Pattern Of Marrow Involvement Research Articles

Patterns of bone marrow infiltration in lymphomas- A retrospective descriptive analysis from a tertiary care centre in Southern India

Bone marrow biopsy (BMB) examination is the gold standard for staging of lymphoma which is interpreted along with other clinical, laboratory and radiological investigations. This study aimed to evaluate the various patterns of BMB infiltration by lymphomas which include Hodgkin and Non Hodgkin lymphoma and the usefulness of BMB compared to bone marrow aspiration (BMA). : In a period of three years, there were 212 cases which showed lymphoma infiltration in bone marrow. We assessed the peripheral blood smear (PBS), BMA and BMB slides and concordance between each was evaluated. BMB slides were assessed for the pattern of involvement. The most frequent subtype was chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (21.70%) followed by Hodgkin lymphoma (HL)(12.73%)and follicular lymphoma (FL)(11.32%). Predominant pattern of infiltration showed by CLL/SLL cases was mixed pattern, by FL was paratrabecular pattern, mantle cell lymphoma(MCL) showed either diffuse or nodular, diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma(BL) showed predominantly diffuse pattern. Hairy cell leukemia (HCL) and peripheral T cell lymphoma (PTCL) showed an interstitial pattern. In HL, the pattern was usually focal nodular however diffuse involvement was seen in a few. Of the 212 cases, 50.94% cases had atypical lymphocytes or lymphocytosis in PBS and 81.14% cases showed infiltration in BMA. Atypical lymphoid cells may not be present at times in peripheral blood or bone marrow aspirate in spite of infiltration in the bone marrow. Different lymphomas show characteristic patterns of marrow involvement.

Monoclonal B-cell lymphocytosis in the bone marrow: revisiting the criteria for chronic lymphocytic leukemia/small lymphocytic lymphoma

Monoclonal B-cell lymphocytosis is a clonal B-cell population in the peripheral blood (PB) of <5x10ˆ9/L without extramedullary (EM) disease, often with a chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) phenotype. The degree of bone marrow (BM) involvement is not currently a part of the diagnostic criteria for MBL or CLL/SLL, but CLL-type MBLs in BM can be seen in patients lacking PB lymphocytosis. Data are limited on the outcome of such cases. We assessed the clinicopathologic characteristics of isolated BM CLL-type MBL in patients who did not meet criteria for CLL/SLL. We evaluated BMs from 2006 to 2018 with CLL-like clonal B-cell populations in patients with a PB absolute lymphocyte count or monoclonal B-cell count of <5×109/L and without definite evidence of EM disease. We investigated the extent and pattern of marrow involvement, PB counts, flow cytometric data, genetics, concurrent hematopoietic diseases, and outcomes including progression and treatment. Thirty cases with BM MBL but <5x10E9/L PB monoclonal B cells and no EM disease were identified. Thirteen of 30 had additional hematopoietic neoplasms. The mean patient age was 74.1 years (median: 77 years, range: 43-91 years). No patients had lymphadenopathy (LAD) or splenomegaly by physical examination. By imaging, nine of 18 had LAD (8/9<1.5cm) and four of 18 had splenomegaly but with other attributable etiologies. Mean PB absolute lymphocyte count (ALC) was 1.8×10E9/L (range: 0.5-5.0×10E9/L). Twenty-four of 30 (80%) had low-level (<20%) BM involvement by MBL, and among these, none with available follow-up data progressed to diagnostic CLL/SLL. Six of 30 (20%) had >20% marrow involvement by MBL. Four of 6 were treated for CLL/SLL due to cytopenias, despite not meeting diagnostic criteria, and all 4 were CD38 or ZAP70 positive and had cytogenetic abnormalities, including trisomy 12. One of 6 developed overt CLL/SLL 3 years later and had cytogenetic abnormalities at the time of MBL diagnosis. One of 6 was monitored without treatment but had no cytogenetic abnormalities.Isolated BM CLL-type MBL represents a diagnostic gray area, and this study highlights the range of clinical outcomes. All cases with <20% BM involvement did not require CLL-specific treatment or progress to CLL/SLL. In the 4 cases where treatment was initiated due to cytopenias, patients had ≥20% BM involvement, CD38 or ZAP70 expression, and cytogenetic abnormalities but lacked a PB ALC of ≥5x10E9/L or LAD ≥1.5cm, suggesting that not all patients with clinically significant disease will meet criteria for CLL/SLL. The results also show that concurrent hematopoietic disorders can complicate the diagnosis, as the disease course or treatment may result in leukopenia, precluding PB absolute lymphocytosis. Though larger studies are needed, the degree of BM involvement, in conjunction with flow cytometric prognostic markers, and cytogenetic abnormalities may be a useful addition to the current diagnostic criteria for CLL/SLL which only considers a PB numerical cutoff and EM involvement.

Distinctive patterns of marrow involvement by classic Hodgkin lymphoma are clues for diagnosis and subtyping.

Classic Hodgkin lymphoma (CHL) is a lymphoid neoplasm deriving from B cells in a rich inflammatory background. There are four histological subtypes with different epidemiological features. Bone marrow involvement by CHL is infrequent, and subtyping CHL from the bone marrow is not suggested as there might be discordant histopathology between the primary tumors and bone marrow specimens. In this study, we aimed to identify the histopathological features of bone marrow involved by CHL and tried to correlate these features with their subtypes. Among the 23 recruited cases, the frequencies of mixed cellularity (MC; 48%, 11/23) and nodular sclerosis (NS; 44%, 10/23) were similar. There were two patterns of marrow involvement: pattern A (fibrous), space-occupying lesions with alternating hypo- and hypercellular areas against a fibrotic background with dilated sinusoids and pattern B (histiocyte-rich), ill-defined granuloma-likelesions in which histiocytes merged with normal hematopoietic and inflammatory cells. Pattern A was more frequent in patients with CHL-NS than CHL-MC (100% vs. 18.2%; p < 0.001). Diagnostic Hodgkin cells and Reed-Sternberg (HRS) cells were identified in all cases, while HRS variant lacunar cells were occasionally discovered, particularly in the CHL-NS subtype (NS 100% vs. MC 9%; p < 0.001). The frequency of EBV association was higher in MC (64%) than that in NS (36%) subtype, but not statistically significant. Of the two patterns of marrow involvement, pattern A was more commonly associated with the NS subtype and less frequently associated with EBV. Recognizingthe patterns of marrow involvement is important for diagnosis and may contribute to the subtyping of CHL.

Diffuse vertebral marrow changes at MRI: Multiple myeloma or normal?

Five MRI patterns of marrow involvement (diffuse, focal, combined diffuse and focal, variegated, and normal) are observed in patients with a marrow proliferative disorder including MM. The wide range of marrow involvement patterns in monoclonal plasma cell proliferative disorders mirrors that of their natural histories that can vary from indolent to rapidly lethal. MRI of the axial bone marrow contributes to stage these disorders, but it should not be obtained for disease detection and characterization because of its limited specificity and sensitivity. At MRI, diffuse benign hematopoietic marrow hyperplasia and marrow heterogeneities in elderly patients mimic the diffuse and variegated patterns observed in MM patients. Careful analysis of fat- and fluid-sensitive MR images and quantitative marrow assessment by using MRI and FDG-PET can contribute in differentiating these changes from those associated with neoplastic marrow infiltration, with some residual overlapping findings.

Clinicopathological Evaluation of Metastatic Carcinomas of Bone Marrow Presenting as Cytopenia

Background – Metastatic carcinomas can involve bone marrow and may lead to subsequent marrow fibrosis and failure. The Bone marrow examination is important in patients diagnosed or patients on chemotherapy for cancer, who presented with peripheral cytopenia. The metastasis of bone marrow by these tumors is a sign of advanced stage of disease with poor prognosis.&#x0D; Methods – Our study is a retrospective study, in which we reviewed a total of 702 bone marrow procedures, out of which 118 bone marrow procedures done in patients with a diagnosis of cancer or patients on chemotherapy presented as cytopenia in Great Eastern Medical College and Hospital during a period of 10 years.&#x0D; Result – In our study of 118 patients 74 males and 44 females. Peripheral smear examination of these cases - 24 out of 32 (75%) presented with anemia, which was the commonest clinical presentation. Others were, thrombocytopenia in 18 (50%), bleeding manifestations in 10 (31.2%), Pancytopenia in 9 (28.1%), bi-cytopenia in 4 (12.5%). During this study period, among 118 malignancies reported in histopathology, 32 cases show bone marrow metastasis. 17.1% were carcinoma breast, 25% were carcinoma stomach 33.3% were carcinoma prostate and carcinoma urinary bladder, 23.5% were SCC carcinoma lung, 0% carcinoma Cervix, all cases of Ewing’s sarcoma, neuroblastoma and poorly differentiated carcinoma show bone marrow metastasis.&#x0D; &#x0D; Conclusion - Bone marrow examination is valuable tool in the diagnosis and staging of hematologic and nonhematological disease, as well as in the assessment of overall bone marrow cellularity, pattern of marrow involvement in metastatic carcinomas.

Whole-Body Low-Dose CT in Multiple Myeloma: Diagnostic Value of Appendicular Medullary Patterns of Attenuation.

OBJECTIVE. The purpose of this article is to analyze whole-body low-dose CT-detected appendicular medullary patterns of attenuation in patients with newly diagnosed multiple myeloma and to determine the diagnostic performance of whole-body low-dose CT in detecting diffuse marrow infiltration. MATERIALS AND METHODS. A total of 76 patients with myeloma who underwent whole-body low-dose CT and spinal MRI at initial assessment were retrospectively analyzed. The medullary cavities of femurs and humeri were evaluated qualitatively and quantitatively on CT. Medullary attenuation and SD-to-mean attenuation ratio were recorded for each long bone. The pattern of marrow involvement on spinal MRI was used as reference. The chi-square test was used to evaluate the relationship between the CT-based appendicular medullary cavity pattern and the MRI pattern, and ROC analysis was performed to assess the diagnostic accuracy of CT attenuation measurements for the differentiation between diffuse and mixed CT-based appendicular medullary cavity patterns. RESULTS. Medullary attenuation differed significantly among mixed, nodular, and diffuse CT-based appendicular medullary cavity patterns in the femurs (mean, 34.23 HU and range, 15-61 HU; mean, 66.26 HU and range, 26-104 HU; mean, 92.80 HU and range, 53-127 HU, respectively) and humeri (mean, 22.18 HU and range, 9-41; mean, 61.18 HU and range, 23-93 HU; mean, 77.50 and range, 25-105 HU, respectively). To discriminate between diffuse and mixed CT-based appendicular medullary cavity patterns, optimal cutoff attenuation values were 63 HU (sensitivity, 97.7%; specificity, 100.0%) for the femurs, and 52 HU (sensitivity, 97.4%; specificity, 100.0%) for the humeri. A total of 24 of 30 (80.0%) patients with a diffuse MRI pattern showed a diffuse CT-based appendicular medullary cavity pattern on whole-body low-dose CT, and all patients with a diffuse CT-based appendicular medullary cavity pattern also showed a diffuse pattern on MRI. CONCLUSION. According to analysis of peripheral medullary patterns of attenuation, whole-body low-dose CT can identify patients with multiple myeloma with diffuse marrow involvement.

Natural History of Skeletal Related Events in Patients with Multiple Myeloma Who Received First- and Second- Line Therapy with Novel Agents: Results from a Single Center Analysis in 620 Patients

Introduction: Skeletal-related events (SREs) that include pathological fractures, spinal cord compression (SCC) and need for radiotherapy or surgery to the bone are frequent complications of multiple myeloma (MM). Although the incidence of SREs at diagnosis is well-documented, there is limited information for the natural history of SREs during treatment with novel agents. Thus, we evaluated the SRE rate in MM patients who received frontline and second line therapy with proteasome inhibitors (PIs) or immunomodulatory drug (IMiD)-based therapies and explored possible correlations with disease or genetic features and type of treatment. Methods: MM patients who received frontline therapy in our center (Department of Clinical Therapeutics, University of Athens, Greece), between 2007-2017, were included in this analysis. Patients had a whole-body skeletal survey using either conventional radiography (WBXR) or low-dose CT (WBLDCT) at diagnosis and then at the time of relapse or whenever clinically indicated. Magnetic Resonance Imaging (MRI) of the spine and pelvis at diagnosis was recorded when available. SNPs in genes that are involved in bone destruction in osteoporosis were also evaluated: LRP5 (rs4988321), GC vitamin D (rs4588), TNFRSF11A (rs3018362), DKK1 (rs1569198), RANKL (rs9594759), OPG (rs6469804) and ERS1 (rs1038304). Results: In total, 620 consecutive patients with symptomatic MM (316M/304F, median age: 65 years) were studied. The median follow-up was 54 months. At diagnosis, osteolytic disease was present in 408 (66%) patients. MRI was available in 390 patients: 149 (38%) patients had focal, 139 (36%) diffuse, 81 (21%) normal and 21 (5%) variegated pattern of marrow involvement. SREs were observed in 271 (44%) patients at diagnosis: 213 (34%) presented with pathological fractures (183 with vertebral fractures, 18 with rib fractures and 15 with long bone fractures; 32 patients had both vertebral and long bone or rib fractures), while 34 (5.5%) patients needed surgery to bone, 45 (7.2%) radiotherapy and 31 (5%) patients presented with SCC. The incidence of SREs was higher in patients with osteolytic lesions (76.4% vs. 12.4%, p&lt;0.0001) or abnormal MRI pattern (49% vs. 11.3%, p&lt;0.0001) at diagnosis. No correlation was found between the presence of SREs at diagnosis and a specific SNP of those studied. Frontline therapy with IMiD-based regimens was given in 38% of patients; 27% patients received bortezomib-based regimens and 28% both IMiD and bortezomib-based therapies (VTD or VRD); 7% received only conventional chemo. Bisphosphonates (BPs) were given to 465 patients (75%) at diagnosis; the vast majority (91%) received zoledronic acid. The remaining 155 patients did not receive upfront BPs, mainly due to renal insufficiency. During first line treatment, 39 (6.3%) patients developed a SRE: 25/341 (7.3%) on bortezomib- (including combos with an IMiD) and 14/235 (6%) on IMiD-based regimens. At the time of first relapse, 4.5% of patients presented with new fractures and 12% required local radiotherapy to bone (SRE rate: 16.5%). The rate of SREs at first progression was much higher in patients who did not receive upfront BPs (92.3% vs. 7.7%). There was no difference in the incidence of SREs at first relapse between patients who received PI- vs. non-PI-based regimens as first line therapy (54.2% vs. 45.8%, p=0.544). During second line therapy, 12.2% of patients developed a SRE, with no difference regarding the second line therapy (PI- or IMiD-based regimens). In total, 126 (20.3%) patients developed at least one SRE, during the course of the first and second line of therapy; this was more common in those who presented with an SRE at diagnosis (33% vs 12%; p&lt;0.03). Conclusions: Our data, which constitutes one of the few systematic reports on the incidence and characteristics of SREs in the era of novel agents, indicate that SREs remain a significant complication in MM. Despite high response rates after first line therapy and the broad use of BPs, more than 20% of patients develop a new SRE during the first and second line treatment or at the time of first relapse. Importantly, patients who do not receive BPs due to renal impairment develop very frequently SREs, suggesting an unmet need in this setting. More effective frontline therapies or more potent bone-targeted agents (denosumab or anti-sclerostin drugs) may manage to further reduce the SREs rate in MM patients, especially in those who cannot receive BPs. Disclosures Terpos: Celgene: Honoraria; Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria. Kastritis:Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria. Gavriatopoulou:Amgen: Honoraria; Takeda: Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses. Dimopoulos:Sanofi Oncology: Research Funding.

Diffusion-Weighted Imaging Improves Accuracy in the Diagnosis of MRI Patterns of Marrow Involvement in Newly Diagnosed Myeloma: Results of a Prospective Study in 99 Patients

Abstract Multiple myeloma (MM) is characterized by the presence of four different patterns of marrow involvement on Magnetic Resonance Imaging (MRI): focal, normal, diffuse and variegated. Diffusion-Weighted Imaging (DWI), which derives its contrast mainly from differences in the diffusivity of water molecules in tissue, with calculation of Apparent Diffusion Coefficient (ADC) values may be used as an adjunct method to increase diagnostic confidence of MRI. This technique has, so far, been applied to a small number of MM patients with promising early results for initial assessment and prognosis. The aim of this prospective study was to evaluate ADC values in a large number of MM patients and establish mean values for each MRI pattern, in search for a more precise MRI technique, which may serve as yet another prognostic tool for this disease. Between 2012 and 2014, 99 patients with newly diagnosed, untreated MM (52M/47F, median age 65 years; range 37-89 years) underwent MRI of the thoracic and lumbosacral spine, including DWI: 34/99 had anemia (Hb &lt;10 g/dl), 12/99 had renal impairment (serum creatinine &gt;2 mg/dL) and 13/99 patients had LDH &gt;250 U/L. The same MRI protocol was applied to 16 healthy, gender and age-matched controls to calculate mean ADC values of normal bone marrow. DWI of the lumbosacral spine was performed with an Echo Planar Imaging sequence using 5 b -values (0, 150, 250, 500, 750 sec/mm2) and ADC maps were generated. In MM patients with a normal or a diffuse MRI pattern, as well as in healthy controls, region of interest (ROI) measurements were obtained on the ADC map from each of the five lumbar vertebral bodies avoiding the region of the basivertebral vessels and any focal non-myelomatous lesion and the mean ADC value was calculated. In MM patients with a focal pattern, ROIs were placed on several focal lesions and the highest ADC value was recorded; in these patients an additional ROI was placed on an uninvolved vertebra in order to record the ADC value of apparently normal bone marrow. Based on visual assessment of T1-weighted images, 21 MM patients had focal, 26 diffuse, 3 variegated and 49 normal MRI pattern. Mean ADC values (±SD, x10-3 mm2/sec) of the bone marrow in MM patients were: 0.360±0.110 (range: 0.153-0.593) for the normal MM pattern, 1.046±0.232 (range: 0.715-1.536) for the focal MM pattern and 0.770±0.135 (range: 0.552-1.017) for the diffuse MM pattern. Mean ADC value of apparently normal marrow in patients with a focal MM pattern was 0.415±0.108 (range: 0.113-0.589), while that of healthy controls was 0.325±0.135 (range: 0.152-0.542). One way analysis of variance (ANOVA) showed a significant difference in ADC values within the groups of the study (p&lt;0.0001). Further analysis using t-test revealed significant differences of ADC values between diffuse and focal MM pattern (p=0.003), diffuse and normal MM pattern (p&lt;0.0001), focal and normal MM pattern (p&lt;0.0001), diffuse MM pattern and healthy volunteers (p&lt;0.0001), focal MM pattern and healthy volunteers (p&lt;0.0001), diffuse MM pattern and apparently normal marrow in focal MM pattern (p&lt;0.0001) and finally between focal MM pattern and apparently normal marrow in focal MM pattern (p&lt;0.0001). No significant differences were found between normal MM pattern and healthy volunteers (p=0.442), normal MM pattern and apparently normal marrow in focal MM pattern (p=0.141), and between apparently normal marrow in focal MM pattern and healthy volunteers (p=0.175). The 95% confidence intervals of the ADC values for each group were calculated and a receiver operating characteristic (ROC) analysis was performed to determine a cut-off value with the highest accuracy to distinguish a diffuse myeloma pattern from normal patterns (normal MM pattern, apparently normal marrow in focal MM pattern, normal marrow in healthy controls). An ADC value above 0.548x10-3 mm2/sec had 100% sensitivity and 98% specificity for the diagnosis of a diffuse MRI pattern, whereas a value of 0.597x10-3 mm2/sec had 96.2% sensitivity and 100% specificity. To our knowledge, this is the first study that evaluates and compares ADC values in the different MRI patterns of MM. We have shown that ADC values of MRI myeloma patterns differ significantly. DWI, by providing a quantitative means of assessing bone marrow involvement, assists the interpretation of other MRI sequences and improves the accuracy of pattern assignment. Disclosures Terpos: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Celgene: Honoraria, Other: travel expenses; Novartis: Honoraria. Dimopoulos:Genesis: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Onyx: Honoraria.

Current status of FDG-PET/CT in staging of adult lymphoma

Staging defines disease location and extent, suggests prognostic information and provides a baseline against which response or disease progression can be compared. Studies in Hodgkin (HL) and non-Hodgkin lymphoma (NHL) generally conclude that PET/CT is more accurate for diagnosing both nodal and extranodal disease than computed tomography (CT), thus having a strong potential impact on the staging of these lymphomas. Due to the high sensitivity and specificity of PET/CT in detecting bone marrow disease in newly diagnosed HL, bone marrow biopsy (BMB) is no longer indicated in HL; in aggressive NHL the detection of bone marrow involvement is still a topic of debate. In patients with a negative PET/CT, BMB is currently suggested to identify discordant histology, but its clinical role need to be further investigated. In indolent lymphoma FDG-PET enables staging the disease and characterization of intensity of glycolytic metabolism and this information provides additional prognostic information. In indolent lymphoma the pattern of marrow involvement is diffuse and PET/CT can be false negative in many cases. The main criteria to interpret staging PET/CT were reviewed. In 2014 were published the updated guidance on the evaluation, staging and response assessment of patients affected by HL and NHL and on the use of PET/CT for staging and response assessment. The guidelines suggest that a reasonable approach would be omit the standard full dose contrast-enhanced CT (ceCT) if not already performed, and perform a low-dose non-enhanced PET/CT as a single imaging modality, with ceCT performed selectively determined by PET/CT findings.

Prospective Evaluation of MRI and PET-CT at Diagnosis and before Maintenance Therapy in Symptomatic Patients with Multiple Myeloma Included in the IFM/DFCI 2009 Trial

IntroductionMagnetic resonance imaging (MRI) of the spine and the pelvis is an important tool to evaluate bone disease in patients with symptomatic multiple myeloma (MM) at the time of diagnosis. In the context of high-dose therapy and autologous stem cell transplantation (ASCT), it has also been reported that the number of MRI focal lesions (> 7) and the presence of diffuse pattern correlate with inferior survival (Walker et al. J Clin Oncol; 25:1121-1128 2007). MRI might help in the better definition of complete response (CR). However, the high number of false positive results suggests that another imaging method, such as Positron emission tomography combined with computed tomography using fluoro-deoxy-glucose (PET-CT), might be of more value in this setting. Moreover, imaging techniques have rarely been compared to minimal residual disease (MRD) evaluated by flow cytometry from bone marrow aspiration in the context of frontline therapy including novel agents and ASCT. The goal of our study was to compare prospectively MRI and PET-CT at 3 different time-points, at diagnosis, after 3 cycles of triplet induction therapy and prior to maintenance therapy in a group of patients enrolled into IFM-DFCI 2009 trial comparing frontline or delayed ASCT.Patients and methodsIn the prospective IFM-DFCI 2009 trial, 700 patients with de novo symptomatic MM eligible for high-dose therapy have been randomized in France and Belgium to receive either 8 cycles of bortezomib-lenalidomide-dexamethasone (VRD) followed by 1-year maintenance with lenalidomide, or 3 cycles of VRD followed by high-dose therapy and ASCT plus 2 cycles of VRD consolidation and 1-year lenalidomide maintenance. 134 / 700 patients were also included in the IMAJEM trial (NCT01309334, also supported by STIC program granted by the French NCI) aimed at comparing in both arms of the IFM-DFCI 2009 study spine and pelvis MRI and whole-body PET-CT at diagnosis (number of lesions, primary end-point), after 3 cycles of VRD, and prior to maintenance (prognosis impact of imaging negativity, secondary end-point). PET-CT and MRI results before maintenance were also compared with MRD assessed by 8-color flow cytometry. MRI and PET-CT data were analyzed locally in each of the 15 participating centers, and systematically reviewed blindly by an independent committee consisting of 2 radiologists and 2 nuclear medicine physicians with extensive experience in MM field.ResultsAt diagnosis, MRI was positive in 127/134 (94.7%), and PET-CT in 122/134 (91%) patients, respectively (McNemar test = 0.94, p-value = 0.33). MRI patterns of marrow involvement were the following: (1) normal in 7 cases (5%); (2) focal lesions (FL) in 46 cases (34%); (3) homogeneous diffuse infiltration in 41 cases (31%); (4) combined diffuse infiltration and FL in 35 cases (26%); and (5) variegated or "salt-and-pepper" pattern with inhomogeneous bone marrow with interposition of fat islands in 5 cases (4%). PET-CT patterns were the following: (1) normal in 12 cases (9%); (2) FL in 44 cases (33%); (3) diffuse infiltration in 12 cases (9%); (4) combined diffuse infiltration and FL in 66 cases (49%); (5) extramedullary disease in 10 cases (7.5%). The median number of FL assessed by PET-CT was 3.ConclusionMRI of the spine and pelvis and whole-body PET-CT are equally effective to detect bone involvement in symptomatic patients at diagnosis. The prognosis relevance of both MRI and PET-CT, and the comparison with MRD assessed by flow cytometry will be presented at the meeting. DisclosuresKarlin:Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Stoppa:Janssen: Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hulin:Celgene Corporation: Honoraria. Marit:Celgene, Janssen: Congress expenses Other.

Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) Is Able to Distinguish Diffuse from Normal MRI Pattern of Marrow Involvement in Patients with Multiple Myeloma

▪Diffuse MRI pattern of marrow involvement correlates with poor prognosis in patients with multiple myeloma (MM) both in the conventional chemotherapy and novel agent era. Sometimes the differentiation of diffuse from normal MRI marrow involvement in MM patients is difficult, particularly in cases of anemia and of low plasma cell marrow infiltration. Diffusion-Weighted Imaging (DWI) is an MRI technique which is based on differences in the diffusivity of water molecules in the respective tissue. Quantitative analysis of DWI can be achieved by calculating the Apparent Diffusion Coefficient (ADC) values from images with two or more different diffusion weightings. There are very limited data in the literature regarding ADC values in MM patients and almost no data for the ADC values in patients with different MRI patterns of marrow involvement. Thus our objective was to calculate and compare ADC values in newly diagnosed patients with MM, to identify possible differences among diffuse, focal, and normal MM MRI patterns and to establish, if possible, a threshold value which might distinguish diffuse from normal MRI patterns.We evaluated 44 patients (18M/26F, median age 66 years; range: 37-89 years) with newly diagnosed, untreated, MM patients and 16 healthy, gender and age-matched controls, with MRI of the lumbosacral spine, using a 1.5 Tesla unit. Conventional MR images were obtained according to bone marrow MRI protocols; MRI patterns of involvement were normal in 22, focal in 11 and diffuse in 11 patients. DWI was obtained with an Echo Planar Imaging sequence using 5 b-values (0, 150, 250, 500, 750 sec/mm2). In MM patients with a normal or a diffuse pattern, as well as in healthy controls, region of interest (ROI) measurements were obtained from each of the five lumbar vertebral bodies avoiding the region of the basivertebral vessels and any focal non-myelomatous lesion and the mean ADC value was calculated. In MM patients with a focal pattern, ROIs were placed on several focal lesions and the highest ADC value was recorded; in these patients an additional ROI was placed on an uninvolved vertebra in order to record the ADC value of apparently normal marrow.Mean ADC values (±SD, x10-3 mm2/sec) were: 0.346±0.107 (range: 0.186-0.544) for the normal MM pattern, 1.188±0.359 (range: 0.715-2.015) for the focal MM pattern and 0.821±0.149 (range: 0.642-1.017) for the diffuse MM pattern [Figure]. Mean ADC value of apparently normal marrow in patients with a focal pattern was 0.403±0.142 (range: 0.113-0.589), while that of healthy controls was 0.325±0.135 (range: 0.152-0.542). One way analysis of variance (ANOVA) showed a significant difference in ADC values within the groups of the study (p<0.0001). Further analysis using t-test revealed significant differences of ADC values between diffuse and focal MM pattern (p=0.003), diffuse and normal MM pattern (p<0.0001), focal and normal MM pattern (p<0.0001), diffuse MM pattern and healthy volunteers (p<0.0001), focal MM pattern and healthy volunteers (p<0.0001), diffuse MM pattern and apparently normal marrow in focal MM pattern (p<0.0001) and finally between focal MM pattern and apparently normal marrow in focal MM pattern (p<0.0001) [Figure]. No significant differences were found between normal MM pattern and healthy volunteers (p=0.442), normal MM pattern and apparently normal marrow in focal MM pattern (p= 0.141), and between apparently normal marrow in focal MM pattern and healthy volunteers (p= 0.175). The 95% confidence intervals of the ADC values for each group were calculated and a receiver operating characteristic (ROC) analysis was performed to determine the cut-off value with the highest accuracy to distinguish a diffuse myeloma pattern from normal patterns (normal MM pattern, apparently normal marrow in focal MM pattern, normal marrow in healthy controls). An ADC value above 0.593x10-3 mm2/sec was found to be diagnostic of diffuse myelomatous infiltration of the bone marrow with a sensitivity and specificity of 100%.We conclude that normal, focal and diffuse MRI patterns of marrow involvement in patients with MM have distinct ranges of ADC values on DWI. An ADC value above 0.593×10-3 mm2/sec is diagnostic of diffuse myelomatous infiltration of the bone marrow with extremely high accuracy and can be used in cases where diffuse pattern cannot be differentiated from normal pattern in conventional MRI. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Bone marrow trephine biopsy involvement by lymphoma: review of histopathological features in 511 specimens and correlation with diagnostic biopsy, aspirate and peripheral blood findings

AimsThis study aimed to evaluate the key features of bone marrow trephine (BMT) biopsy involvement by lymphoma.Methods511 cases were assessed for percentage of marrow involvement, pattern of involvement (diffuse, nodular,...

Skeletal-Related Events In Patients With Multiple Myeloma In The Era Of Novel Agents: Low Incidence Of Pathological Fractures After Treatment

Skeletal-related events (SREs) which include pathological fractures, spinal cord compression (SCC) and a need for radiotherapy or surgery to bone are frequent complications of multiple myeloma (MM). Although, the frequency and characteristics of SREs in MM patients who received conventional chemotherapy (CC) or thalidomide-based regimens along with bisphosphonates (BPs) have been described, there are no data available in the era of proteasome inhibitors or novel IMiDs. Thus, we retrospectively evaluated the records of 400 consecutive patients with symptomatic MM (207M/193F, median age: 63 years) who were diagnosed, treated and followed in a single center. All patients had a whole body skeletal survey using conventional radiography at diagnosis and then at the time of relapse or whenever clinically indicated, while MRI of the spine and pelvis at diagnosis was available for 223 patients. Furthermore, we tested 125 patients for SNPs in genes that are involved in the biology of bone destruction: LRP5 (rs4988321), GC vitamin D (rs4588), TNFRSF11A (rs3018362), DKK1 (rs1569198), RANKL (rs9594759), OPG (rs6469804) and ERS1 (rs1038304).At diagnosis, the skeletal survey detected osteolytic disease in 284 (71%) patients. In MRI, 34.5% of the patients had focal, 40.5% diffuse, 21% normal, and 4% a variegated pattern of marrow involvement. SREs were observed in 167 (41.7%) patients at diagnosis: 104 (26%) patients presented with pathological fractures (87 with vertebral fractures, 18 with rib fractures and 17 with fractures of the long bones; 22 patients had both vertebral and long bone or rib fractures), while 22 (5.5%) patients required surgery to bone, 21 (5.2%) radiotherapy and 20 (5%) patients presented with SCC. The incidence of SREs was higher in patients with osteolytic lesions (49.5% vs. 24%, p<0.001) or abnormal MRI pattern (49.7% vs. 23.3%, p=0.001). However, we noted that approximately 1/4 patients without lytic lesions in plain X-rays or with normal MRI pattern presented with a SRE at diagnosis. Patients homozygous for RANKL polymorphism had lower incidence of osteolysis at diagnosis (14/28, 50%) versus all others (76%, p=0.009), suggesting that this polymorphism may protect bone loss in MM, as it has been suggested for normal population.Frontline therapy with IMiD-based regimens was given in 172 (43%) patients, while 80 (20%) patients received bortezomib-based regimens, 111 (27.7%) both IMiD and bortezomib (VTD or VRD) and 37 (9.2%) patients CC. BPs were given in all but 86 patients (21.5%) at diagnosis, mainly due to renal insufficiency; however, almost 60% of them (n=51) received BPs later in the course of their therapy. The vast majority (91%) of patients received zoledronic acid (ZA). Due to renal impairment, ZA was discontinued in 6 patients, while the dose was reduced in 44. During first line treatment, 7 (1.75%) patients developed a SRE: 2 on bortezomib- and 5 on IMiD-based regimens. The rate of SREs was higher in patients who did not receive upfront BPs (4.7% vs. 1%; p=0.021).The median follow-up was 39 months. At the time of first relapse (data available for 176 patients), 3 patients presented with fractures and 35 patients required local radiotherapy to bone (SRE incidence: 21.6%). Patients who had received only bortezomib-based regimens (VD or VCD, n=20) had lower SRE rate (2/20, 10%) vs. all others (36/156, 22%, p=0.173); the 3 patients with fractures had received MPT (n=2) or RD (n=1). In total, during the course of their disease, 52.8% of the patients presented with at least one SRE. Presentation with SREs at diagnosis did not predispose for SREs during the disease course, regardless of anti-myeloma treatment, possibly due to the low number of fractures and the higher number of radiation needed after frontline therapy.In summary, our data from the first systematic report on the incidence and characteristics of SREs in the era of novel agents indicate that SREs remain a significant complication in MM. Importantly, despite high response rates after first line therapy more than 20% of patients required radiotherapy at the time of relapse. The fracture rate was very low during first line therapy and at first relapse probably due to the extensive use of potent BPs and bortezomib, which has bone anabolic effects. The use of modern imaging techniques (i.e. PET/CT or LDWBCT) that can detect bone masses earlier and lead to earlier initiation of treatment may reduce the SRE incidence in the near future. Disclosures:No relevant conflicts of interest to declare.

High C-Terminal Cross-Linking Telopeptide of Collagen Type-I (CTX) Predicts for Poor Overall Survival in Patients with Multiple Myeloma Who Receive Frontline Therapy with Immunomodulatory Drugs (IMiDs) but Not with Bortezomib-Based Regimens

Abstract 935Lytic bone disease is a frequent complication of multiple myeloma (MM). Biochemical markers of bone metabolism provide information on bone dynamics and reflect activity in the bones. Several studies show that different bone markers are altered in myeloma patients, reflect the extent of bone disease and correlate with survival in the conventional chemotherapy era. Nevertheless, there is almost no information about their impact on the survival of myeloma patients who are treated upfront with novel agents.To address this issue we studied 122 consecutive, unselected, newly diagnosed patients with symptomatic MM (66M/56F, median age 71 years, range 36–88 years) who were diagnosed and treated in a single center (University of Athens, Greece). All patients received upfront novel agents: 75 patients IMiDs-based and 47 patients bortezomib-based regimens. The following bone remodeling markers were evaluated in the patients’ serum before the administration of any kind of therapy: i) osteoclast regulators: sRANKL and osteoprotegerin (OPG); ii) osteoblast inhibitor dickkopf-1 (Dkk-1); iii) bone resorption markers: CTX and TRACP-5b; and iv) bone formation markers: bone-specific alkaline phosphatase (bALP) and osteocalcin. The above molecules were also measured in 36 gender- and age-matched, healthy controls. Evidence of bone involvement was documented using plain radiographs and MRI of the spine in all patients.Twenty-five (20%) patients had ISS-I disease, while 46 (37%) patients had ISS-II and 51 (41%) stage ISS-III disease. Fifty-eight (47%) patients had Hb<10 g/dl and 24 (19%) patients had serum creatinine >2 mg/dl. The presence of lytic bone disease was documented in 76% of the patients. MRI evaluation of the spine revealed that 41% of the patients had focal, 38% diffuse, 19% normal, and 2% a variegated pattern of marrow involvement. At diagnosis, MM patients had increased serum concentrations of sRANKL (mean±SD: 0.4±0.5 pmol/L vs. 0.1±0.2 pmol/L; p<0.001), OPG (6.4±3.3 pmol/L vs. 4.2±1.7 pmol/L; p<0.001), CTX (0.90±0.97 ng/ml vs. 0.3±0.2 ng/ml; p<0.001),TRACP-5b (2.7±2 U/L vs. 1.6±0.7 U/L; p<0.001), Dkk-1 (59.4±38.7 ng/ml vs. 32.8±13 ng/ml; p<0.001) and sRANKL/OPG ratio (0.08±0.13 vs. 0.04±0.05; p=0.003) and decreased levels of bALP (21.6±15.1 U/L vs. 29.4±7.8 U/L; p=0.003) compared to controls, while their levels correlated with the extend of bone disease. Patients with diffuse pattern had higher CTX concentrations compared to all other others (0.95±1.2 ng/ml vs. 0.6±0.51 ng/ml; p=0.04). The median survival of all patients was 59 months. In the univariate analysis, among the studied bone markers, only CTX, as a continuous variable, was predictive of survival (HR: 1.292, p=0.024). Patients with low CTX concentrations (<0.28 ng/ml; lower quartile; N=29) had superior survival compared to patients with higher CTX concentrations (not reached vs. 54 months respectively; p=0.034). This was more profound in patients treated with IMiDs-based regimens: the median survival of those with low CTX levels (<0.28 ng/ml) has not been reached yet vs. 39 months of all others (p=0.02; Figure). There was no difference regarding the effect of CTX on survival between patients who received upfront thalidomide- or lenalidomide-based regimens. On the contrary, in patients who were treated with bortezomib-based schemes, high CTX could not define a poor prognosis group of patients. In patients with normal or focal MRI pattern of bone marrow involvement, low CTX concentrations also correlated with superior survival compared to all other patients (not reached vs. 54 months respectively; p=0.04). Serum LDH (as dichotomous variable >225 U/L; p=0.011, and as continuous variable; p=0.019), ISS stage (p=0.02) and anemia (Hb<10 g/dl; p=0.01) were also associated with survival in the univariate analysis. The presence of osteolytic disease at diagnosis had no impact on survival. In the multivariate analysis only ISS (p=0.02) and LDH (>225 U/L; p=0.038) were predictive for survival.Our study suggests that in the era of novel agents, only CTX, among 7 serum bone remodeling markers, correlated with survival. In particular, high CTX levels can distinguish a subset of patients who receive frontline IMiDs-based therapies and who have poor prognosis. This was not observed with bortezomib-based therapies, possibly due to the beneficial effect of bortezomib on bone metabolism. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Diffuse Pattern of Bone Marrow Involvement in MRI Is Associated with High Risk Cytogenetics and Poor Outcome in Newly Diagnosed, Symptomatic Patients with Multiple Myeloma,

Abstract 3920Magnetic Resonance Imaging (MRI) and specific recurrent cytogenetic abnormalities offer important prognostic information for multiple myeloma (MM) patients. However, limited data are available about the association between cytogenetic abnormalities and MRI patterns of marrow infiltration. To address this issue, we analyzed 203 newly-diagnosed, symptomatic patients who were treated in a single center, in Athens (Greece). The pattern of marrow involvement in MRI was recognized as: (1) normal when there was no evidence of abnormal signal; (2) focal which consisted of localized areas of abnormal marrow; (3) diffuse, in which the normal bone marrow is completely replaced; and (4) variegated which consists of innumerable small foci of disease on a background of intact marrow. Cytogenetic studies by FISH were performed in CD138 selected plasma cells using standard methodology.Eighty-six (42%) patients had focal pattern, 79 (39%) diffuse, 28 (14%) normal and 10 (5%) variegated pattern. Due to the low number of patients with variegated pattern and to our previous finding that variegated and diffuse patterns have similar outcomes, we analyzed these two patterns together. Patients with normal MRI pattern presented with better performance status (86% had ECOG PS ≤1 vs. 47% and 45% of patients with focal or diffuse patterns, p<0.001). Patients with focal or diffuse infiltration had features of advanced disease, such as anemia (Hb <10 g/dl; p<0.001), elevated serum LDH ≥300 IU/L (p=0.008) and advanced ISS stage (p<0.001). Patients with focal MRI pattern presented less often with renal impairment (eGFR <50 ml/min; p=0.017) but more often with lytic bone disease (p<0.001).The presence of del17p was more common in patients with diffuse pattern (22% vs. 10% in patients with focal and none in those with normal pattern, p=0.04). Similarly, add1q21 was more common in patients with diffuse pattern (37% vs. 13% and 15% for patients with focal or normal pattern; p=0.038). Del13q was observed also more frequent in diffuse pattern (48% vs. 28% and 24% for focal and normal pattern, p=0.056) while there were no significant differences in the frequency of t(4;14) and t(14;16) among patients with different MRI patterns. In general, 56% of patients with diffuse MRI pattern had high risk cytogenetics [any of del17p, add1q21, t(4;14) or t(14;16)] vs. 31% and 22% of patients with focal and normal patterns (p=0.012).Most patients (70%) received first line therapy based on novel agents (thalidomide, bortezomib or lenalidomide). Response to first line therapy was similar for patients with different MRI patterns (76%, 77.5% and 75% for focal, diffuse and normal pattern, respectively). However, patients who were treated upfront with conventional chemotherapy (CC) and had a diffuse MRI pattern had inferior response (46% vs. 79% and 83% for patients with focal and normal patterns, respectively, p=0.024). When patients were treated with novel agent-based frontline therapy, the response rates were similar among MRI patterns (89%, 74% and 73% for diffuse, focal and normal MRI patterns, respectively; p=NS).The median survival for patients with normal, focal and diffuse MRI patterns was 102, 57 and 37 months, respectively (p<0.001). The respective median survival for patients who were treated with CC was: not reached yet, 51 and 23.5 months (p<0.001) and in those who received novel agent-based regimens was 47 months for diffuse pattern vs. not reached for patients with focal or normal MRI pattern (p=0.05). When we adjusted for other clinical factors and for treatment type, then diffuse MRI pattern was independently associated with poor survival (HR: 3.018, p=0.024). Other factors that were independently associated with poor survival were age (>75 years; p<0.001), CC (p=0.001), ISS (p<0.001) and serum LDH ≥ 300 IU/L (p=0.05). When high risk cytogenetics were included in the multivariate model then only high risk cytogenetics (HR: 2, p=0.046), ISS stage (p=0.027) and serum LDH ≥300 IU/L were independently associated with poor survival.In conclusion, diffuse MRI pattern of bone marrow infiltration is associated with the presence of high risk cytogenetics, such as del17p and add1q21. The strong correlation of diffuse pattern with poor survival, even in the era of novel agents, suggests the need for more effective therapies for those patients and highlights the importance of the performance of baseline MRI in all patients with symptomatic disease. Disclosures:No relevant conflicts of interest to declare.

Whole body MRI in type I Gaucher patients: Evaluation of skeletal involvement

Background Bone disease is a serious complication of type 1 Gaucher disease, which if untreated can result in pain, disability and reduced quality of life. MRI is the method of choice for assessing and monitoring bone involvement in Gaucher patients. MRI bone evaluation has been predominantly carried out on the lumbar spine and/or lower extremities using quantitative or semi-quantitative methods. We describe evaluation of skeletal involvement in Gaucher patients using whole body MRI scanning. Methods Whole body MRI was performed in 39 adult type I Gaucher patients using a 1.5 T superconducting magnet with total imaging matrix technology. A standard MRI protocol was performed in all patients using coronal T1-, T2-weighted (thighs) and STIR-sequences of the whole body, sagittal T1-, T2- (lumbar spine) and STIR-sequences of the entire axial skeleton. Bone marrow involvement was analysed using the Düsseldorf Gaucher score (DGS), bone marrow burden score (BMB), and vertebra-disc-ratio (VDR). Pelvis, humerus, legs and spine were also analysed using the pattern of marrow involvement described by homogeneous type A or non-homogeneous type B morphology. Avascular necrosis (AVN) of the humeral head was determined. Results Whole body MRI was well tolerated and of diagnostic value in all patients. Thirty one out of 39 patients (79%) showed bone involvement. In fifteen of these 31 patients (48%) humeral bone involvement was observed. The morphological appearance of bone involvement (type A or B) was consistent across the humerus, legs and pelvis. The infiltration pattern was also similar across cervical, thoracic and lumbar vertebral bodies. Humeral bone involvement was present in 89% of patients with type B morphology compared with 32% of patients with type A morphology (p < 0.005). Humeral involvement was detected more frequently in patients with severe bone involvement as determined by higher DGS and BMB scores, than in patients with lower DGS and BMB scores (p < 0.0001 and p = 0.0016). AVN of the humeral head was detected in 6 patients (19%). Conclusions In this group of patients, severe bone involvement in the lumbar spine and lower extremities and type B morphology was also associated with humeral involvement. The morphological infiltration pattern was consistent in the entire skeleton indicating the systemic character of bone disease. Whole body MRI presents a feasible means of assessing the entire skeletal system and could be a valuable diagnostic and monitoring tool in the management of patients with type 1 Gaucher disease.

Clinical, Immunophenotypic, and Genetic Characterization of Small Lymphocyte–Like Plasma Cell Myeloma

We reviewed bone marrow studies from 351 multiple myeloma (MM) cases, selecting 12 cases (3.4%) with predominantly small lymphocyte-like morphologic features resembling B-cell lymphoma, and correlated their genetic and clinical features. All exhibited a diffuse interstitial pattern of marrow involvement. Small lymphocyte-like plasma cells were all CD45- with bright CD38 and CD138 expression and CD20 expression in 5 cases. No case had an increase in bone marrow B lymphocytes by flow cytometry. Of 12 cases, 9 were classified as the CD-2 molecular class by gene expression profiling (GEP). The 29 CD-2 class cases with (n = 9) and without (n = 20) small lymphocyte-like features could not be discerned from one another using global GEP. Event-free, but not overall, survival was significantly better in cases with small lymphocyte-like features among those sharing the CD-2 subtype. Small lymphocyte-like MM is a rare, morphologically challenging variant distinguished from B-cell lymphoma by lack of CD45 and presence of CD138 and the clinical presentation of MM. Most cases share a common GEP signature dominated by hyperexpression of cyclin D1 or cyclin D3 genes, with increased expression of the B-cell genes CD20 and VPREB3.

Clinical and Prognostic Relevance of Magnetic Resonance Imaging of the Spine in Newly Diagnosed Multiple Myeloma Patients Receiving Autologous Stem Cell Transplantation.

Abstract 4885Magnetic resonance imaging (MRI) of the spine has demonstrated to be a useful tool for a correct staging of multiple myeloma (MM), as it is more sensitive than plain x-rays in detecting vertebral lesions. Furthermore, both pattern of bone marrow involvement (focal, diffuse or normal), and number of focal lesions can be detected, and this could contribute to better define the prognosis and the outcome of newly diagnosed patients. In the present study we prospectively evaluated the clinical and prognostic role of spinal MRI in 152 newly diagnosed MM patients (89M, 63F, median age = 56yrs) that subsequently received high-dose chemotherapy and autologous stem cell transplantion, either single (n=43) or double (n=109). Pattern of marrow involvement was normal in 11% of the cases, diffuse in 20% and focal in 69%, with 34% of the patients showing > 7 focal lesions. Patients with a diffuse pattern or a focal pattern with > 7 lesions showed a significantly higher bone marrow plasma cell infiltration (p=0.04) and beta2 microglobulin values (p= 0.04) as compared to patients with a focal pattern with < 7 lesions. Response rate to the assigned treatment program was similar in the three groups of patients, with > VGPR obtained in 63% of the patients with a diffuse pattern, and in 70% of those with a focal pattern. Median progression-free survival (PFS) was significantly longer in patients with < 7 focal lesions as compared to those with >7 lesions or a diffuse pattern (55 vs 46 months p=0.05). Normalization of MRI was more frequently obtained in patients with < 7 lesions (67% vs 38% in patients with > 7 lesions, p=0.005); patients achieving a normal MRI pattern showed a significantly longer PFS (67 months) as compared to patients failing to achieve a negative MRI at the end of treatment (p=0.0000). According to our data, MRI confirms its prognostic role in newly diagnosed MM receiving high-dose therapy and autologous stem-cell transplantation; a diffuse pattern of bone marrow involvement or a focal pattern with > 7 lesions are predictive of a more aggressive outcome of the disease; furthermore normalization of MRI pattern after therapy is predictive of a longer progression-free survival DisclosuresNo relevant conflicts of interest to declare.

Diffuse MRI Marrow Pattern Correlates with Increased Angiogenesis, Advanced Disease Features and Poor Prognosis in Newly-Diagnosed Patients with Multiple Myeloma Treated with Novel Agents.

Abstract 829The aim of this study was to evaluate the prognostic value of bone marrow magnetic resonance imaging (MRI) in newly-diagnosed myeloma (MM) patients who received novel agent-based therapy and to explore possible correlations of MRI pattern with clinical and laboratory data. Eighty-two consecutive MM patients (43M/39F, median age: 65 years) at diagnosis were studied. MRI of the spine was performed within 1-2 weeks following diagnosis. T1-weighted, STIR and contrast-enhanced T1-weighted sagittal MR images of the thoracic and lumbar spine were obtained with a 1.5 T unit (Phillips, Eindhoven, the Netherlands). Marrow involvement was characterized as normal, focal, diffuse or variegated. Microvessel density (MVD) was evaluated in marrow trephine biopsies at the time of diagnosis. The following serum indices of bone metabolism and angiogenesis were measured on the day of MRI: i) osteoclast stimulators [sRANKL, osteoprotegerin (OPG), osteopontin (OPN) and macrophage inflammatory protein-1alpha (MIP-1alpha)], ii) dickkopf-1 (Dkk-1), iii) bone resorption markers [C- and N-terminal cross-linking telopeptide of collagen type-I (CTX and NTX, respectively) and TRACP-5b], iv) bone formation markers [bone alkaline phosphatase (bALP) and osteocalcin (OC)], and v) angiogenic cytokines [VEGF, VEGF-A, angiogenin (ANG), angiopoietin-1 (ANGP-1), angiopoietin-2 (ANGP-2) and bFGF]. MRI evaluation of the spine revealed that 34 (41.5%) patients had focal, 26 (31.7%) diffuse, 18 (22%) normal, and 4 (4.9%) had a variegated pattern of marrow involvement. Low-grade angiogenesis, as assessed by MVD, was present in 32 (39%) patients, while 33 (40%) had intermediate-grade and 17 (20%) patients had high-grade angiogenesis. Twenty-one of 26 (80%) patients with a diffuse MR pattern had intermediate or high-grade angiogenesis in contrast to 14/34 (41%) patients with focal involvement (p=0.01) and 12/18 (66%) with normal MR pattern (p=0.037). Patients had increased values of VEGF (p<0.001), VEGF-A (p<0.001), ANGP-2 (p<0.001) and bFGF (p=0.001), and reduced values of ANGP1/ANGP2 ratio (p<0.01) compared to healthy controls (n=36). Patients with a diffuse pattern were the only patients who had increased ANG compared to controls (p=0.004). Patients with diffuse pattern had higher levels of serum VEGF and VEGF-A compared to patients with normal (p=0.028 and p=0.006, respectively) and focal pattern (p=0.009 and p<0.01, respectively) and borderline elevated ANG compared to normal pattern (p=0.06). Myeloma patients had increased values of sRANKL (p<0.001), sRANKL/OPG ratio (p=0.004), NTX (p<0.001), CTX (p<0.001), TRACP-5b (p<0.001), Dkk-1 (p=0.01), and OPN (p<0.001) and borderline reduced values of bALP (p=0.09) compared to controls. Patients with normal MRI pattern showed no difference in terms of Dkk-1 and bone formation markers compared to controls. Patients with diffuse pattern of marrow involvement had reduced values of bone formation markers (p=0.01), while patients with focal pattern had only a borderline reduction of OC (p=0.09). Both diffuse and focal MRI patterns had increased Dkk-1 levels. All abnormal MRI patterns had increased levels of NTX, CTX and TRACP-5b and increased levels of osteoclast stimulators sRANKL/OPG, MIP-1alpha and OPN. Diffuse and variegated patterns of infiltration correlated with greater bone marrow plasma cell infiltration (p=0.043) and advanced ISS stage (p=0.018). All patients received a combination regimen that contained at least one novel anti-myeloma agent (IMiD and/or bortezomib) at some point during the course of their disease. The median follow-up of the patients was 25 months. Patients with diffuse or variegated pattern had a median survival of 29 months, patients with focal pattern had a median survival of 62 months, while the median survival of patients with normal MRI pattern has not been reached at the time of the analysis (p=0.009). Multivariate analysis showed that only MRI pattern and ISS stage were independent prognostic factors for survival. In conclusion, our analysis provides strong evidence that diffuse MRI pattern of marrow involvement correlates with increased angiogenesis, adverse disease features and inferior survival in MM patients who were treated with novel agents. Such patients may be considered for upfront treatment with combinations of novel agents. Our results highlight the important prognostic value of MRI in MM and support its routine use in MM patients. Disclosures:No relevant conflicts of interest to declare.

Clinical and Prognostic Relevance of Magnetic Resonance Imaging of the Spine in Newly Diagnosed Multiple Myeloma Patients Receiving Autologous Stem Cell Transplantation.

Magnetic resonance imaging (MRI) of the spine has demonstrated to be a useful tool for correct staging of multiple myeloma (MM), as it is more sensitive than plain x-rays in detecting vertebral lesions. Furthermore, different patterns of bone marrow involvement (focal, diffuse or normal) can be depicted, and this could contribute to better define the prognosis in newly diagnosed patients. In the present study we prospectively evaluated the clinical and prognostic role of spinal MRI in 120 newly diagnosed MM patients (68M, 52F, median age = 56yrs) that subsequently received high-dose chemotherapy and autologous stem cell transplantion, either single (n=28) or double (n=92). Pattern of marrow involvement was focal in 72 cases (60%), diffuse in 29 (24%) and negative in 19 (16%). Patients with a diffuse pattern showed a significantly higher bone marrow plasma cell infiltration (p=0.05) and beta2 microglobulin values (p= 0.04) as compared to patients with a focal pattern; stage III disease according to ISS was observed in 29%, 8% and 1% of patients with a diffuse, focal or negative pattern, respectively. Response rate to treatment program was similar in the three groups of patients, with a stringently defined CR obtained in 34% of patients with a focal pattern, 29% in those with a diffuse pattern and 35% in patients with a negative MRI. Median progression-free survival showed a trend in favor of patients with a negative MRI (54 months) as compared to those with a focal or diffuse pattern (42 and 38 months, respectively). A focal pattern of bone marrow involvement was associated with a significantly higher probability of experiencing an overt vertebral lesion (73% vs 48% in patients with diffuse pattern, p=0.03), including either a compression fracture or a vertebral mass. Consistently with this finding, also extra-spinal bone lesions were more common in patients with a focal pattern (66%) as compared to patients with a diffuse or negative pattern (42% and 6% respectively) (p=0.05). Serum crosslaps were significantly increased in patients with a focal pattern (7032 pmol/L±635SE vs 5431pmol/L±812SE in those with a diffuse pattern, p=0.04). According to our data, a diffuse pattern of bone marrow involvement could be predictive of a more aggressive disease, even though these data needs to be confirmed in a larger series of patients. A focal pattern of bone marrow involvement at diagnosis could help to identify MM patients more prone to develop skeletal complications, so that a careful monitoring and bisphosphonate therapy should be recommended.