Bone Involvement In Multiple Myeloma Research Articles

Is whole body low dose CT still necessary in the era of 18F-FDG PET/CT for the assessment of bone disease in multiple myeloma patients?

Whole body low dose computed tomography (WBLDCT) is the first-choice imaging modality to identify bone involvement in multiple myeloma (MM). Because the unenhanced LDCT co-registered to positron emission tomography (PET) (LDCT/PET) has similar technical characteristics to WBLDCT, we aimed to assess its reliability in the detection of bone disease, for employing fluorine-18-fluorodeoxyglucose (18F-FDG) PET/CT as unique multimodality imaging method in MM patients. Thirty three consecutive MM patients were prospectively enrolled and evaluated with WBLDCT to assess bone involvement. In addition, patients underwent 18F-FDG PET/CT using a disease-tailored optimized LDCT protocol. To compare both methods, skeletal anatomical regions were identified and a per-region and per-patient analysis were performed using Cohen's k test. Low dose computed tomography/PET sensitivity, specificity and accuracy were also calculated. The two imaging modalities resulted highly concordant considering both patient-based (k=0.841) and region-based analysis; some discrepancies were observed in dorsal spine (k=0.809) and thorax (k=0.756). Low dose computed tomography/PET sensitivity, specificity and accuracy were 89.4%, 98.3% and 93.5%, respectively. Low dose computed tomography co-registered PET has comparable performance to WBLDCT. If confirmed on a lager sample, these encouraging results suggest the possibility to use this multimodal hybrid imaging as the only method for MM evaluation, rather than both exams, providing both morphologic and metabolic information in one session with impact on patient compliance, health care spending and especially radiation exposure.

Comparison of Conventional Xrays with CT Based Approaches for Detection of Lytic Lesions in Multiple Myeloma

Comparison of Conventional Xrays with CT Based Approaches for Detection of Lytic Lesions in Multiple Myeloma

Computed tomography-based skeletal segmentation for quantitative PET metrics of bone involvement in multiple myeloma.

PurposeQuantifications in nuclear medicine are occasionally limited by the lack of standardization for defining volumes of interest (VOIs) on functional images. In the present article, we propose the use of computed tomography (CT)–based skeletal segmentation to determine anatomically the VOI in order to calculate quantitative parameters of fluorine 18 fluorodeoxyglucose (18F-FDG) PET/CT images from patients with multiple myeloma.MethodsWe evaluated 101 whole-body 18F-FDG PET/CTs of 58 patients with multiple myeloma. An initial subjective visual analysis of the PET images was used to classify the bone involvement as negative/mild, moderate, or marked. Then, a fully automated CT–based segmentation of the skeleton was performed on PET images. The maximum, mean, and SD of the standardized uptake values (SUVmax, SUVmean, and SDSUV) were calculated for bone tissue and compared with the visual analysis.ResultsForty-five (44.5%), 32 (31.7%), and 24 (23.8%) PET images were, respectively, classified as negative/mild, moderate, or marked bone involvement. All quantitative parameters were significantly related to the visual assessment of bone involvement. This association was stronger for the SUVmean [odds ratio (OR): 10.52 (95% confidence interval (CI), 5.68–19.48); P < 0.0001] and for the SDSUV [OR: 5.58 (95% CI, 3.31–9.42); P < 0.001) than for the SUVmax [OR: 1.01 (95% CI, 1.003–1.022); P = 0.003].ConclusionCT–based skeletal segmentation allows for automated and therefore reproducible calculation of PET quantitative parameters of bone involvement in patients with multiple myeloma. Using this method, the SUVmean and its respective SD correlated better with the visual analysis of 18F-FDG PET images than SUVmax. Its value in staging and evaluating therapy response needs to be evaluated.

Proposal for a Quantitative 18F-FDG PET/CT Metabolic Parameter to Assess the Intensity of Bone Involvement in Multiple Myeloma

Many efforts have been made to standardize the interpretation of 18F-FDG PET/CT in multiple myeloma (MM) with qualitative visual analysis or with quantitative metabolic parameters using various methods for lesion segmentation of PET images. The aim of this study was to propose a quantitative method for bone and bone marrow evaluation of 18F-FDG PET/CT considering the extent and intensity of bone 18F-FDG uptake: Intensity of Bone Involvement (IBI). Whole body 18F-FDG PET/CT of 59 consecutive MM patients were evaluated. Compact bone tissue was segmented in PET images using a global threshold for HU of the registered CT image. A whole skeleton mask was created and the percentage of its volume with 18F-FDG uptake above hepatic uptake was calculated (Percentage of Bone Involvement - PBI). IBI was defined by multiplying PBI by mean SUV above hepatic uptake. IBI was compared with visual analysis performed by two experienced nuclear medicine physicians. IBI calculation was feasible in all images (range:0.00–1.35). Visual analysis categorized PET exams into three groups (negative/mild, moderate and marked bone involvement), that had different ranges of IBI (multi comparison analysis, p < 0.0001). There was an inverse correlation between the patients’ hemoglobin values and IBI (r = −0.248;p = 0.02). IBI score is an objective measure of bone and bone marrow involvement in MM, allowing the categorization of patients in different degrees of aggressiveness of the bone disease. The next step is to validate IBI in a larger group of patients, before and after treatment and in a multicentre setting.

Interest of Diffusion Weighted Magnetic Resonance Imaging for the Evaluation of Bone Marrow Infiltration in Multiple Myeloma, Smoldering Myeloma and Monoclonal Gammopathy of Undetermined Significance.

Abstract 4874 IntroductionMonoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM) are two asymptomatic early stages of multiple myeloma, and are characterized by the absence of bone involvement. In contrast, bone lytic lesions are common complications of multiple myeloma. Magnetic resonance imaging (MRI) has improved the evaluation of bone involvement in multiple myeloma. Moreover MRI allows visualization of the medullary cavity and a direct assessment of the degree of myeloma cell infiltration before bone destruction becomes visible on plain radiographs. Diffusion weighted magnetic resonance imaging (DWI) probes the diffusion of water in the body. This sequence yields qualitative and quantitative information that reflects the tissue cellularity and cell membrane intregrity and thus complements morphological information obtained by conventional MRI. It shows considerable promise for detecting and characterizing tumors and evaluating treatment response. ObjectiveOur objective was to study the potential interest of diffusion weighted MRI for the evaluation of bone marrow infiltration in multiple myeloma, SMM and MGUS. Diagnostic criteria used were those defined by the International Myeloma Working Group. Patients and methodsThis retrospective study was conducted over a period of 8 months (November 2008 - June 2009) in Internal Medicine and Hematology departments of our institution. All patients who had a whole body MRI for evaluation of multiple myeloma, SMM or MGUS were included. We choose to study simultaneously 3 complementary sequences: T1 weighted, short time inversion recovery (STIR) and diffusion weighted. ResultsSeventy patients were included in this study: 9 MGUS, 19 SMM and 42 symptomatic multiple myeloma (16 at diagnosis and 27 at relapse). They were 30 men and 40 women. The median age was 64 years (36 - 89 years). Thirty one of the 42 multiple myeloma patients have focal bone lesions. Focal lesions were observed in the 3 MRI sequences and diffusion did not detect new lesions. Regarding bone marrow infiltration assessment by MRI, four groups of patients could be identified: - Group 1 (20 patients – 28.6%): normal signal in T1, STIR, and diffusion. - Group 2 (19 patients – 27.1%): abnormal signal involving the whole spine on the STIR or diffusion weighted sequences and with a normal signal of the spine on T1.- Group 3 (25 patients – 35.7%): abnormal signal involving the whole spine on the STIR and diffusion weighted sequences and with a normal signal of the spine on T1.- Group 4 (6 patients – 8.6%): abnormal signal involving the whole spine on the 3 sequences. For the 28 patients with either MGUS or SMM, the distribution in the 4 groups was respectively 13 patients (46.4%), 7 patients (25.0%), 7 patients (25.0%) and 1 patient (3.6%) for group 1,2 3 and 4. Regarding the 42 cases of symptomatic multiple myeloma, 7 patients (16.7%) were classified in group 1, 12 (28.6%) in group 2, 18 (42.9%) in group 3 and 5 (11.9%) in group 4. There was no correlation between number of focal lesions and degree of diffuse infiltration. The degree of bone marrow infiltration evaluated by MRI was not correlated with Durie and Salmon stage, ISS, monoclonal component concentration or bone marrow plasmocytosis. DiscussionDiffusion weighted magnetic resonance imaging combined with conventional sequences (T1 and STIR) can distinguish 4 groups of patients with different aspects of bone marrow infiltration. Fifteen patients (53.6%) with either MGUS or SMM had various degree of bone marrow infiltration without any focal lesions. A prospective study on a large population of MGUS and SMM is needed to assess the impact of these asymptomatic infiltrations on the risk of malignant transformation. The degree of bone marrow infiltration evaluated by MRI is very heterogeneous between patients with multiple myeloma and not correlated with classical prognostic factors. Further prospective studies are necessary to investigate the possible prognostic impact of these different groups on the evolution of myeloma. DisclosuresNo relevant conflicts of interest to declare.

Connective tissue growth factor is an indicator of bone involvement in multiple myeloma, but matrix metalloproteinase‐9 is not

Bone disease (BD) in multiple myeloma (MM) is because of the activation of osteoclasts and impairment of osteoblast differentiation. Connective tissue growth factor (CTGF) is known to participate in the differentiation of mesenchymal stem cells to committed osteoprogenitor cells. We analysed the concentration of circulating CTGF in 35 MM patients and 22 malignant lymphoma (ML) patients and 14 normal individuals. CTGF is protease-sensitive and thus is found as both an N-terminal half fragment (N-half CTGF) and whole (W-CTGF). Serum levels of W-CTGF and N-half CTGF + W-CTGF were determined by separate sandwich enzyme-linked immunosorbent assays. The level of W-CTGF was significantly lower (P < 0.005) in MM patients compared with ML patients and normal individuals, while N-half + W-CTGF was similar in all groups. Furthermore, W-CTGF was significantly lower in MM patients with BD compared with those without BD (P < 0.005) and this was independent of previous treatment. Matrix metalloproteinase (MMP)-9 is produced by myeloma cells and is thought to be related to BD in MM. However, MMP-9 does not cleave CTGF and serum MMP-9 level was not related to BD in MM. Thus, CTGF is an indicator of BD in MM; its metabolism and function in MM should be clarified.

Connective Tissue Growth Factor (CTGF) Is an Indicator of Bone Involvement in Multiple Myeloma.

Bone disease in multiple myeloma (MM) is due to not only the activation of osteoclasts but also the impairment of osteoblast differentiation. Recent studies showed the overexpression of the Wnt signaling antagonists FRZB (secreted Frizzled-related protein 3, sFRP-3) and dickkopf1 (DKK1) is important in MM-related bone disease. Bone morphogenetic proteins (BMPs) and connective tissue growth factor (CTGF) are known to play essential roles in promoting the proliferation of early osteoprogenitor cells, specifically, differentiation from mesenchymal stem cells (MSC) to committed osteoprogenitor cells. Expression of CTGF is reported to be up-regulated by Wnt3A or BMPs stimulation. CTGF has four domains each of which participates in macromolecular interactions that are relevant to CTGF action as a modulating factor. In particular, Domain 2 is known to bind BMPs and thus block downstream signalling. The two N- and C-half domains are connected by a central hinge region which is protease sensitive. Some matrix metalloproteinases (MMP-2, 3, 7, 13) cleave this region. Study of clinical samples has shown that a major form of CTGF in the circulation is the N-half fragment. We analyzed the concentration of circulating CTGF in 39 patients with MM and 22 patients with malignant lymphoma (ML). Full length CTGF and N-half CTGF + full length CTGF in patient serum samples were detected and quantitated by separate sandwich ELISAs. The level of N-half CTGF was significantly higher in patients with MM compared to patients with ML (these subjects have normal BM) (p<0.001). Furthermore, serum content of N-half CTGF was significantly higher (p<0.001) in MM patients with bone disease compared to those without bone involvement. This may relate to BMP effects on bone physiology. Perhaps the CTGF N-half-fragment is a more effective BMP antagonist than intact CTGF. Alternatively, N-half CTGF may be less potent than intact CTGF for promoting osteoblast differentiation. First, we expected that cutting CTGF by MMP-13 produced by myeloma cells might be a cause of bone disease in MM. However, although the expression of MMP-13 was detected in myeloma cells by RT-PCR, cytoplasmic MMP-13 was positive only in MM patients with progressive disease (PD), and the level of serum MMP-13 was less than the sensitivity by ELISA. Furthermore, we analyzed the level of serum MMP-9 because it reportedly plays a role in the activation of osteoclasts. However, there was no significant difference between patients with MM and ML, and also no difference between MM patients with and without bone disease. We did not detect a significant difference of MMP9 expression between MM patients with and without bone disease by RQ-PCR. These results suggest that CTGF, N-half CTGF or both play a role in MM to promote bone involvement. In addition, evaluation of CTGF and CTGF fragments may serve as a useful approach to evaluate disease progression. The cause of high CTGF N-half-fragment in patients with MM should be clarified.

Temporal Bone Involvement in Multiple Myeloma

Temporal Bone Involvement in Multiple Myeloma

Temporal Bone Involvement in Multiple Myeloma

Temporal Bone Involvement in Multiple Myeloma

First‐line therapy with thalidomide, dexamethasone and zoledronic acid decreases bone resorption markers in patients with multiple myeloma

Bone involvement is frequently observed in multiple myeloma (MM) patients both at diagnosis and during the course of the disease. The evaluation of biochemical markers of bone turnover could allow a dynamic evaluation of the effects of a given therapy on bone metabolism. In the present study, markers of bone resorption [urinary free pyridinoline (PYD), deoxypyridinoline (DPYD), N-terminal telopeptide of collagen I (NTX) and C-terminal telopeptide (serum crosslaps)] and of bone formation [bone alkaline phosphatase (BAP) and osteocalcin] were evaluated at diagnosis and after induction therapy in 40 patients (23M, 17F, median age = 53.5 yr) enrolled in the 'Bologna 2002' clinical trial. By study design, all patients received 4 months of combined thalidomide (100 mg/d for 2 wk then 200 mg/d), dexamethasone (40 mg/d on days 1-4, 9-12, 17-20/28 on odd cycles and on days 1-4 on even cycles) and zoledronic acid (4 mg/28 d). At diagnosis, although bone resorption markers were increased in more than 40% of the patients, only NTX (P = 0.029) and crosslaps (P = 0.000) were significantly related to the extent of skeletal lesions, as assessed by X-ray. After 4 months of therapy, a significant decrease in mean (+/-SE) urinary NTX (52.7 +/-6.9 nmol/mmol creatinine +/-6.9 vs. 14 +/- 1.42 nmol/mmol creatinine, P = 0.000) and serum crosslaps (6242.4 +/-945 pmol/L vs. 1414.9 +/- 173.8 pmol/L, P = 0.000) was observed in patients obtaining > or =partial response, at variance to what has been detected in patients showing <partial response. Among all bone resorption markers, urinary NTX and serum crosslaps seem to be strictly related to the extent of bone involvement in MM. Combined thalidomide + dexamethasone and zoledronic acid seem to be highly effective in reducing bone resorption in sensitive patients, although the relative contribution of each drug cannot yet be determined.

Whole Body MRI Versus Skeletal Survey in Multple Myeloma.

BACKGROUND: Bone involvement in myeloma is conventionally assessed by radiographic skeletal survey (plain x-rays of spine, skull, chest, pelvis and long bones). However this may not pick up bony involvement in all patients who may then present with serious complications of myeloma bone disease such as spinal cord compression. Whole body MRI may be better than skeletal survey at evaluating myeloma bone involvement.AIMS: To compare the evaluation of myeloma bone involvement by conventional radiographic skeletal survey (RSS) with whole body magnetic resonance imaging (MRI).METHODS: 35 patients with multiple myeloma (median age 68 yrs, range 46–81) underwent conventional RSS and whole body MRI. 19 of the patients had newly diagnosed multiple myeloma and 16 had relapsed multiple myeloma. The extent of myeloma bone involvement was evaluated in both RSS and MRI as follows: the body was divided up into ten areas: skull, cervical spine, ribs, thoracic spine, lumbar spine, pelvis, right arm, left arm, right leg, left leg. In each area the extent of myeloma bone involvement was scored in both RSS and MRI as follows: 0 = normal; 1 = one focus of abnormality; 2 = more than one focus of abnormality; 3 = diffuse disease. The scores for each of the ten areas were combined to give an overall score out of thirty for both RSS and MRI.RESULTS: 30 of the 35 patients (85.7%) had evidence of bone involvement on MRI. This compares with 22 out of the 35 (62.9%) on RSS. The mean score for the extent of myeloma bone involvement on MRI was significantly higher than that for RSS (MRI mean score: 15.5 out of 30 (median 17, range 0–30); RSS mean score: 5.5 out of 30 (median 3, range 0 to 24); p<0.001). MRI was superior to RSS in all ten areas evaluated both in terms of lesion detection and extent of disease. The greatest difference between MRI and RSS was seen in the cervical, thoracic and lumbar spine, while the smallest difference was seen in the ribs and skull. Eight of the patients had no bone involvement detectable on RSS but did have bone involvement on MRI and this resulted in upstaging on Durie-Salmon staging in four patients.SUMMARY/CONCLUSIONS: RSS has limited sensitivity and a significant ionising patient dose. It is a cumbersome procedure taking up to 30 minutes. Whole body MRI gives improved sensitivity and appreciation of anatomic location of disease. It is non-ionising and can be rapidly acquired at low cost. We conclude that whole body MRI is superior to conventional RSS in both the identification and evaluation of extent of bone involvement in multiple myeloma.

Comparison of urinary markers for bone resorption in multiple myeloma

Multiple myeloma causes extensive bone remodeling. Classical biochemical markers such as urinary calcium have poor sensitivity for detecting multiple myeloma bone remodeling. New biochemicals have been developed including a carboxyterminal telopeptide of collagen I (CTX). We used an immunoenzymatic assay to determine urinary CTX in 60 patients with multiple myeloma. This marker was evaluated with regard to total pyridinolines, urinary calcium, radiological features, pain and response to treatment with bisphosphonates. In patients with bone involvement, CTX concentrations were significantly higher (+230%) than those of deoxypyridinoline (DPD) (+175%) and pyridinolines (PYD) (+130%). In all patients we have found a close correlation between CTX and DPD but not between CTX and PYD. Compared to radiological features, CTX was more sensitive (97%) and specific (96%) than DPD. After treatment by bisphosphonates, the fall in CTX concentrations was paralleled to urinary calcium and more marked than pyridinolines. Although our results need to be confirmed, CTX appears to be a potential marker to explore bone involvement in multiple myeloma.

Prospective Randomized Trial of Dichloromethylene Bisphosphonate (Clodronate) in Patients with Multiple Myeloma Requiring Treatment. A Multicenter Study

<i>Background</i>: Characteristic features of multiple myeloma are bone resorption, osteoporosis and osteolytic lesions. Bisphosphonates can inhibit osteoclast activity and bone resorption. In this controlled randomized multicenter trial the effect of the bisphosphonate clodronate on the progression of bone involvement in multiple myeloma was evaluated. <i>Patients and Methods</i>: 170 patients with multiple myeloma requiring treatment and with bone involvement were recruited and randomized. All patients received 15 mg/m² i.v. melphalan on day 1 and 60 mg/m2 p.o. predisone on days 1-4 every 4 weeks. Patients randomized to the bisphosphonate arm received 1,600 mg clodronate p.o./day for 1 year. Bone response was evaluated on the basis of X-ray controls of the skeleton at baseline, 6, and 12 months staging. In addition chemotherapy response, blood chemistry, cytology, pain, and analgesic drug consumption were documented. <i>Results</i>: After one year of treatment there was a higher bone response in the clodronate group (13%) when compared to the control group (6%, n.s.). The difference was mainly due to the change of the osteolytic lesions. Hypercalcemia was observed more often in the control group. The number of progressive sites was lower in the clodronate group (mean 0.49 vs. 0.66, result after one year, p = 0.09). The bone resorption index was significantly reduced in the clodronate group, but not in the control group. A reduction of pain and analgesic consumption was observed under clodronate treatment.

Biochemical assessment of bone disease in multiple myeloma

In patients with multiple myeloma, with moderate and severe bone disease, the urinary hydroxyproline excretion was disproportionately elevated with respect to the activity of bone isoenzyme of alkaline phosphatase when compared with the relationship between the variables observed in 58 age- and sex-matched controls and in 50 healthy young subjects. A significant positive correlation was found between urinary hydroxyproline excretion and the clinical variables related to the extent of bone involvement in multiple myeloma (X-rays, patient's performance status, anaemia). In 9 out of 13 patients with moderate and severe bone disease the chemotherapy-induced remission was associated with a significant (p less than 0.05) rise in the activity of bone isoenzyme of alkaline phosphatase and decrease (p less than 0.005) in urinary hydroxyproline excretion. In successfully treated patients, the relationship between the biochemical variables indicated increased but proportionate extents of whole-body rates of bone formation and resorption. This was not the case in patients in whom no chemotherapy-induced remission was noted. The simultaneous evaluation of the activity of bone isoenzyme of serum alkaline phosphatase and urinary excretion of hydroxyproline improves the assessment of bone involvement in multiple myeloma and the efficacy of treatment.