance (MGUS). Methods: We studied 22 MM patients and 18 MGUS patients presenting over an 18‐month period and compared their data with those from 20 age‐ and sex‐matched patients presenting with primary osteoporosis. According to the Salmon and Durie classification, there were eight patients with stage I, nine with stage II and five with stage III disease. All patients had densitometric evidence of osteoporosis and were classified according to bone marrow evidence of plasma cell dyscrasia. Measured variables included markers of bone formation and bone resorption, and plasma cytokines. Results: Patients with MM and MGUS did not differ with respect to their mean age, male : female sex ratio, height, weight, serum calcium, 25‐hydroxyvitamin D and parathyroid hormone concentrations. Patients with MM had significantly lower concentrations of haemoglobin (109 vs 135 g/L) and serum transforming growth factor (TGF)‐β (261 vs 348 pg/mL) than patients with MGUS, and higher concentrations of serum paraproteins (31.1 vs 7.4 g/L), β2‐microglobulin (3.5 vs 2.2 g/L), % plasma cell numbers (35.3 vs 2.1%) and urinary deoxypyridinoline excretion rates (u‐DPYD; 7.7 vs 5.9 nmol/mmol creatinine; P < 0.05 for all comparisons). In multivariate analysis, the serum paraprotein (β coefficient = –0.067; 95% confidence intervals (CI), –0.019 to –0.005; P = 0.0012), u‐DPYD excretion rates (β coefficient = –0.012; 95% CI, –0.113 to –0.02; P = 0.0058) and serum TGF‐β concentrations (β coefficient = –0.002; 95% CI, –0.0002 to –0.02; P = 0.02) were the most important variables differentiating between MM and MGUS, after excluding lytic bone lesions, % plasma cell numbers and haemoglobin concentrations. Conclusions: The well‐established criteria for diagnosing MM include the presence of lytic bone lesions, plasmacytosis, haemoglobin and paraprotein concentrations. The u‐DPYD excretion rate, a sensitive non‐invasive marker of bone resorption, may help in differentiating between MM and MGUS, as well as serving as a marker of underlying bone disease activity in these patients. (Intern Med J 2001; 31: 272–278)     

Erythropoietin response in anaemic patients with multiple myeloma and other lymphoid malignancies infiltrating the bone marrow.

Immunoreactive erythropoietin levels were measured in 42 patients with lymphoid malignancies with anaemia and bone marrow involvement. Results were compared to a control group of 16 patients suffering from anaemia due to other causes. Significant inverse correlations between serum erythropoietin level and haemoglobin concentration were shown for the patients with lymphoid malignancies and also for the control subjects. Overall, the erythropoietin levels of patients with lymphoid malignancies with bone marrow infiltration and with normal renal function did not differ significantly from erythropoietin levels of the anaemic controls. We conclude that anaemia in patients with lymphoproliferative disorders with bone marrow infiltration and normal renal function is caused primarily by a diminished/inadequate response to erythropoietin at the level of the target cell.     

Immunodeficiency and immunotherapy in multiple myeloma

Multiple myeloma is a malignant tumour of plasma cells that remains incurable for the vast majority of patients, with a median survival of 2-3 years. It is characterized by the patchy accumulation of tumour cells within bone marrow leading to variable anaemia, bone destruction, hypercalcaemia, renal failure and infections. Immune dysfunction is an important feature of the disease and leads to infections that are both a major cause of morbidity and mortality and may promote tumour growth and resistance to chemotherapy. Numerous defects of the immune system have been described in multiple myeloma although the relative clinical importance of these remains elusive. There has been considerable interest in the identification of an autologous response against myeloma. Although T cells and humoral responses directed against myeloma-associated antigens have been described, it is uncertain if the immune system plays a role in preventing or controlling myeloma cell growth. There is increasing interest in the potential role of immunotherapy but the success of these interventions is likely to be modified by the immunologically hostile environment associated with multiple myeloma. This review attempts to summarize the current knowledge relating to the immune defects found in multiple myeloma.     

The bone marrow stromal compartment in multiple myeloma patients retains capability for osteogenic differentiation in vitro: defining the stromal defect in myeloma

Defects in bone repair contribute to multiple myeloma (MM) bone disease. It is unknown whether this reflects failure of osteogenic differentiation from mesenchymal stromal cells (MSC), inherent stromal defects or mature cell dysfunction. We quantified the number of fibroblast colony‐forming units (CFU‐f) and osteoblast colony‐forming units (CFU‐ob) in freshly isolated bone marrow (BM) from healthy individuals (N = 10) and MM patients (N = 54). CFU‐f and CFU‐ob were present in MM BM, at comparable frequency to normal subjects, irrespective of disease stage, and the presence of bone disease. Adherent cultures from MM BM are able to differentiate into osteoblasts, as indicated by the early upregulation of RUNX2, SP7, AXIN2 and DLX5, and the production of alkaline phosphatase and calcium. Coculture with MM cells failed to prevent osteogenic differentiation of adult human MSC. On the other hand, MM cells induced cell cycle progression in resting MSC in a cell contact dependent manner. This effect was confirmed using both primary CD138+ cells and MM cell lines, and was not seen with B or T cell lines. Our data confirm the presence of osteoblast progenitors and the preservation of osteogenic function in MM, however dysregulation of cell cycle control may contribute to the loss of normal bone homeostasis that ultimately results in osteolytic bone loss.     

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.     

硼替佐米对多发性骨髓瘤骨病的作用及其机制探讨

目的观察硼替佐米联合地塞米松方案(BD方案)对多发性骨髓瘤(MM)骨痛的疗效并初步探讨其作用机制。方法观察2006年10月至2009年4月中山大学附属第一医院血液科收治的59例接受BD方案和33例接受VADM方案(长春新碱、阿霉素、地塞米松与马法兰联合)的MM患者骨痛缓解、活动能力改善及骨事件发生情况;用酶联免疫吸附试验(ELISA)检测其中25例患者治疗前后抗酒石酸酸性磷酸酶(TRACP-5b)、骨碱性磷酸酶(BALP)及Wnt信号通路抑制因子DKK1的浓度。结果BD组在骨痛缓解率、活动能力改善和骨相关事件发生率方面均优于VADM组[分别为75.7%对50.0%,64.9%对20.8%和13.8%对57.8%(P均<0.05)]。与化疗前相比,BD组患者化疗后BALP浓度升高[(15.90±11.88)U/L对(48.98±47.07)U/L],TRACP-5b水平下降[(4.04±1.92)U/L对(2.22±1.53)U/L],DKK1水平下降[(19.08±11.78)μg/L对(9.78±5.14)μg/L],差异有统计学意义(P均<0.05)。结论BD方案对MM患者骨病有显著疗效;可促进骨髓瘤患者...     

Bone marrow angiogenesis and progression in multiple myeloma

Tumour growth is angiogenesis-dependent. We found a high correlation between the extent of bone marrow angiogenesis, evaluated as microvessel area, and the proliferating (S-phase) fraction of marrow plasma cells, evaluated as labelling index (LI), in patients with multiple myeloma (MM) and in those with monoclonal gammopathies of undetermined significance (MGUS). Angiogenesis itself was significantly associated with active as opposed to non-active MM and MGUS. The highest microvessel area accompanied rapidly progressive MM with the highest LI. When a cut-off value of 2% or greater of the microvessel area was used, most patients with active MM were classified correctly. The risk of active disease in patients with MM increased in parallel with the microvessel area. A causal relationship between plasma cell growth, activity phase in MM and marrow angiogenesis is suggested. Since angiogenesis proceeds in step with the enlargement of plasma cell tumours and the activity phase in MM, its measurement could be a useful prognostic marker in patients with plasma cell proliferative disorders.     

Vitamin D deficiency does not alter biochemical markers of bone metabolism before or after autograft in patients with multiple myeloma

So far, only one study has demonstrated a high incidence of vitamin D deficiency in patients with multiple myeloma. Vitamin D deficiency may alter bone remodelling in myeloma. In this study, we aimed to determine the prevalence of vitamin D deficiency and to assess its impact on bone remodelling and bone mineral density before and after autologous stem cell transplantation (ASCT). Patients and methods: In 39 consecutive patients receiving high‐dose chemotherapy (melphalan 200 mg/m²) followed by ASCT for multiple myeloma, we measured before (T0) and 12 months after ASCT (T12) serum calcium, 25‐OH‐D, PTH 1‐84, bone alkaline phosphatase (bALP), serum C‐terminal cross‐linking telopeptide and lumbar spine bone mineral density (BMD). Results: Mean vitamin D levels were low: 15 ± 5 ng/mL (9–18) at T0 and 16 ± 5 ng/mL (14–22) at T12. Twenty‐six patients (68%) had vitamin D deficiency (25‐OH‐D < 20 ng/mL) at T0 and 58% at T12. Patients in the vitamin D‐deficient group had higher serum PTH levels than those in the vitamin D‐sufficient group : 71 ± 24 pg/mL vs. 52 ± 18 pg/mL (P = 0.04). Biochemical bone markers were identical in both groups at T0 and T12. Z‐score values did not significantly differ between the two groups at T0 and T12. There were no correlations between 25‐OH‐D and BMD or bone marker levels. Conclusion: Vitamin D deficiency does not impair biochemical markers of bone metabolism in patients with multiple myeloma, before or after ASCT.     

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.     

Clinical utility of C‐terminal telopeptide of type 1 collagen in multiple myeloma

Myeloma bone disease (MBD) is a major cause of morbidity in multiple myeloma (MM). We investigated bone turnover markers (BTM) as relapse predictors and biomarkers for monitoring MBD. We measured C‐terminal telopeptide of type I collagen (CTX‐1), and Procollagen type 1 N Propeptide (P1NP) in 86 MM patients and 26 controls. CTX‐1 was higher in newly diagnosed patients compared to control, remission and relapse (P < 0·05), and decreased following treatment. In the setting of relapse, a CTX‐1 rise greater than the calculated least significant change (LSC) was observed in 26% of patients 3–6 months prior to relapse (P = 0·007), and in 60·8% up to 3 months before relapse (P = 0·015). Statistically significant changes in CTX‐1 levels were also observed in patients who were with and without bisphosphonate therapy at the time of relapse. In patients with normal renal function, mean CTX‐1 level was highest in the newly diagnosed group (0·771 ± 0·400 μg/l), and lowest in the remission group (0·099 ± 0·070 μg/l) (P < 0·0001). P1NP levels were not statistically different across the patient groups. We conclude that CTX‐1, measured on an automated hospital laboratory platform, has a role in routine treatment monitoring and predicting relapse of MBD, even in patients on bisphosphonates.     

Long-term oral pamidronate treatment inhibits osteoclastic bone resorption and bone turnover without affecting osteoblastic function in multiple myeloma

Abstract: This study was performed as a cross-sectional substudy to the Danish–Swedish Pamidronate Study, a randomized placebo-controlled multicentre trial in multiple myeloma. The purpose was to evaluate the biological effects of long-term treatment with oral pamidronate 300 mg daily on bone metabolism by using histomorphometry and analysis of cytokines and biochemical markers of bone turnover. Sixteen patients were included after median 27.5 months of protocolized treatment; 10 patients received active treatment and 6 patients placebo. When compared with placebo, pamidronate treatment was associated with: (a) marked decreased osteoclastic resorption rate (0.86±0.59 μm/d vs. 5.7±5.0 μm/d, p=0.002), and diminished activation frequency (0.20±0.18 yr^?1 vs. 0.72±0.55 yr^?1, p=0.014); (b) compensatory reduced volume referent bone formation rate (0.17±0.21 yr^?1 vs. 0.71±0.54 yr^?1, p=0.007), but unaltered mineral appositional rate; (c) neutral (–0.66±5.6 mm) vs. negative (–2.15±2.2 μm, p=0.013) bone balance per remodelling cycle; (d) higher trabecular bone volume (21.0±6.2% vs. 13.0±3.7%, p=0.01); (e) suppressed urinary excretion and serum levels of some of the biochemical markers of bone metabolism; and (f) significant reduction of circulating soluble interleukin-6 receptor (IL-6sR) (25.9±4.1 ng/ml vs. 32.1±6.6 ng/ml, p=0.04), and (g) a uniform tendency of lower serum and marrow plasma levels of IL-6, IL-1β, and TNFα. Thus oral pamidronate was absorbed in biologically active amounts, and reduced overall bone resorption and bone turnover without impairing osteoblastic bone formation. The observation that cytokine and cytokine receptor levels were reduced extends the possible and potential beneficial actions of bisphosphonates in multiple myeloma.