Volume Localized In Vivo Proton MR Spectroscopy of Multiple Myeloma: Variation of Water-Fat Ratio in Patients Receiving Chemotherapy Correlates with Clinical Response.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4863-4863
Author(s):  
Albert Oriol ◽  
Daniel Valverde ◽  
Jaume Capellades ◽  
Miquel Cabañas ◽  
Carles Arús ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Magnetic Resonance ◽  
Partial Response ◽  
Vertebral Body ◽  
Response To Therapy ◽  
Proton Nuclear Magnetic Resonance ◽  
Lumbar Vertebral Body ◽  
Water Signal ◽  
Water Resonance

Abstract Introduction. Bone marrow magnetic resonance (MR) imaging provides important information i<SPACER size="24">n the evaluation of patients with multiple myeloma (MM) but MR assessment of response to therapy is highly subjective. Proton nuclear magnetic resonance spectroscopy (1H MRS) may be able to measure the ratio of lipid to water resonance signal intensities (LWR) and thus reflect the relative percentages of cellular and fatty bone marrow within a defined three-dimensional volume (voxel). These measurements could be used to quantify the degree of cytoreduction in MM patients. Patients and Methods. Twenty-one consecutive patients (10 male; median age 65 years, range 44–82) with newly diagnosed multiple myeloma underwent a MR exploration of the fifth lumbar vertebral body before the initiation of treatment. Patients completing therapy were reevaluated. Dorso-lumbar imaging studies were carried out in a 1.5T system with a saggital spin-echo T1-weighted sequence (TR 437 ms / TE 15 ms). A 2-cm-thick transverse center section of the L5 lumbar vertebral body was sampled to place the voxel. Spectroscopic data were acquired with a stimulated echo acquisition mode (STEAM) sequence without water suppression with repetition time 5 s and echo time 40 ms. To calculate the area of the water signal, the peak was fit to a single Lorenzian curve centered at 4.75 ppm. The area of the lipid resonances was fit to 3 Lorenzian curves centered at 0.89 (-CH3), 1.34 and 2.2 (-CH2) ppm. The areas obtained were used to calculate the LWR for each voxel. The LWR was defined as the sum of the area of the 3 lipid fitted resonances divided by the area of the fitted water resonance. Results. The spectra showed a water peak and a compounded lipid peak separated by approximately 3.1 ppm. LWRs ranged from 0 to 15 (mean 1.748, SD 3.741). Seven patients were treated with melphalan and prednisone (MP) and 14 received 3 cycles of vincristine, BCNU, cyclophosphamide, melphalan and prednisone alternating with 3 cyles of vincristine, BCNU, doxorrubicin and dexametasone (VBCMP/VBAD). Therapy was interrupted for at least 4 weeks before the MR evaluation. Two patients under MP could not be reevaluated. One patient under VBCMP/VBAD suffered extensive L5 collapse that invalidated a second MR study. Four patients progressed under treatment and only 1 of them could be re-submitted to MR. A patient who achieved a partial response after VBCMP/VBAD refused to undergo a MR re-evaluation. Pre and post treatment MR studies were available in 14 patients (progression 1, no response 3, partial response 3, complete response 7). LWR increased in 11/14 patients (78%) (p=0.034). However, 7/7 (100%) complete responders presented a LWR increase (p=0.018) while only 4/7 (57%) non-responders did. No significant differences were observed among partial responders or patients non-responding or progressing. Conclusions. Changes i LWR as assessed by 1H NMR correlated with response to chemotherapy in patients with multiple myeloma, thus this technique may be used to measure noninvasively the response to treatment in these patients.

scholarly journals Prognostic significance of magnetic resonance imaging of bone marrow in previously untreated patients with multiple myeloma

2005 ◽  
Vol 16 (11) ◽  
pp. 1824-1828 ◽  
Author(s):  
L.A. Moulopoulos ◽  
D. Gika ◽  
A. Anagnostopoulos ◽  
K. Delasalle ◽  
D. Weber ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Magnetic Resonance ◽  
Prognostic Significance ◽  
Resonance Imaging

scholarly journals T Cells Genetically Modified to Express an Anti–B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma

2018 ◽  
Vol 36 (22) ◽  
pp. 2267-2280 ◽  
Author(s):  
Jennifer N. Brudno ◽  
Irina Maric ◽  
Steven D. Hartman ◽  
Jeremy J. Rose ◽  
Michael Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
Partial Response ◽  
B Cell ◽  
Residual Disease ◽  
Cell Maturation ◽  
B Cell Maturation ◽  
Minimal Residual ◽  
B Cell Maturation Antigen

Purpose Therapies with novel mechanisms of action are needed for multiple myeloma (MM). T cells can be genetically modified to express chimeric antigen receptors (CARs), which are artificial proteins that target T cells to antigens. B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells but not normal essential cells. We conducted the first-in-humans clinical trial, to our knowledge, of T cells expressing a CAR targeting BCMA (CAR-BCMA). Patients and Methods Sixteen patients received 9 × 106 CAR-BCMA T cells/kg at the highest dose level of the trial; we are reporting results of these 16 patients. The patients had a median of 9.5 prior lines of MM therapy. Sixty-three percent of patients had MM refractory to the last treatment regimen before protocol enrollment. T cells were transduced with a γ-retroviral vector encoding CAR-BCMA. Patients received CAR-BCMA T cells after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. Results The overall response rate was 81%, with 63% very good partial response or complete response. Median event-free survival was 31 weeks. Responses included eradication of extensive bone marrow myeloma and resolution of soft-tissue plasmacytomas. All 11 patients who obtained an anti-MM response of partial response or better and had MM evaluable for minimal residual disease obtained bone marrow minimal residual disease–negative status. High peak blood CAR+ cell levels were associated with anti-MM responses. Cytokine-release syndrome toxicities were severe in some cases but were reversible. Blood CAR-BCMA T cells were predominantly highly differentiated CD8+ T cells 6 to 9 days after infusion. BCMA antigen loss from MM was observed. Conclusion CAR-BCMA T cells had substantial activity against heavily treated relapsed/refractory MM. Our results should encourage additional development of CAR T-cell therapies for MM.

C-met Receptor as a Potential Target for the Treatment of Patients with Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3395-3395
Author(s):  
Marcin Majka ◽  
Artur Jurczyszyn ◽  
Anna Zebzda ◽  
Wojciech Czogala ◽  
Ewa Lesko ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Lines ◽  
Protein Level ◽  
Bone Marrow Cells ◽  
Response To Therapy ◽  
Poor Responders ◽  
Met Receptor ◽  
Potential Target ◽  
Marrow Cells

Abstract Despite progress in the treatment of Multiple Myeloma (MM), it is still an incurable disease with average survival of 3–4 years. Because MM is often resistant to conventional therapies, new treatment strategies are necessary. The presence of elevated HGF (Hepatocytic Grow Factor) expression has been well documented in multiple myeloma. The c-met oncogene has been shown to be present in MM cell lines at the mRNA and protein level. Some data suggested that this axis could be responsible for proliferation and inhibition of apoptosis in MM cells. In this study we have analyzed c-met expression in 15 patients with (MM) before and after treatment. Seven of these pts responded well and eight pts responded poorly to the employed therapy. All 15 pts were c-met positive before therapy. Bone marrow cellularity of patients who responded well was 76% before (range: 10% – 100%) and 46% after treatment (range: 40% – 60%). In this group plasmocyte infiltration of bone marrow consisted of 59% before (range: 10% – 80%) and 9% after chemotherapy (range: 0% – 20%). Five of them had undetectable c-met positive cells among bone marrow cells after treatment. In the group of poor responders cellularity of bone marrow was 40% (range: 20% – 70%) before treatment and 46% (range: 20% – 70%) after therapy. Plasmocytes consisted of 20% (range: 10% – 50%) of bone marrow cells before and 44% (range: 10% – 90%) after treatment. All patients in this group had cells positive for c-met receptor after therapeutic regiment. This results suggested that c-met-HGF axis might be a good target for alternative therapy in MM. We looked for potential therapeutics that interferes with this axis and we found that geldanamycin (GA) has been shown to decrease expression of c-met at the protein level in several different cell types. Using inhibitors that belongs to geldanamycin family (GA, 17AAG and 17DMAG) we treated MM cell lines and primary sample. We found that these molecules strongly inhibited expression of c-met in both MM cell lines and patients sample as assessed by western blot analysis. We also tested the influence of these inhibitors on proliferation of MM cells. We found that 100nM dose of GA and 17DMAG inhibited growth of MM cell lines by 80% and 100nM dose of 17AAG inhibited growth of these cells by 20%. Primary cells were more resistant to treatment but we still obtained 30% inhibition with GA and 17DMAG. 17AAG was ineffective and proliferation decreased by less than 10%. Grow inhibition was probably not only due to c-met-HGF axis blockade because these molecules also inhibit other proteins (AKT, RAF). In our experiments we have shown that the level of c-met expression correlates with response to therapy. Patients who respond well had substantially decreased number of c-met positive plasmocytes after chemotherapy in comparison to poor responders. We have also showed that drugs that block c-met-HGF axis could be used in treatment of MM. These drugs could potentially inhibit cells proliferation, increase apoptosis and disrupt MM cells interaction with bone marrow environment. Based on these data we postulate that the c-met receptor is a potential target for MM therapy especially in patients who do not respond to the first line of treatment.

Impact of Whole-Body Magnetic Resonance Imaging on Staging in Patients with Newly Diagnosed Plasma Cell Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5061-5061
Author(s):  
Martin Zoz ◽  
Andreas Baldauf ◽  
Anne Schipp ◽  
Jens Hillengass ◽  
Anthony D. Ho ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Magnetic Resonance ◽  
Conventional Radiography ◽  
Whole Body ◽  
Newly Diagnosed ◽  
Resonance Imaging ◽  
Cell Disease ◽  
Body Magnetic Resonance Imaging

Abstract INTRODUCTION: MRI has a high sensitivity in determining changes in bone marrow induced by metastatic disease or primary neoplasms of the bone marrow. Whole-Body Magnetic Resonance Imaging (WB-MRI) is a novel imaging technique that displays nearly the complete skeletal system in one exam. We investigated the differences between conventional skeletal survey and WB-MRI and their impact on staging of patients with newly diagnosed plasma cell disease. METHOD AND MATERIALS: In 41 consecutive patients with newly diagnosed MGUS (n=5), Multiple Myeloma (n=34) or AL-Amyloidosis (n=2) conventional radiographs and WB-MRI (coronar T1 tse and T2 tirm sequences and sagittal T2 star sequences, 1,5 T MRI with parallel imaging, Siemens Avanto®) were performed. Radiographs and scans were evaluated for diffuse and focal bone marrow involvement in consent by two experienced radiologists blinded for patient name and study time. Staging was performed including clinical data according to the Salmon/Durie classification system and the Durie/Salmon PLUS classification system with inclusion of WB-MRI. RESULTS: In 24 (59%) patients there were no lesions in conventional radiography or MRI. In 17 (41 %) patients results of MRI and conventional radiography were discrepant. 4 (10%) patients had lesions only in MRI, 3 (7%) only in conventional radiography and 10 (24%) in both techniques but in different localization. In 16 (38%) patients with radiological signs of osteopenia there was no diffuse infiltration in MRI or vice versa. We systematically analysed the consequences of WB-MRI on staging of patients based on the newly proposed staging system Durie/Salmon PLUS. Replacing conventional radiographs by WB-MRI resulted in reclassification of 12 patients. 3 patients were reclassified from MGUS or stage I into stage II or III. 9 patients were downstaged from stage III or II into stage I or MGUS. CONCLUSION: WB-MRI is a valuable technique for the initial work-up of patients with Multiple Myeloma. In comparison with conventional skeletal survey there are often differing results with impact on clinical staging and influence on therapy decision. WB-MRI can give additional information in patients with unclear staging situation before onset of therapy. Further evaluation of WB-MRI within prospective studies is warranted in particular with respect to prognostic impact regarding overall prognosis as well as regarding local complications. Until then WB-MRI should be used complementary to conventional radiography or CT-techniques that provide accurate imaging of the bone.

Elimination of CD20-Expressing Cells in Multiple Myeloma by Iodine I-131 Tositumomab (Bexxar®) Correlates with Response to Therapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5176-5176 ◽  
Author(s):  
Andrzej J. Jakubowiak ◽  
Malathi Hari ◽  
Tara Kendall ◽  
Yasser Khaled ◽  
Shin Mineishi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Partial Response ◽  
Clinical Outcomes ◽  
Plasma Cells ◽  
Response To Therapy ◽  
Myeloma Cells ◽  
Consolidation Treatment ◽  
Anti Cd20

Abstract It has been proposed that treatment failures in multiple myeloma (MM) are related to the chemoresistance of a subset of malignant myeloma cells with clonogenic potential to the anti-myeloma drugs (Matsui et al., Cancer Research2008, 68:190). Studies suggest that these putative myeloma stem cells (MSC) are CD138neg and express CD20, which is usually absent in more differentiated malignant plasma cells (Matsui et al., Blood2004, 15:2332). These findings provided a rationale for a treatment strategy to eliminate chemoresistant clonogenic MSC using anti-CD20 antibodies. To evaluate the clinical effects of anti-CD20 treatment, we developed a phase II trial with Bexxar as a consolidation treatment for MM. We hypothesized that Bexxar would be more efficacious than unlabeled antibody in the eradication of highly radiosensitive myeloma cells by both direct and cross-fire effects. Preclinical studies showed that tositumomab, the antibody used in Bexxar, inhibited colony formation of clonogenic myeloma cells. To be eligible for Bexxar treatment, patients must have completed at least 4 cycles of therapy (1st to 3rd line) and have measurable disease in a plateau of at least partial response (PR). To date, 10 of 30 patients have been enrolled, of which 5 were treated with Bexxar after completion of initial therapy prior to proceeding to autologous stem cell transplant (ASCT). Patients proceeding to ASCT required hematopoietic stem cells collection prior to Bexxar and 3 months after Bexxar. Eight patients are evaluable for response and toxicities. At 3 months post Bexxar, 1 patient achieved a partial response (PR), 4 patients had stable disease (SD), and 1 patient progressed (PD). At 1 year post Bexxar, 1 patient with initial PR achieved CR and remains in CR, 1 patient is in unconfirmed CR, 2 are in partial response (PR), and 3 remain in SD. After a median 20 months of followup (range 4–24), all patient are alive, 4 in continued response, 3 with SD. Hematological toxicities were mild to moderate (1 patient grade 3 and 4 patients grade 2 thrombocytopenia, 4 patients grade 2 neutropenia). Non-hematological toxicity was limited to HAMA (6 patients). Out of patients who received Bexxar prior to transplant, 3 collected stem cells post-Bexxar without problems, one requires re-collection. Three patients who proceeded to ASCT to date using the post-Bexxar stem cell collection, engrafted at 11–12 days, and had no unexpected toxicities with ASCT. We also analyzed CD20+ cells in bone marrow aspirates (BM) and stem cell collections (SCC) using samples collected from 4 patients before and after Bexxar. Bexxar treatment eliminated a median 80% of CD20+ cells (range 23–97). For a given patient, elimination of CD20+ cells from SCC correlated with elimination of CD20+ cells from BM. The most complete elimination of CD20+ cells from BM was observed in 2 patients who at 1 year achieved CR (94% and 97%), compared to patients who achieved PR (23% and 68%). We conclude that anti-CD20 consolidation treatment of myeloma patients with Bexxar used as targeted therapy against clonogenic myeloma cells is feasible and well tolerated. Clinical outcomes to date are encouraging considering that clonogenic MSC represent <5% of malignant plasma cells and delayed responses observed in this study could be expected. While early, clinical outcomes appear to correlate with the efficacy of the CD20+ cell elimination by Bexxar treatment in myeloma.

Multiple Copies of MLL Is The Most Commonly Detected Cytogenetic Abnormality In Newly Diagnosed Multiple Myeloma and May Modify Disease Risk

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1910-1910 ◽  
Author(s):  
Chrystal Landry ◽  
Dory Londono ◽  
Sean M. Devlin ◽  
Alex Lesokhin ◽  
Nikoletta Lendvai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Protein Translation ◽  
Response To Therapy ◽  
Cytogenetic Abnormality ◽  
Newly Diagnosed

Abstract Background Multiple myeloma (MM) is a heterogeneous condition with variable disease course, response to therapy, and survival outcome. Cytogenetics and fluorescent in-situ hybridization (FISH) have identified several recurrent chromosomal aberrations in MM and play important and independent roles in risk stratification (Munshi et al. Blood 2011). However, the pathogenesis of the disorder remains poorly understood. Next-generation sequencing has recently identified that MM involves mutations of genes with roles in protein translation, histone methylation, and blood coagulation (Chapman et al. Nature 2011). Based on the observation that extra copies of MLL, a histone methyltransferase known to regulate the homeotic transcription factor HOXA9 that is highly expressed in MM, is frequently detected in MM, we sought to define the incidence and prognostic significance of excess MLL in MM patients. Methods We identified 188 patients with newly diagnosed MM who had cytogenetics and/or FISH performed on initial, pre-treatment bone marrow specimens at Memorial Sloan-Kettering Cancer Center between January 2009 and December 2012. Standard karyotype and FISH were performed as previously described (Cigudosa et al. Blood 1998, Gerritsen et al. Blood 1992). Probes included LSI IgH/FGF3, LSI IgH/CCND1, LSI IgH/MAF, LSI MLL, LSI p53/cep17, LSI13q14.3/13q34, LSI ETV6, LSI CBFB, LSI 1p36/1q25, and LSI 5,9,15 from Abbott Molecular. Fisher's exact test evaluated the association between MLL and selected abnormalities. Kaplan-Meier methodology estimated overall survival from the date of BM evaluation, and survival was compared using a logrank test. Results In unselected bone marrow specimens, abnormalities were detected by karyotype in 17% (27/156) and FISH in 47% (87/186) of patients tested. Hyperdiploidy, which has been associated with longer survival, was identified in 23% (43/187) of patients, while the unfavorable risk abnormalities, including loss of p53, deletion 13q (by karyotype), translocation (4;14) and excess 1q were seen in 8% (15/179), 8% (12/156), 4% (7/176) and 16% (29/178) of patients, respectively. Translocation (11;14) was seen in 4 patients; translocation (14;16) was not identified in any patient. 28% (51/183) of patients had extra copies of MLL, which was the most frequent genetic abnormality identified. Unexpectedly, this abnormality was significantly associated with both favorable (hyperdiploidy, P = <0.001) and unfavorable (deletion 13q, P = 0.043; excess 1q P = 0.001) risk genetics. While having excess MLL had no impact on the overall survival of standard-risk patients, defined as neither hyperdiploid nor with unfavorable genetics (N = 100), patients with poor-risk genetics (N = 46) and extra copies of MLL had a trend toward better survival, P = 0.06 (Figure 1). Conclusions Karyotype and FISH studies identified excess MLL as the most frequent cytogenetic abnormality in a large cohort of newly diagnosed MM patients. In patients with MM and unfavorable cytogenetics, the presence of excess MLL may ameliorate some of the adverse impact of associated with these abnormalities. Understanding the functional significance of excess MLL, perhaps as it relates to frequently dysregulated HOXA9 in MM, may provide insight into disease pathogenesis and/or identify drugable targets. Disclosures: No relevant conflicts of interest to declare.

Vertebral Body Signal Changes in Spinal Cord Infarction: Histopathological Confirmation

2007 ◽  
Vol 20 (5) ◽  
pp. 580-585 ◽  
Author(s):  
S.G. Srikanth ◽  
H.S. Chandrashekhar ◽  
J.J.S. Shankar ◽  
S. Ravishankar ◽  
S.K. Shankar
Keyword(s):  
Computed Tomography ◽  
Spinal Cord ◽  
Bone Marrow ◽  
Magnetic Resonance ◽  
Vertebral Body ◽  
Spinal Cord Infarction ◽  
Guided Biopsy ◽  
Signal Changes ◽  
T2 Hyperintensity

Spinal cord infarctions are rare. They are difficult to diagnose clinically and remain undiagnosed even after extensive investigations. Magnetic Resonance (MR) features include hyperintensity of the cord on T2W images. Few cases of spinal cord infarction associated with vertebral body infarction are reported in the literature. We describe another five cases of spinal cord infarction with histopathological confirmation of the vertebral body signal changes. MR examinations of five patients who presented with acute spontaneous spinal cord syndrome were reviewed. Abnormal MR features of the spinal cord included signal changes within the parenchyma, best demonstrated on T2W images. These cord changes were associated with vertebral body T2 hyperintensity in all the patients and in one patient, the computed tomography guided biopsy of vertebral body lesion reported infarction. MR is sensitive to detect spinal cord infarctions and associated vascular and bony changes. The associated signal abnormalities in the bone marrow are a corroborative sign in the diagnosis of spinal cord infarction which was proved by histopathology.

scholarly journals A pilot study of 3D tissue-engineered bone marrow culture as a tool to predict patient response to therapy in multiple myeloma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kinan Alhallak ◽  
Amanda Jeske ◽  
Pilar de la Puente ◽  
Jennifer Sun ◽  
Mark Fiala ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Clinical Response ◽  
Ex Vivo ◽  
Drug Efficacy ◽  
Improve Patient Care ◽  
Hematologic Malignancies ◽  
Time Frame ◽  
Response To Therapy

AbstractCancer patients undergo detrimental toxicities and ineffective treatments especially in the relapsed setting, due to failed treatment attempts. The development of a tool that predicts the clinical response of individual patients to therapy is greatly desired. We have developed a novel patient-derived 3D tissue engineered bone marrow (3DTEBM) technology that closely recapitulate the pathophysiological conditions in the bone marrow and allows ex vivo proliferation of tumor cells of hematologic malignancies. In this study, we used the 3DTEBM to predict the clinical response of individual multiple myeloma (MM) patients to different therapeutic regimens. We found that while no correlation was observed between in vitro efficacy in classic 2D culture systems of drugs used for MM with their clinical efficacious concentration, the efficacious concentration in the 3DTEBM were directly correlated. Furthermore, the 3DTEBM model retrospectively predicted the clinical response to different treatment regimens in 89% of the MM patient cohort. These results demonstrated that the 3DTEBM is a feasible platform which can predict MM clinical responses with high accuracy and within a clinically actionable time frame. Utilization of this technology to predict drug efficacy and the likelihood of treatment failure could significantly improve patient care and treatment in many ways, particularly in the relapsed and refractory setting. Future studies are needed to validate the 3DTEBM model as a tool for predicting clinical efficacy.

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