scholarly journals Clonal Plasma Cells in AL Amyloidosis Are Dependent on Anti-Apoptotic BCL-2 Family Proteins

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2654-2654
Author(s):  
Cameron Fraser ◽  
Vaishali Sanchorawala ◽  
Kristopher Sarosiek ◽  
Shayna Sarosiek
Keyword(s):  
Bone Marrow ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Al Amyloidosis ◽  
Functional Assay ◽  
Current Standard ◽  
Novel Therapy ◽  
Bh3 Mimetics ◽  
Hematologic Disorders ◽  
Apoptotic Proteins

Abstract Background: Immunoglobulin light chain (AL) amyloidosis is characterized by the production of clonal serum free light chains, which misfold and accumulate in tissues causing life threatening organ dysfunction and ultimately death. The treatment of AL amyloidosis targets the underlying population of clonal plasma cells, but existing therapies are not curative and ineffectively control the disease in many patients. Recent data have shown tremendous success in targeting anti-apoptotic BCL-2 family proteins as a novel therapy in hematologic disorders due to alterations in apoptosis and the function of anti-apoptotic proteins in malignant cells. BH3 profiling, a quantitative and functional assay that measures apoptotic priming and dependence on anti-apoptotic BCL-2 family members, has been used to identify and target apoptotic dependencies in hematologic disorders. Novel inhibitors of anti-apoptotic proteins, referred to as BH3 mimetics, have not yet been explored in AL amyloidosis due to insufficient understanding of apoptotic dependencies in this disease. Methods: To date, bone marrow aspirates have been collected from 44 patients with newly diagnosed or relapsed/refractory AL amyloidosis being evaluated at the Amyloidosis Center at Boston University. BH3 profiling was performed on clonal plasma cells to measure dependencies on anti-apoptotic BCL-2 family proteins. Clonal cells were also treated with BH3 mimetics in vitro, including BCL-2, BCL-xL, and MCL-1 inhibitors as single agents, as well as in combination with current standard therapies (bortezomib, ixazomib, lenalidomide, and pomalidomide). Results: Of the 44 enrolled patients, 16 are female (36%) and 28 are male (64%). The median age is 70 years (range, 47 to 84). Six patients were treatment naïve and the remainder had previous or current treatment for AL amyloidosis. Data obtained with BH3 profiling demonstrated that clonal plasma cells exhibit strong dependencies on anti-apoptotic BCL-2 family proteins, which may be altered by concurrent treatment with standard therapies. In the majority of patients, clonal plasma cells are highly dependent on the anti-apoptotic protein MCL-1 and undergo apoptosis when treated with an MCL-1 inhibitor. Intriguingly, this dependence is altered by treatment with proteasome inhibitors: clonal plasma cells become highly dependent on BCL-2 and undergo apoptosis in response to co-treatment with bortezomib and the FDA-approved BCL-2 inhibitor venetoclax. Conclusions: BH3 profiling can effectively measure apoptotic dependencies in clonal plasma cells derived from bone marrow aspirates in patients with AL amyloidosis. Dependencies on BCL-2 family proteins (particularly MCL-1) are strong, but some variability between patients was observed, especially in combination with standard therapies. Biomarker-driven deployment of BH3 mimetics for treatment of AL amyloidosis would likely be highly effective. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clonal plasma cells in AL amyloidosis are dependent on pro survival BCL-2 family proteins and sensitive to BH3 mimetics

2019 ◽  
Author(s):  
Cameron Fraser ◽  
Adam Presser ◽  
Vaishali Sanchorawala ◽  
Shayna Sarosiek ◽  
Kristopher Sarosiek
Keyword(s):  
Protein Misfolding ◽  
Amyloid Fibrils ◽  
Plasma Cells ◽  
Alkylating Agents ◽  
Single Agent ◽  
Current Treatment ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Current Standard ◽  
Bh3 Mimetics

Immunoglobulin light chain (AL) amyloidosis is a protein misfolding disorder characterized by the production of amyloidogenic immunoglobulin light chains by clonal populations of plasma cells. These abnormal light chains misfold and accumulate as amyloid fibrils in healthy tissues causing devastating multi-organ dysfunction that is rapidly fatal. Current treatment regimens, which include proteasome inhibitors, alkylating agents, and immunomodulatory agents, were developed for the treatment of the more common plasma cell disease, multiple myeloma, and have limited efficacy in AL amyloidosis as demonstrated by the median survival of 2-3 years. The recent development of novel small-molecule inhibitors of the major pro-survival proteins from the apoptosis-regulating BCL-2 family has created an opportunity to therapeutically target abnormal cell populations, yet identifying the extent of these dependencies and how to target them clinically has thus far been challenging. Using bone marrow-derived plasma cells from 45 patients with AL amyloidosis, we find that clonal plasma cells are highly primed to undergo apoptosis and exhibit strong dependencies on pro-survival BCL-2 family proteins. Specifically, we find that clonal plasma cells in a majority of patients are highly dependent on the pro-survival protein MCL-1 and undergo apoptosis when treated with an MCL-1 inhibitor as a single agent. In addition, BCL-2 inhibition sensitizes clonal plasma cells to several current standard of care therapies. Our results suggest that BH3 mimetics, when deployed rationally, may be highly effective therapies for AL amyloidosis.

Dysregulation of miRNAs In AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4648-4648
Author(s):  
Liangping Weng ◽  
Brain Spencer ◽  
Pam Soo Hoo ◽  
Lawreen Connors ◽  
Carl O'Hara ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Micro Rna ◽  
Chromosome 3 ◽  
Al Amyloidosis ◽  
Stem Loop ◽  
Micro Rnas ◽  
Bone Marrow Plasma ◽  
Apoptosis Gene

Abstract Abstract 4648 Bone marrow plasma cells (BMPC) were purified from aspirates obtained from patients with AL amyloidosis using anti-CD138 immunomagnetic beads, and from controls. Expression levels of micro RNAs (miRNAs) were compared by microarray. The levels of ten miRNAs were found to be increased more than 1.5-fold in BMPC of AL amyloidosis patients. These results were confirmed using stem-loop RT-qPCR for miR-148a, miR-26a, and miR-16, the most highly upregulated miRNAs in the AL samples. miR-16, a micro RNA linked to other hematopoietic diseases, was significantly increased in the AL group at baseline and also in treated patients with persistent monoclonal plasma cells in the bone marrow, but not in patients who achieved a hematologic remission after therapy and normal polyclonal BMPCs. miR-16 can be derived from the miR-16-1/mirR-15a cluster on chromosome 13 or the miR-16-2/miR-15b cluster on chromosome 3. The expression of miR-15b was much higher than miR15a in AL and control BMPC samples; this suggests that miR-16 in plasma cells is mostly derived from chromosome 3. The anti-apoptosis gene BCL-2, a putative target mRNA that can be down-regulated by miR-16, was present in the BMPCs from the AL group despite the elevated levels of miR-16. Our data suggest that miRNAs are dysregulated in clonal plasma cells from AL amyloidosis patients and that abnormal levels of miRNAs may be potential biomarkers for disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals BH3 Profiling Identifies Bcl-2 Dependency in Multiple Myeloma and Predicts Sensitivity to BH3 Mimetics

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 417-417
Author(s):  
Cyrille Touzeau ◽  
Jeremy Ryan ◽  
Philippe Moreau ◽  
Triona Ni Chonghaile ◽  
Steven Le Gouill ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Plasma Cells ◽  
Functional Assay ◽  
Bh3 Mimetics ◽  
High Affinity ◽  
In Vitro Sensitivity ◽  
Apoptotic Proteins ◽  
Bh3 Mimetic

Abstract Despite significant improvement in the treatment of Multiple Myeloma (MM), patients still experience relapse and the disease remains incurable. Cellular fate decision in response to drug therapy is mainly determined by the interactions among BCL-2 family members. Thus anti-apoptotic BCL-2 family proteins represent an attractive target for therapy. BH3 profiling is a functional assay that identifies the tumor cell’s addiction to anti-apoptotic members, such as BCL-2, BCL-XL or MCL-1. In the present study, we determined the BCL-2, BCL-XL and MCL-1 dependency of both MM cell lines and primary myeloma samples, and then tested the ability of BH3 profiling to predict the in vitrosensitivity to BH3 mimetics. First, the BCL-2, BCL-XL or MCL-1 dependence of MM cell lines (n=11) was measured using BH3 profiling. After cell permeabilization, mitochondria were exposed to standardized amounts of peptides derived from the BH3 domains of BH3-only proteins. For instance, the BAD BH3-only peptide binds with high affinity to BCL-2 and BCL-XL, whereas HRK and MS1 peptides bind with high affinity only to BCL-XL and MCL-1, respectively. The cytochrome c release induced by each peptide was quantified by FACS analysis. Dependence on individual anti-apoptotic proteins was found to be very heterogeneous from one cell line to another. Most cell lines (7/11) were found to be MCL-1 dependent. Five cell lines were found to be Bcl-XL dependent and 2 cell lines BCL-2 dependent. Notably, 3 cell lines showed co-dependence to both MCL-1 and BCL-XL anti-apoptotic proteins. We then determined the in vitro sensitivity of MM cell lines to the BH3 mimetics ABT-199 (BC-2 specific) and ABT-263 (BCL-2, BCL-XL and BCL-w specific). Only 3 cell lines out of 11 were found sensitive to ABT-199 and 263 (LD50<100 nM). Interestingly, as we have previously found in other cancers, BH3 profiling predicted sensitivity to ABT-199 and 263 treatment. We then determined the mitochondrial priming of primary plasma cells obtained from 11 MM patients. BH3 profiling was performed on CD138-purified plasma cells. As observed with MM cell lines, patient samples showed heterogeneous dependency to anti-apoptotic proteins: MCL-1 (n=3), BCL-2 (n=2), Bcl-XL (n=2). Of note, mitochondria of 5 patient samples were found to be independent of BCL-2, BCL-XL or MCL-1. Cells were cultured with/without ABT-199 and 263 during 16 hours and then cell death was assessed by flow cytometry after annexin V staining. Two and 4 samples were found sensitive (LD50 < 100 nM) to ABT-199 and ABT-263, respectively. Once again, BH3 profiling with the BAD peptide correlated with in vitro sensitivity to ABT-199 and 263. To conclude, Multiple Myeloma is a heterogeneous disease regarding its dependence to anti-apoptotic proteins, and cannot be considered as monolithically MCL-1 or BCL-2 dependent. Rather, this determination must be made individually. BH3 profiling allows the identification of a BCL-2 dependent subset of MM patients and predicts ABT-199 in vitro sensitivity. It is of clinical interest to identify BCL-2 dependency in MM due to the current development of the oral BH3 mimetic ABT-199 that showed very promising results in BCL-2 dependent malignancies. Disclosures Off Label Use: The presentation discuss the sensitivity of myeloma cells to the Bcl-2 specific BH3 mimetic ABT-199. Le Gouill:Roche: Consultancy; Janssen: Consultancy. Letai:Abbvie: Consultancy.

Bone disease as the first manifestation of systemic AL-amyloidosis

2020 ◽  
Vol 92 (7) ◽  
pp. 85-89
Author(s):  
L. P. Mendeleeva ◽  
I. G. Rekhtina ◽  
A. M. Kovrigina ◽  
I. E. Kostina ◽  
V. A. Khyshova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Disease ◽  
Plasma Cells ◽  
Interventricular Septum ◽  
Bone Destruction ◽  
Amyloid Deposition ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Linear Type

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib werent detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.85% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (/44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous scarring of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.

scholarly journals Systemic AL amyloidosis with high bone marrow plasma cells (BMPCs) infiltration: a case report and literature review

2019 ◽  
Vol 4 ◽  
pp. I 30-30
Author(s):  
Hui-Wen Wang ◽  
Rong Tang ◽  
Xiang-Cheng Xiao ◽  
Wei Liu ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Case Report ◽  
Literature Review ◽  
Plasma Cells ◽  
Al Amyloidosis ◽  
Bone Marrow Plasma ◽  
High Bone

The Role of B Cell-Activating Factor (BAFF) in the Biology of Multiple Myeloma (MM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3380-3380 ◽  
Author(s):  
Noopur Raje ◽  
Shaji Kumar ◽  
Teru Hideshima ◽  
Kenji Ishitsuka ◽  
Hiroshi Yasui ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
B Cell ◽  
Cell Lines ◽  
Plasma Cells ◽  
Cell Development ◽  
Newly Diagnosed ◽  
Growth And Survival ◽  
Affymetrix U133a ◽  
Apoptotic Proteins

Abstract BAFF is a member of the tumor necrosis factor (TNF) family and is critical for the maintenance and homeostasis of normal B-cell development. Importantly, BAFF promotes the generation of rapidly dividing immunoglobulin secreting plasmablasts from activated memory B cells by enhancing their survival. Given that MM is a cancer of plasma cells and that the signaling cascades implicated in receptor ligand interactions of BAFF are crucial in MM cell biology, we hypothesized that this cytokine may play a critical role in MM cell development, survival, and proliferation. We performed gene expression profiling (GEP) on CD 138+ plasma cells isolated from 90 MM patients (45 newly diagnosed and 45 relapsed) and 11 healthy controls using the Affymetrix U133A arrays. Our data demonstrates increased expression of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA), 2 receptors used by BAFF to exert its effects. Our data also shows an increased expression of a proliferation-inducing ligand (APRIL), another member of the TNF family with homology to BAFF. Expression levels of BAFF and BAFF-R could not be determined because of lack of these probe sets on the Affymetrix U133A arrays. GEP analysis shows increased BCMA expression (p&lt;0.0001, student T test) on newly diagnosed and relapsed MM versus normal plasma cells. Flow cytometry on MM cell lines demonstrated a differential expression of the three receptors of BAFF, with BCMA present on most cell lines but BAFF-R expressed at low levels only on LR5 cells and DOX40 MM cells. In contrast, flow cytometry performed on MM patient cells demonstrated the presence of all 3 receptors on CD 138+ cells. ELISA assays performed on 30 MM sera demonstrated a mean BAFF level of 618 pg/ml (range: 128–2126pg/ml) versus 235pg/ml (range: 158–326pg/ml) in 7 normal donor sera. Fifty six% (17/30) of MM patients had BAFF levels in excess of the highest value noted in normals. To understand the role BAFF might play in the biology of MM, we studied the effects of recombinant BAFF (rh-BAFF) on MM cells directly and in the context of its bone marrow microenvironment. (abstract # 554746) rh-BAFF conferred a survival advantage to MM cells and protected them against dexamethasone-induced cytotoxicity. Importantly, anti-apoptotic proteins Bcl2 and Mcl-1 were upregulated, as were growth and survival signals belonging to the JAK/STAT and MAPKinase pathways. Conversely, neutralizing antibody to BAFF blocked, at least in part, blocked the upregulation of anti-apoptotic proteins with associated growth and survival, confirming that these effects were due to BAFF. Importantly, all of these signals were downregulated even in the presence of bone marrow stromal cells (BMSCs). These data therefore show a role for BAFF mediating MM cell survival and provide the framework for inhibiting BAFF, either alone or in combination with dexamethasone, to improve patient outcome in MM.

Human Granulocytic Anaplasmosis: a Case Report and Review of Literature.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4518-4518
Author(s):  
Jian Ouyang ◽  
Qiguo Zhang ◽  
Jingyan Xu ◽  
Bing Chen ◽  
Rong-Fu Zhou
Keyword(s):  
Bone Marrow ◽  
Hemophagocytic Syndrome ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Diagnosis And Treatment ◽  
Case Presentation ◽  
Human Granulocytic Anaplasmosis ◽  
Granulocytic Anaplasmosis ◽  
Laboratory Features ◽  
Bone Marrow Plasma

Abstract Abstract 4518 Purpose To discuss the clinical and laboratory features, diagnosis and treatment of human granulocytic anaplasmosis. Methods We present the clinical and laboratory features, diagnosis and treatment of a patient with human granulocytic anaplasmosis. Case presentation The patient with human granulocytic anaplasmosis presented with fever,cough?Adiarrhea?Amyalgia?Afacies typhosa?Arelative infrequent pulse and swelling of lymph nodes. Laboratory examination showed the patient had leukopenia?Athrombocytopenia?Aproteinuria?Aliver injury?Ablood clotting abnormal?AEBV-DNA positive. We also found the patient's ferritin?Acreatase?Aamylase and lipase increased. In the patient's bone marrow, plasma cells were increased, hemophagocyte and intragranulocytic inclusions were found. The patient did not respond to the treatment of imipenem, cefepime hydrochloride and teicoplanin. But he was treated successfully with moxifloxacin. Conclusion Patient with human granulocytic anaplasmosis can present leukopenia, thrombocytopenia, blood clotting abnormal and plasma cells increased in bone marrow. It's quite necessary to make differential diagnosis with some blood diseases. The patient can be accompanied with EBV infection and hemophagocytic syndrome. The patient can be cured by antibiotics-quinolones. Disclosures: No relevant conflicts of interest to declare.

High Dose Melphalan with Autologous Stem Cell Transplantation Overcomes Poor Prognosis of Primary Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1350-1350
Author(s):  
Simrit Parmar ◽  
Mubeen Khan ◽  
Gabriela Rondon ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Plasma Cells ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Bone Marrow Plasma ◽  
Organ Response ◽  
High Dose Melphalan

Abstract Abstract 1350 Background: Systemic Primary AL Amyloidosis is a rare but potentially fatal disease resulting from tissue deposits of amyloid fibrils derived from monoclonal immunoglobulin light chains. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) is associated with hematologic and organ responses and improved survival. Methods: In this retrospective analysis we identified 46 patients with primary AL amyloidosis who received auto HCT between 01/1998 to 05/2010 at MDACC. Organ responses were determined using Amyloidosis Consensus Criteria. Results: The median age at auto HSCT was 56 years (34-74) where 61% were males and 35% were older than 60 years of age. 61% had lambda light chain restriction and only 4% had cytogenetic abnormalities. Disease characteristics are summarized in Table 1. The median time from diagnosis to auto HCT was 6.6 months (2.2-29.4 months). 22 pts (47.8%) had one organ, 19 pts (41.3%) had 2 organ and 4 pts (8.7%) had 3 organ involvement. 11 pts (23.9%) had heart and 35 pts (76.1%) had kidney involvement. The median follow up from the time of diagnosis was 22.4 months and from time of auto HCT was 16.7 months. High dose Melphalan dose was 200mg/m2 in 24 pts (52%) and 140mg/m2 in 22 (47.8%). There were 4 early deaths and 4 pts whose follow up was less than 3 months and their response was not assessed. Out of the 38 evaluable patients, the post-transplant organ responses were as follows ≥PR 25(66%), ≥stable disease 35(92%) (Table2). The hematologic responses were: CR=5 (13%), ≥VGPR=10(26%), ≥PR=26 (68%), ≥SD=37(97%). One patient had progressive disease. There was a correlation between organ response and hematologic response (chi square;p<10-3). The day-100 treatment related mortality (TRM) was 8.7% and 1-yr TRM was 13%. The median progression-free (PFS) and overall survival (OS) from auto HCT was 73.8 months and not reached (from transplant). The median PFS and OS from diagnosis were 93 months and 59.8 months respectively. In multivariate analysis, heart involvement (p=0.01), female sex (p=0.011), age ≥60 years (p=0.002), bone marrow plasma cells≥10% (p=0.043) and Beta-2 microglobulin>3.5mg/l (p=0.02) were associated with poor OS. Improved OS correlated with organ response (52.6 vs 11.4 months; p=0.01) and hematologic response (52.6 vs.6.1months; p=0.002). Hemoglobin <10 g/dl (p=0.047), bone marrow plasma cells≥10% (p=0.043) and age≥60 years (p=0.075) were associated with shorter PFS. Hematologc response (p=0.48) and organ response (p=0.12) were not associated with improved PFS. Conclusion: In this analysis the outcome of patients with primary systemic AL amyloidosis was durable with auto HCT with acceptable mortality risk and improved survival. Disclosures: No relevant conflicts of interest to declare.

Outcomes and Treatments of Relapsed AL Amyloidosis Following Stem Cell Transplant

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1858-1858 ◽  
Author(s):  
Rahma Warsame ◽  
Soo-Mee Bang ◽  
Shaji K. Kumar ◽  
Martha Q Lacy ◽  
Francis K Buadi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplant ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Treatment Options ◽  
Autologous Stem Cell Transplant ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Post Transplant

Abstract Abstract 1858 Systemic light chain amyloidosis (AL amyloidosis) is a condition where clonal plasma cells produce misfolded insoluble immunoglobulin light chains that deposit in various organs causing progressive organ dysfunction. Chemotherapy and autologous stem cell transplant (ASCT) when eligible is the standard treatment options for patients with AL amyloidosis. There are several studies who report long term outcomes of patient post ASCT. However, there is a paucity of literature describing the outcomes of patients who have received ASCT but have relapsed. We performed a retrospective study to assess the outcomes and treatment regimens employed following relapse after ASCT. Between 1996 and 2009, 410 patients received ASCT at the Mayo Clinic as first line therapy. Of those 410 patients 42 patients died within 3 months of transplant, 64 patients died without documented relapse, 158 patients were alive without documented progression, and 146 patients had documented progression. Those 146 patients are the subject of our study. The median time to hematologic relapse was 2 years (range: 0.2–15.5 years). At relapse, 59 patients were treated with IMiD based therapy, 36 with alkylator based therapy, 24 with bortezomib, 15 with steroids, and 5 with second ASCT. The respective hematologic response rates were 58%, 33%, 50%, 53%, and 60%. The remaining six patients were not evaluable for response for one other following reasons: organ transplants; no further therapy; inevaluable disease. With a median post relapse follow up of 3.6 years, the median overall survival (OS) from the first post ASCT relapse was 4.6 years. The median post transplant follow up was 6.1 years, the median OS for these patients was 7.3 years from the time of transplant. These data provide novel information about outcomes after SCT relapse, which should be useful not only for patients and doctors but also for investigators designing studies for salvage therapies post-transplant. Disclosures: No relevant conflicts of interest to declare.

Metabolomics Identifies Potential Biomarkers of Multiple Myeloma Development and Progression

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3985-3985
Author(s):  
Francesca Fontana ◽  
Josè Manuel garcia Manteiga ◽  
Magda Marcatti ◽  
Francesca Lorentino ◽  
Giovanni Tonon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
In Vitro Tests ◽  
Incurable Cancer ◽  
Disease Evolution ◽  
Cell Counts ◽  
Bone Marrow Plasma ◽  
Active Disease

Abstract Abstract 3985 Multiple myeloma is a malignancy of plasma cells, which grows at multiple foci in the bone marrow, secretes monoclonal immunoglobulins, and typically induces skeletal destruction, hypercalcemia, anemia, and renal failure. Although it remains an incurable cancer, novel therapeutic regimens have improved overall survival in the last decade. Multiple myeloma originates from post germinal center, terminally differentiated B lymphocytes through a multi-step process involving early and late genetic changes. Multiple myeloma is preceded by monoclonal gammopathy of undetermined significance (MGUS), a frequent age-progressive premalignant expansion of bone marrow plasma cells that behave benignly despite the presence of most myeloma-specific genetic abnormalities. Indeed, development and progression of multiple myeloma are believed to rely on vicious interactions with the bone marrow environment, offering a paradigm to investigate the bone-cancer relationship. In particular, bone and stromal cells are known to be diverted by cancer cells through altered cytokine circuitry. The resulting enhanced osteoclastogenesis and neoangiogenesis, and reduced osteoblast differentiation and activity sustain cancer cell survival, proliferation, migration and chemoresistance. Such crucial interactions, however, have only partially been elucidated in their complexity, dynamics and exact role in disease evolution. A better knowledge of this interplay, still elusive, could help identify prognostic markers, pathomechanisms, and therapeutic targets for future validation. Aiming to achieve an unbiased, comprehensive assessment of the extracellular milieu during multiple myeloma genesis and progression, we performed a metabolomic analysis of patient-derived peripheral and bone marrow plasma by ultra high performance liquid and gas chromatography followed by mass spectrometry. By feature transformation-based multivariate analyses, metabolic profiling of both peripheral and bone marrow plasma successfully discriminated active disease from control conditions (health, MGUS or remission). Moreover, both central and peripheral metabolic scores significantly correlated with bone marrow plasma cell counts. Significant changes in the peripheral metabolome were found to be associated with abnormal renal function in the subset of myeloma patients. Noteworthy, however, renal dysfunction-associated features failed to independently predict disease load, while non-overlapping disease vs. control analyses consistently identified a number of metabolites associated with disease. Among these, increased levels of the C3f-derived peptide, HWESASLL, and loss of circulating lysophosphocholines emerged as hallmarks of active disease. In vitro tests on myeloma cell lines and primary patient-derived cells revealed a previously unsuspected direct trophic role exerted by lysophosphocholines on malignant plasma cells. Altogether, our data demonstrate that metabolomics is a powerful approach suitable for studying the complex interactions of multiple myeloma with the bone marrow environment and general metabolism. This novel strategy holds potential to identify unanticipated markers and pathways involved in development and progression of multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document