scholarly journals Multiple myeloma BM-MSCs increase the tumorigenicity of MM cells via transfer of VLA4-enriched microvesicles

2019 ◽  
Vol 41 (1) ◽  
pp. 100-110
Author(s):  
Mahmoud Dabbah ◽  
Osnat Jarchowsky-Dolberg ◽  
Oshrat Attar-Schneider ◽  
Shelly Tartakover Matalon ◽  
Metsada Pasmanik-Chor ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Translation Initiation ◽  
Clinical Characteristics ◽  
Drug Response ◽  
Plasma Cells ◽  
Response To Treatment ◽  
Disease Therapy

Abstract Multiple myeloma (MM) cells accumulate in the bone marrow (BM) where their interactions impede disease therapy. We have shown that microvesicles (MVs) derived from BM mesenchymal stem cells (MSCs) of MM patients promote the malignant traits via modulation of translation initiation (TI), whereas MVs from normal donors (ND) do not. Here, we observed that this phenomenon is contingent on a MVs’ protein constituent, and determined correlations between the MVs from the tumor microenvironment, for example, MM BM-MSCs and patients’ clinical characteristics. BM-MSCs’ MVs (ND/MM) proteomes were assayed (mass spectrometry) and compared. Elevated integrin CD49d (X80) and CD29 (X2) was determined in MM-MSCs’ MVs and correlated with patients’ staging and treatment response (free light chain, BM plasma cells count, stage, response to treatment). BM-MSCs’ MVs uptake into MM cell lines was assayed (flow cytometry) with/without integrin inhibitors (RGD, natalizumab, and anti-CD29 monoclonal antibody) and recipient cells were analyzed for cell count, migration, MAPKs, TI, and drug response (doxorubicin, Velcade). Their inhibition, particularly together, attenuated the uptake of MM-MSCs MVs (but not ND-MSCs MVs) into MM cells and reduced MM cells’ signaling, phenotype, and increased drug response. This study exposed a critical novel role for CD49d/CD29 on MM-MSCs MVs and presented a discriminate method to inhibit cancer promoting action of MM-MSCs MVs while retaining the anticancer function of ND-MSCs-MVs. Moreover, these findings demonstrate yet again the intricacy of the microenvironment involvement in the malignant process and highlight new therapeutic avenues to be explored.

Clinical and Prognostic Impact of (11;14)(q13;q32) Translocation on Patients with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5507-5507
Author(s):  
Daisuke Miura ◽  
Kentaro Narita ◽  
Ayumi Kuzume ◽  
Rikako Tabata ◽  
Toshiki Terao ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Cells ◽  
Clinical Characteristics ◽  
Mononuclear Cells ◽  
Plasma Cells ◽  
Stage Iii ◽  
Prognostic Impact ◽  
Cd20 Expression ◽  
The Impact

Introduction. Translocations involving chromosome 14 at band q32, the immunoglobulin heavy chain (IgH) locus, are considered to be the most important initiating events for the development of multiple myeloma (MM). Among the IgH translocations in MM, t(11;14)(q13;q32) is the most frequently reported, and associated with a lymphoplasmacytic morphology. This translocation have been traditionally considered as standard-risk chromosomal abnormality compared to other translocations such as t(4;14) or t(14;16), although some controversies on the prognostic impact of this translocation still remain. This study aimed to clarify the clinical and prognostic impact of t(11;14) in Japanese patients in relation to other clinical variables such as immunophenotype of the tumor cells, other cytogenetic abnormalities, and use of stem cell transplantation (SCT). Patients and methods. Among the 244 consecutive patients with newly diagnosed MM, treated at Kameda Medical Center between April 2009 and July 2019, 234 patients, having cytogenetic analysis data (including t(11;14), t(4;14), t(14;16), and del(17p) by interphase fluorescence in situ hybridization (iFISH)) fully available, were included in this study. Data regarding the patients' clinical and laboratory characteristics, including the International Staging System (ISS), immunophenotype of the tumor cells, baseline circulating plasma cells (CPCs), treatment responses, disease progression, and survival status, were collected. iFISH was performed with CD138-purified bone marrow plasma cells, and the cut off values for translocation were ≥ 10% and for del(17p) ≥ 20%. Using multicolor flow cytometry, surface marker analysis of bone marrow samples and quantification of pre-treatment CPCs on peripheral blood mononuclear cells were simultaneously performed. CPCs were reported as the percentage of total mononuclear cells. Patients were considered to be negative for clonal CPCs at a sensitivity of 10−4 (0.01%) clonal plasma cells for all events evaluated. Results. The incidence of patients harboring t(11;14) was 24.4% (n = 57); t(11;14) was detected significantly high in light-chain-only subtypes (P < 0.001). We compared clinical characteristics of patients carrying t(11;14) with others. Myeloma cells with t(11;14) were associated with negative expression of CD56 (P < 0.001), CD117 (P = 0.046), and CD200 (P = 0.006), and positive expression of CD20 (P = 0.01) and CD81 (P = 0.035). Patients with t(11;14) were associated with positive CPCs (P = 0.011). In order to focus on the impact of t(11;14), we divided the patients into 4 groups: (A) no specific cytogenetic abnormality listed above (n = 137), (B) t(11;14) group (n = 57), (C) t(4;14) or t(14;16) group (n = 29), and (D) del(17p) only (n = 10), and the clinical characteristics and survival of the patients were compared across the three groups (A), (B), and (C). Almost all the patients (> 95%) in this cohort received bortezomib-based therapy. Median progression-free survival (PFS) and overall survival (OS) of patients in (A), (B), and (C) groups were 55.6, 34.2, and 30.2 months (m) (A vs. B, P = 0.036, and A vs. C, P = 0.031), and not reached, 51.2, and 79.8 m (A vs. B, P = 0.11, and A vs. C, P = 1.00), respectively. However, patients harboring t(11;14) were further divided into CD20-positive and -negative groups, the latter having poor prognosis (36.1 vs. 26.7, P = 1.0 for median PFS, and not reached vs. 44.2, P = 0.029 for median OS). Compared to other groups, patients without CD20 expression had significantly shorter OS (vs. A, vs. B, P = 0.024, 0.035, respectively), whereas those with CD20 expression tended to have longer OS, without statistical significance (Figure 1).Univariate analysis revealed ISS stage III, creatinine > 2.0 mg/dL, use of SCT, t(11;14) without CD20 expression, and age ≥ 70 years to be associated with shorter OS, whereas multivariate analysis demonstrated ISS stage III, use of SCT, and t(11;14) without expression CD20 (HR 1.88; 95% CI 1.10-3.21; P = 0.021) to be independent prognostic factors for poor OS. Conclusions. Our findings demonstrated that patients harboring t(11;14) had distinct clinical and immunophenotypic characteristics, two subsets of the disease entities with a clearly different survival according to CD20 expression. Disclosures Matsue: Ono Pharmaceutical: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Novartis Pharma K.K: Honoraria; Celgene: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria.

scholarly journals Impact of Osseous and Non-Osseous Extramedullary Disease in Multiple Myeloma: Clinical Characteristics and Outcomes in a Latin American Population

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5527-5527
Author(s):  
Cesar Vargas-Serafin ◽  
Aldo A Acosta-Medina ◽  
Juan Rangel-Patiño ◽  
Daniela Perez-Samano ◽  
Deborah M. Martinez-Banos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Latin American ◽  
Clinical Characteristics ◽  
Plasma Cells ◽  
Progression Free Survival ◽  
American Population ◽  
Synchronous Tumor ◽  
Increased Risk ◽  
Latin American Population

Introduction Extramedullary myeloma (EMM) is the synchronous presence of clonal plasma cells (CPC) in both bone marrow and distant sites. Its frequency is reported among 6-20% of multiple myeloma (MM) patients and can manifest as osseous plasmacytoma (OP) or non-osseous plasmacytoma (NOP). Previous reports outline a more aggressive clinical behavior in patients presenting with EMM and in Latin American population. However, there is scarce data regarding EMM in Latin American patients. The aim of this study was to describe the clinical characteristics and impact of EMM on survival outcomes in all patients diagnosed and followed at our institution. Methods Retrospective single-center study that included >18-year-old MM patients, as defined by the IMWG criteria. EMM was defined as the presence of CPC in any osseous or non-osseous tissue outside of the bone marrow or as the demonstration of a synchronous tumor at a non-accessible site by imaging methods. Results A total of 199 patients were included. Demographic and clinical characteristics are shown in Figure 1. Sixty-three patients had EMM (31.8%), of which 45 cases (71.4%) presented at diagnosis and 18 (28.6%) at progression. Forty-eight cases (76.2%) were diagnosed by biopsy and 15 (23.8%) by imaging studies. Fifty-four percent (n=34) of the cases presented as OP and 46% (n=29) as NOP. Most-frequently involved sites included the spine and chest wall in OP and abdomen and thorax in NOP (Figure 2). EMM was associated with lower comorbidity rates and higher incidence of renal failure. Mean progression-free survival (PFS) and overall survival (OS) were 22.9 and 43.7 months, respectively. EMM at any time of disease course resulted on lower PFS and OS (15.7 months vs. 26.2 months, p=0.04; 32.1 months vs. 65.1 months, p=0.03). The presence of NOP was related with lower OS (28.4 months vs. 59.2 months, p<0.01). A higher ECOG (HR 1.62; 95%CI 1.04-2.53; p=0.034), less profound responses to treatment (HR 0.30; 95%CI 0.21-0.40; p<0.001), and the presence of EMM (HR 1.53; 95%CI 1.04-2.25; p=0.032) were associated with worse PFS; while both high ISS (HR 1.54; 95%CI 1.0-2.2; p=0.018) and less profound responses (HR 0.52; 95%CI 0.37-0.73; p<0.001) resulted in worse OS in multivariate analysis. Other factors affecting PFS and OS are shown in Figure 3. Conclusion We observed higher rates of EMM in our cohort when compared with the reported literature. The presence of EMM was associated with poor prognosis as evidenced by lower PFS and OS. When comparing OP vs. NOP EMM, NOP conferred an increased risk of early mortality. Results suggest that more aggressive disease biology, higher tumor burden, and/or delayed referral for diagnosis and therapy in our population of MM patients contribute to these unfavorable outcomes. It is imperative that our knowledge on high-risk MM groups, including EMM, in minorities is expanded. Latin American countries are urged to work together in collaborative research to confirm these results in order to properly identify patients who may benefit from more intensive treatment that might result in the improvement of long-term outcomes. Disclosures Martinez-Banos: Celgene, Amgen: Other: Advisory Board.

Cyclooxygenase-2 (COX-2) in Multiple Myeloma: Prognostic Marker or Therapeutic Target?.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5051-5051
Author(s):  
Roger G. Owen ◽  
Im Fan ◽  
Sheila J.M. O’Connor ◽  
Faith E. Davies ◽  
Rebecca A. Rollett ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Therapeutic Target ◽  
Plasma Cells ◽  
Prognostic Significance ◽  
Cyclooxygenase 2 ◽  
Lymphoid Cells ◽  
Bone Marrow Biopsies ◽  
Cox 2

Abstract Cyclooxygenase-2 (COX-2) is the key enzyme involved in prostaglandin synthesis. It appears to support the growth of a number of solid tumours including colon, breast, ovary, lung and uterine cervix and may be an important therapeutic target in at least some of these tumours. COX-2 expression has recently been evaluated (by immunohistochemistry using polyclonal anti-COX-2 antibodies) in multiple myeloma (MM) where expression was documented in 33–57% of patients. COX-2 expression in these studies was strongly associated with an adverse outcome. In addition there is some emerging data to suggest that the use of aspirin in MM may improve survival rates. In order to further evaluate this we have used a monoclonal antibody (Clone SP21, Labvision, Fremont, Ca) to assess COX-2 expression in both normal and neoplastic plasma cells. 52 specimens were assessed using standard streptavidin-biotin immunoperoxidase techniques using a known COX-2+ colon cancer as a positive control. Strong uniform COX-2 expression was seen in 32/33 (97%) of myeloma patients assessed and was also documented in all patients with MGUS (n=10). COX-2 expression was also documented in reactive plasmacytic lesions (oral mucosa, skin and lymph node, n=6) as well as normal bone marrow plasma cells (n=6). Megakaryocytes stained positively in all bone marrow biopsies examined and provided a useful positive internal control while erythroid, myeloid and lymphoid cells were consistently negative. We would conclude that COX-2 is strongly expressed by both normal and neoplastic plasma cells suggesting that COX-2 is a potential therapeutic target in MM. The apparent increase in the proportion of myeloma patients expressing COX-2 in the present study reflects the use of a monoclonal antibody in our immunohistology studies. The fact that polyclonal antibodies identify a lower proportion of patients who appear to have an inferior outcome suggests that the level of expression is of prognostic significance rather than its presence or absence. This is worthy of further study using more appropriate techniques such as RQ-PCR.

Daratumumab, a CD38 Monoclonal Antibody in Patients with Multiple Myeloma - Data From a Dose-Escalation Phase I/II Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 73-73 ◽  
Author(s):  
Torben Plesner ◽  
Henk Lokhorst ◽  
Peter Gimsing ◽  
Hareth Nahi ◽  
Steen Lisby ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Plasma Cells ◽  
Plasma Concentrations ◽  
Efficacy Data ◽  
Advisory Committees ◽  
Bone Marrow Plasma

Abstract Abstract 73 Background Daratumumab (HuMax™-CD38) is a human CD38 monoclonal antibody with broad-spectrum killing activity and effectively mediates killing of CD38-expressing tumor cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. In this present ongoing first-in-human (FIH) dose-escalation study of daratumumab in pts with multiple myeloma (MM) (ClinicalTrials.gov CT00574288), the safety profile has been acceptable and preliminary efficacy data have already been published1,2. Here we present data from the dose escalation part of the study. Objectives The primary objective was to establish the safety profile. The secondary objectives were to establish the maximum tolerated dose (MTD), assessment of efficacy, pharmacokinetics (PK) and immunogenicity – Anti-Drug-Antibodies (ADA). Methods Pts ≥18 years and diagnosed with MM requiring systemic therapy and considered relapsed or refractory to at least two different prior lines of therapy and ineligible for ASCT were enrolled. The study was based on a 3+3 dose-escalation design. Daratumumab was administered over a 9-week period consisting of 2 pre- and 7 full doses. The doses ranged from 0.005 mg/kg to 24 mg/kg. Prednisolone/methylprednisolone was administered to prevent infusion related events (IREs) in a maximum dose equivalent to 27mg dexamethasone per week. Daratumumab plasma concentrations were measured by ELISA. Evaluation of efficacy data was according to IMGW guidelines3. A bridging ElectroChemiLuminesence (ELC) method on the MesoScale Discovery platform was used to detect ADA responses in pts to daratumumab. The results presented are based on data analyzed before database lock. Results Data from 32 pts including 2 pts in the ongoing 24mg/kg cohort were collected until now. Median age was 61 years (42–76). The median number of prior treatment lines was: 6.3 (2–12). PK analysis showed plasma peak levels as expected, but relatively rapid clearance at low dose levels. The clearance rate decreased with increasing dose suggesting an effect of target binding on the PK. At doses ≥ 4 mg/kg, daratumumab trough levels were consistent ≥ 10 μg/ml and observed PK values approximately estimated PK values (Figure 1). Preliminary efficacy evaluation in this abstract was based on best response to paraprotein as reflected by change in serum or urine M-component or free light chains (FLC) according to IMGW guidelines3. For groups ≤ 2 mg/kg, 4/20 pts achieved a reduction in paraprotein (12%, 14%, 19%, 55%); in the 4 mg/kg group, 3/3 pts had a reduction in paraprotein of 49%, 100%, and 64%, respectively. In the 8 mg/kg group, 2/3 pts had a reduction in paraprotein of 39%, and 100%, respectively whereas in the 16mg/kg cohort, 2/3 pts had a reduction in paraprotein of 50%, and 33%, respectively. A reduction of 80%-100% in the bone marrow plasma cells was seen in the 4 mg/kg group and onwards. No detectable ADA responses were found in the pts. No DLTs were reported in the 2, 4, 8 and 16mg/kg cohorts. The most common adverse events reported were infusion related events. The observed IREs occurred predominantly during the initial infusions, 10% of pts reported IREs during the pre-dose, 30% during the first full infusion with a gradual decrease in frequency after the 2nd full infusion. No dose relationship was observed. Most IREs had onset within 3–4 hours of infusion, two of the IREs were grade 3 and the remaining grade 1–2. Four IREs were SAEs; however, since implementation of steroids before all infusions and dilution of trial drug, no serious IREs were reported in the 4, 8 and 16mg/kg cohorts. Conclusion In pts with relapsed or refractory MM treated with daratumumab, a marked reduction in paraprotein and bone marrow plasma cells was observed in the higher dose cohorts. This has not previously been demonstrated with a single-agent monoclonal antibody in MM. No unexpected buildup of daratumumab was seen and in pts treated with 4mg/kg and upwards the observed plasma concentrations were close to those predicted. No ADA responses were detected. The MTD was not yet established and the toxicity was manageable. All data available from part 1 will be presented at the meeting. Disclosures: Plesner: Genmab: Consultancy; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Lokhorst:Genmab: Consultancy. Lisby:Genmab: Employment. Richardson:Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

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.

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