scholarly journals Defining the Differentiation Stage of Multiple Myeloma Plasma Cells: Biological and Clinical Significance

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 25-25
Author(s):  
Bruno Paiva ◽  
Noemi Puig ◽  
María-Belén Vidriales ◽  
Norma Carmen Gutierrez ◽  
Miguel T Hernandez ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Principal Component ◽  
Progression Free Survival ◽  
Down Regulation ◽  
Phenotypic Data ◽  
Cytogenetic Abnormalities ◽  
Differentiation Stage ◽  
Color Combinations ◽  
End Stage

Abstract B-cell lymphopoiesis ends in terminally differentiated bone marrow (BM) plasma cells (PCs). While initially PCs have been viewed mainly as short-lived end-stage B-cells, there is now evidence that this is a heterogeneous cellular compartment in which new-born plasmablasts and long-lived PCs also coexist. The transition between both is characterized by phenotypic modifications, which include higher CD38/CD138 expression alongside HLADR and CD19 down-regulation. CD19 function and expression are regulated by CD81 and accordingly, three normal BM PC subsets can be delineated according to the expression levels of both markers: CD19+/CD81+, CD19-/CD81+, and CD19-/CD81-. However, no additional phenotypic information exists on such normal subsets, nor about how myeloma PC differentiation relates to its normal counterpart. Here, we used 23-color multidimensional flow cytometry (MFC) and principal component analysis (PCA) to phenotypically characterize normal BM PC differentiation in 10 healthy donors and its malignant counterpart in 115 elderly newly-diagnosed multiple myeloma (MM) patients included in the PETHEMA/GEM2010MAS65 study. First, we adopted novel MFC software technology to, after merging and calculating phenotypic data obtained from four 8-color combinations, define the immunophenotypic expression profile (iPEP) of normal BM PCs and characterize their differentiation pathway through PCA. Accordingly, we observed that from the CD19+/CD81+ subset through the CD19-/CD81+ and CD19-/CD81- stages (corresponding to 64%, 32% and 4% of total PCs, respectively) there is a continuous down-regulation on the amount of expression of CD54 (P=.008), CD44 (P=.03) and CD27 (P=.07). By contrast, a trend towards increased levels of CD28 (P=.06), CD38 (P=.05) and CD56 (P=.09) was also observed, suggesting an accumulation of potentially less active and more differentiated PCs from the CD19+/CD81+ to the CD19-/CD81- stages. Using the same approach as described above to determine the iPEP of myeloma PC clones from each individual patient, we then integrated such iPEPs into the normal PC differentiation pathway to investigate, through PCA, the stage and corresponding normal counterpart of each patient myeloma PC clone. From the 115 patients included in this analysis, 3 (3%) had myeloma PCs fitting within the CD19+/CD81+ differentiation stage and 21 (18%) within the CD19-/CD81+ subset, whereas the remaining 91 cases (79%) fitted within potentially more differentiated CD19-/CD81- stages. Virtually no cases with myeloma PC clones corresponding to the CD19+/CD81+ and CD19-/CD81+ differentiation stages had ISS stage I (8%), as compared to 30% in patients with a more differentiated PC CD19-/CD81- signature (P=.03). Furthermore, patients with myeloma PC clones matching the CD19+/CD81+ and CD19-/CD81+ differentiation stages showed a trend for higher incidence of extramedullary plasmacytomas (22% vs 9%; P=.09). Interestingly, almost half of patients with myeloma PC clones in potentially less differentiated stages had no cytogenetic abnormalities [t(IGH), +1q, del(13q), and/or del(17p)] as compared to cases with myeloma PCs matching with the CD19-/CD81- normal PC counterpart (44% vs. 16%, respectively; P=.01). However, whenever present, the type (standard- vs high-risk) of such cytogenetic abnormalities did not differ between both subgroups. Finally, we investigated if the differentiation stage of myeloma PC clones influenced patients’ prognosis, and noted that progression-free survival (PFS) of cases in less and intermediate differentiation stages was significantly inferior PFS as compared to patients with a mature CD19-/CD81- myeloma PC clone (median of 24 months vs not reached, respectively; P=.02). Noteworthy, identical patient prognostication for PFS (P=.02) was observed when the analysis was restricted to cytogenetically-defined standard-risk cases, thus identifying a subgroup of patients with more aggressive MM despite favorable cytogenetic profiles. In summary, we showed that in the vast majority (~80%) of MM patients the PC clone phenotypically matches more differentiated normal PC counterpart subsets. Patients harboring less differentiated clones show a higher incidence of ISS stage II/III and extramedullary disease despite fewer cytogenetic abnormalities, as well as significantly inferior PFS as compared to cases with more differentiated myeloma PC clones. Disclosures Ocio: Array Biopharma: Honoraria, Research Funding.

scholarly journals Relationship of Bone Marrow Plasma Cell Morphology with Cytogenetic Abnormalities in Patients with Multiple Myeloma

2021 ◽  
Author(s):  
Vikram Narang ◽  
Maneet Luthra ◽  
Avantika Garg ◽  
Amit Dhiman ◽  
Neena Sood
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Descriptive Analysis ◽  
Cross Sectional Study ◽  
Chi Square ◽  
Morphological Pattern ◽  
Cross Sectional ◽  
Cytogenetic Abnormalities ◽  
Cytogenetic Studies ◽  
Chi Square Test

Introduction: Cytogenetics has become an integral part of Multiple Myeloma (MM) diagnosis and prognostication. A combination of conventional cytogenetics and interphase Fluorescence In Situ Hybridization (FISH) is currently used to stratify tumours into high, intermediate and standard risk disease. Aim: To compare the morphological details of plasma cells with cytogenetic abnormalities. Materials and Methods: The present retrospective cross sectional study was conducted at Department of Pathology Dayanand Medical College and Hospital, Ludhiana in three and a half year duration (1st January 2014 to 30th June 2017). All the diagnosed MM patients in whom cytogenetic was available were included and descriptive analysis was done using Chi-Square test and relevant statistical analysis using SPSS 21 version. Correlation was done with various morphological pattern (plasmacytic, plasma blastic). Results: Cytogenetic studies were performed on 42 cases using FISH technique (n=31, 81.6%) and GTG (Giemsa) banding (n=4, 10.5%). Three (7.9%) patients were tested with both methods. In the present study, all the patients (n=2,100%) with plasmablastic morphology who got tested with cytogenetics had del13q14.3 and none of the patients with normal genome (n=22) had plasmablastic morphology. Conclusion: Morphologic patterns of plasma cells and cytogenetic studies correlate well and can together help in better prognostication of MM patients.

PTEN Gene Deletions in Patients with Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4889-4889
Author(s):  
Xiao Ying Qi ◽  
A. Keith Stewart ◽  
Hong Chang
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Progression Free Survival ◽  
Myeloma Cell ◽  
Suppressor Gene ◽  
High Dose Chemotherapy ◽  
Pten Gene ◽  
Allelic Loss ◽  
High Dose ◽  
13Q Deletion

Abstract PTEN, a tumor suppressor gene, negatively regulates the anti-apoptotic action of akt phosphorylation. Allelic loss or mutation of this gene has been detected in many solid tumors and more recently in human myeloma cell lines (HMCLs). Expression of PTEN has resulted in growth inhibition and apoptosis of a HMCL, suggesting that it may play a role in the pathogenesis of multiple myeloma (MM). However, the PTEN status in tumor cells from patients with MM has not been determined. Using a triple staining method combining staining for cytoplasmic light chains and fluorescence in situ hybridization (FISH) with chromosome 10-centromere and PTEN-gene specific probes, we analyzed clonal plasma cells from 71 patients with MM, 10 with plasma cell leukemia (PCL) and 10 HMCLs. Hemizygous PTEN deletions were detected in 4 of 71 (5.6%) MM patients, 2 of 10 (20%) PCLs, and 2 of 10 (20%) HMCLs. The percentages of clonal plasma cells containing PTEN deletions ranged from 21–90% (median, 56%). Three of the 4 patients with PTEN deletions were detected at diagnosis with stage III disease (Duire-Salmon) and 1 was detected at relapse. Two patients had IgG kappa, 1 IgG lambda and 1 free lambda light chain. To correlate the PTEN status with other known genetic abnormalities in MM, we investigated 4 MM and 2 PCLs with PTEN deletions using FISH for chromosome13q, p53 status, translocations t(11;14), t(4;14) and t(14;16). One MM had a 13q deletion, 1 PCL had a t(11;14), and the other PCL had a t(14;16), a 13q deletion and a p53 deletion. All 4 MM patients with hemizygous PTEN deletions received melphalan based high-dose chemotherapy and autologous stem cell support. Their median overall survival (OS) was 48.1months, and progression free survival (PFS) was 42.8 months as compared to patients without PTEN deletions (OS, not reached, PFS, 25.8 months) (p=0.51 for OS, p=0.67 for PFS). Our results indicate that PTEN deletions are uncommon in MM patients and therefore unlikely represent a primary event for MM. PTEN deletions appear to occur in the advance stage of the disease, and are more frequently involved in PCL or HMCLs suggesting that deletions of PTEN may be associated with disease progression in a subset of MM.

Clarithromycin (Biaxin®), Low Dose Thalidomide and Dexamethasone (BLT-D) in Newly Diagnosed and Previously Treated African American Patients with Multiple Myeloma: A Retrospective, Single Institution Experience.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3501-3501
Author(s):  
Jack Jacoub ◽  
Joao L. Ascensao ◽  
Boyer James ◽  
Thomas O’Connor ◽  
Reema Batra ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
African American ◽  
Partial Response ◽  
Plasma Cells ◽  
Progression Free Survival ◽  
Staging System ◽  
Stage I ◽  
M Protein ◽  
Duration Of Treatment ◽  
Previously Treated

Abstract Introduction : African-Americans (AA) are twice as likely to develop multiple myeloma (MM) than Caucasians but are largely underrepresented in clinical trials. Thalidmode plus dexamethasone is an established therapy in MM. Biaxin® may augment the efficacy of this combination possibly via potentiating steroid activity (M. Coleman, et al. Leuk Lymphoma 2002, R. Niesvizky, et al. Blood 2003, Abs #832). Methods : We conducted a retrospective review of all AA patients (pts) with symptomatic MM treated with BLT-D from 2002-present. Treatment consisted of Thalidomide 50–200mg daily, Biaxin 500mg twice daily and dexamethasone 40mg weekly. All pts received monthly bisphosphonate therapy and aspirin 81–325mg daily. Response criteria was defined as follows: complete response (CR) = no detectable M-protein, marrow plasma cells <5%; very good partial response (VGPR) = decrease in M-protein by >90%; partial response (PR) = decrease in M-protein by >50%; stable disease (SD) = M-protein decrease by <50% without clinical progression; no response (NR)= progression with no change or increase in M-protein or response <4wks. Progression free survival (PFS) was defined from the start of BLT-D until discontinuation or change in therapy due to progressive disease as clinically indicated. Toxicity was graded according to WHO criteria. Results :15 pts received BLT-D and their characteristics were as follows: all were males; median age 66 (range 30–78); IgG=53%, IgA=20%, light chain only=27%; Durie-Salmon stage I=20%, II=33%, III=47%; International Staging System stage I=20%, II=47%, III=13%, undefined = 20%; 7 were previously treated (5 pts had 1 prior regimen, 2 pts had ≥2 prior regimens). In previously treated pts (n=7) responses were as follows: no CR, 2 VGPR (28%), 3 PR (43%), 1 SD (14%) and 1 NR (14%) for an overall response rate (ORR) of 87%. Their duration of treatment ranged from 4–32 mos and median PFS in responders (VGPR+PR+SD) was 29.5 mos (range 23–35). 3 pts had BLT-D discontinued after 12–15 months of therapy and remained in stable plateau phase off therapy for > 1 year; one was referred for ASCT after 14 mo; one continues stable at 15 mo and the third relapsed at 12 months but failed to respond again to BLT-D. Responses in treatment naive pts (n=8) were as follows: no CR, 3 VGPR (38%), 1 PR (13%) and 2 SD (25%), 2 NR (25%) for an ORR of 75%. Their duration of therapy ranged from 3–20 mos and median PFS in responding patients was 11 mos (range 7–20). The longest survivor in this group (37 mos) received an ASCT after 12 mos of therapy. 13 pts (87%) remain alive at a median follow-up of 24 mos (range 8–37). Grade 3–4 toxicity consisted of 3 DVTs + 1 PE (27%), 5 hypergycemias (33%), 2 infections (13%) and 1 peripheral neuropathy (7%). Additionally, 1 pt developed superficial thrombophlebitis; 1 QT prolongation resolving with Biaxin discontinuation; 5 others with neuropathy; and 2 others with hyperglycemia. Conclusion : BLT-D is feasible and effective therapy in African-American patients with MM and is capable of inducing durable responses. However, we encountered significant thrombotic and endocrine toxicity that appears out of proportion to what has been previously reported with thalidomide plus dexamethasone alone. Furthermore, aspirin thromboprophylaxis at daily doses of 81–325 mg appears suboptimal in preventing thromboembolic events in this group of patients when prescribed this regimen.

Final Results from the Phase IIa Study of the Anti-CXCL12 Spiegelmer® Olaptesed Pegol (NOX-A12) in Combination with Bortezomib and Dexamethasone in Patients with Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2111-2111 ◽  
Author(s):  
Heinz Ludwig ◽  
Katja Weisel ◽  
Maria Teresa Petrucci ◽  
Xavier Leleu ◽  
Anna Maria Cafro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Dose ◽  
High Risk ◽  
Partial Response ◽  
Plasma Cells ◽  
Progression Free Survival ◽  
M Protein ◽  
Dose Titration ◽  
Free Survival ◽  
Protein Change

Abstract Background Olaptesed, an L-stereo-isomer RNA aptamer, binds and neutralizes the chemokine CXCL12. By interaction with the chemokine receptors CXCR4 and CXCR7, CXCL12 is responsible for trafficking and homing of normal and malignant blood cells to the bone marrow. Preclinical studies have shown synergistic activity of CXCL12-targeting and anti-myeloma agents, specifically bortezomib (BTZ). Thus, targeting the myeloma niche may increase treatment efficacy. Aims This open label single arm study was conducted to assess the activity and safety of olaptesed when added to the combination of BTZ and dexamethasone (DEX) in patients with relapsed / refractory multiple myeloma (MM). Patients and Methods Twenty-eight relapsed or refractory MM patients (males:females 14:14) were enrolled and treated according to a dose titration design. Olaptesed was administered intravenously at doses increasing from 1 mg/kg to 2 mg/kg and 4 mg/kg in cycles 1, 2 and 3, respectively, at 1 hour prior to bortezomib administration. During cycles 4 to 8, olaptesed was dosed at the highest individually titrated dose. BTZ (1.3 mg/m2) was given on days 1, 4, 8 and 11 as intravenous injection. Oral DEX (20 mg) was added on the day of and on the day after BTZ administration. Response was evaluated based on the uniform IMWG response criteria (Rajkumar SV et. al. Blood 2011; 117: 4691-5). Plasma cell mobilization was studied after a pilot dose of 1 to 4 mg/kg olaptesed administered to the initial 10 patients before start of the regular treatment regimen. Results From Aug 2012 to Feb 2014 we enrolled 28 patients who had received a median of 2 (range 1-6) lines of prior therapy. Pretreatments were lenalidomide (LEN) in 20, BTZ in 14 and carfilzomib in 1 patient. Ten patients had autologous stem cell transplantations prior to entering this study. The patient population enrolled presented predominantly with advanced disease and with adverse outcome predictors. Ten patients had ISS stage III. High-risk cytogenetics were identified in 9 of the 20 patients (45%) with FISH testing available for t(4;14), t(14;16) and/or del17p. Eleven patients were refractory to their last prior treatment, which contained BTZ in 8 cases. After two early withdrawals, 26 patients were available for outcome evaluations. The median number of completed cycles was 8. Progression led to treatment termination in 8 patients. The dose of olaptesed was titrated to 4 mg/kg in all 18 patients treated for 3 or more cycles. The single dose of olaptesed administered to 10 pilot-patients effectively mobilized plasma cells, which increased by approximately 200% for up to 3 days. Based on “best response” of the 26 evaluable patients, the overall response rate was 73%: Two patients (8%) achieved a complete response (CR), 6 patients (23%) a very good partial response (VGPR) and 11 patients (42%) a partial response (PR). Minimal response was recorded in 2 patients (8%), 4 patients (15%) had stable disease and 1 patient (4%) progressive disease. In the 9 evaluable patients with high-risk cytogenetics, the clinical responses were similar. The ORR was 67% with VGPR in 3 (33%) and PR in 3 (33%) patients. Of the 14 patients pre-treated with BTZ, 1 had a CR and 8 a PR (ORR 64%). M-protein decreased rapidly from treatment cycle 1 to cycle 4 with a decrease of ≥50% being observed in 15 of the 26 evaluable patients. Figure 1 shows a waterfall plot of the maximum observed decrease in M-protein. Figure 1: Waterfall Plot of Maximum M-Protein Change Figure 1:. Waterfall Plot of Maximum M-Protein Change Median progression-free survival (PFS) of the evaluable population was 6.5 months. It was also 6.5 months in the 9 patients with high-risk cytogenetics and 6.3 months in the 14 patients pre-treated with BTZ (Figure 2). The median follow-up was 6.3 months. Figure 2: Progression-Free Survival Figure 2:. Progression-Free Survival Treatment with olaptesed in combination with BTZ-DEX was safe and well tolerated without any appreciable increase in adverse events. Conclusions A single dose of olaptesed effectively mobilized plasma cells. Olaptesed in combination with BTZ and DEX resulted in an ORR rate of 73% and PFS of 6.5 months. Response rates and PFS were similar in patients with or without high risk cytogenetic features or with or without previous exposure to BTZ. The combination regimen was well tolerated. These findings merit further exploration of this strategy in randomized trials. Disclosures Weisel: NOXXON Pharma AG: Consultancy. Petrucci:Celgene: Honoraria; Jannsen-Cilag: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria. Leleu:Janssen, Celgene, leopharma, Takeda, Amgen, Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Laurent:Bristol-Myers Squibb: Honoraria. Kruschinski:NOXXON Pharma AG: Employment. Dümmler:NOXXON Pharma AG: Employment. Riecke:NOXXON Pharma AG: Employment. Engelhardt:NOXXON Pharma AG: Consultancy.

scholarly journals Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma

Blood ◽  
2016 ◽  
Vol 127 (6) ◽  
pp. 681-695 ◽  
Author(s):  
Niels W. C. J. van de Donk ◽  
Philippe Moreau ◽  
Torben Plesner ◽  
Antonio Palumbo ◽  
Francesca Gay ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Plasma Cells ◽  
Blood Compatibility ◽  
Single Agent ◽  
Progression Free Survival ◽  
Complete Response ◽  
Therapeutic Antibody ◽  
Drug Discontinuation ◽  
Therapeutic Antibodies

AbstractImmunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pretreated MM, and preliminary results from studies with relapsed/refractory patients have shown enhanced therapeutic efficacy when daratumumab and isatuximab are combined with other agents. Furthermore, although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotuzumab is added to lenalidomide-dexamethasone or bortezomib-dexamethasone. Importantly, there has been no significant additive toxicity when these monoclonal antibodies are combined with other anti-MM agents, other than infusion-related reactions specific to the therapeutic antibody. Prevention and management of infusion reactions is important to avoid drug discontinuation, which may in turn lead to reduced efficacy of anti-MM therapy. Therapeutic antibodies interfere with several laboratory tests. First, interference of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting antibodies, interfere with blood compatibility testing and thereby complicate the safe release of blood products. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates daratumumab interference with transfusion laboratory serologic tests. Finally, therapeutic antibodies may complicate flow cytometric evaluation of normal and neoplastic plasma cells, since the therapeutic antibody can affect the availability of the epitope for binding of commercially available diagnostic antibodies.

scholarly journals Association of loss of spleen visualization on whole-body diffusion-weighted imaging with prognosis and tumor burden in patients with multiple myeloma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Toshiki Terao ◽  
Youichi Machida ◽  
Ukihide Tateishi ◽  
Takafumi Tsushima ◽  
Kentaro Narita ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Diffusion Weighted Imaging ◽  
Plasma Cells ◽  
Progression Free Survival ◽  
Myeloma Cell ◽  
Extramedullary Hematopoiesis ◽  
Tumor Burden ◽  
Whole Body ◽  
Diffusion Weighted ◽  
Worse Prognosis

AbstractThis study investigated the clinical significance of loss of spleen visualization (LSV) on whole-body diffusion-weighted imaging (WB-DWI) in patients with multiple myeloma (MM). The WB-DWI of 96 patients with newly diagnosed MM (NDMM) and 15 patients with smoldering MM (sMM) were retrospectively reviewed. LSV was observed in 56 patients with NDMM (58.3%) and 1 patient with sMM (6.7%). Patients with NDMM with LSV had a higher median infiltration of bone marrow plasma cells (80.0% vs. 50.0%, p < 0.001) and median total diffusion volume (median; 540.2 vs. 137.0 mL, p = 0.003) than patients without LSV. Patients with LSV had a lower spleen-to-spinal cord ratio (0.36 vs. 0.96, p < 0.001) and worse 2-year overall survival (OS) (84.6% vs. 100%, p = 0.032). Patients who did not recover spleen visualization during treatment had a worse prognosis, even when they obtained very good partial response (median progression-free survival: 13.2 months). Spleen histopathological findings revealed higher cellularity and diffuse myeloma cell infiltration in a patient with LSV and splenic amyloidosis without extramedullary hematopoiesis in a patient without LSV. Therefore, LSV indicates worse prognosis for patients with MM, even when the patient responds to treatment. Further studies are warranted to clarify the immunological role of spleen in MM.

Phase II Randomized Trial of Bevacizumab Versus Bevacizumab and Thalidomide for Relapsed/Refractory Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2571-2571 ◽  
Author(s):  
George Somlo ◽  
William Bellamy ◽  
Todd M. Zimmerman ◽  
Paul Frankel ◽  
Joe Tuscano ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplant ◽  
Plasma Cells ◽  
Progression Free Survival ◽  
Staining Intensity ◽  
Cell Transplant ◽  
Myeloma Cells ◽  
Anti Vegf ◽  
Grade 3

Abstract Vascular endothelial growth factor (VEGF) plays a seminal role in neo-angiogenesis. VEGF is present on myeloma cells, and its receptors, VEGFR1 (Flt-1) and VEGFR2 (KDR) are detectable on the surface of neighboring myeloid and monocytic elements. Hence, VEGF is implicated in the pathogenesis of multiple myeloma (MM). Thalidomide, an important agent in the treatment of MM, among its many postulated mechanisms of actions also inhibits VEGF-mediated neo-angiogenesis. We set out to test the feasibility and explore the efficacy of combining an anti-VEGF agent with thalidomide. With the availability of the anti-VEGF antibody rhuMAB bevacizumab, a trial of bevacizumab 10 mg/kg given intravenously every 2 weeks alone (in thalidomide-exposed patients) versus a randomized comparison of bevacizumab +/− thalidomide 50–400 mg/day (in thalidomide naive patients) was initiated by the California Cancer Consortium. Twelve patients (median age:58 years; range:50–75) with initial stages of I (n:2), II (n:2) and III (n: 8), all with refractory MM have been enrolled. Patients received a median of 1 prior regimen (range:0–5). Six patients had failed an autologous stem cell transplant prior to enrollment. In patients who have received bevacizumab alone, grade 3 toxicities included fatigue and neutropenia (1), hypertension (1), and hyponatremia (1). In the group receiving bevacizumab and thalidomide, grade 3 lymphopenia was observed in 1 patient during cycle 3, and one patient was taken off study due to exacerbation of pre-exisiting (diet pill induced) pulmonary hypertension and was considered inevaluable. Median time to progression for the 6 patients treated with bevacizumab alone was 2 (range 1–4) months. Progression-free survival for the 5 evaluable patients treated with bevacizumab and thalidomide is 6 +, 7, 8 +, 10, and 30 + months, with 2 patients still on study and in response. Two of these patients did not progress but were taken off study (one for patient’s choice, and one due to the physician’s choice to pursue a stem cell transplant at 7.5 months, this patient is listed above as in response at 30 + months). Immunohistochemical staining (IHC) revealed 2 + to 4 + expression of VEGF on myeloma cells in 7 cases of the available 8 pre-treatment bone marrow samples. Weak staining (1+) of VEGFR1 was observed on the surface of myeloma cells in 5 cases. VEGFR2 expression was also observed on plasma cells by IHC (1+ to 2+) in 5 cases. Myeloma cells from a patient treated with bevacizumab alone for a duration of 4 months, and from a patient receiving bevacizumab and thalidomide for 7.5 months before going on to transplant, demonstrated the strongest staining intensity for VEGF. Due to slow accrual the study had been closed to accrual, although 2 patients continue on the bevacizumab and thalidomide arm. However, in light of our findings further testing of bevacizumab, preferably in combination with other active agents is warranted. Supported by NO1 CM 17101.

OSU03012, a Novel Celecoxib Derivative, Induces Apoptosis in Multiple Myeloma Cells Independently of Caspase Activation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5075-5075
Author(s):  
Shuhong Zhang ◽  
Valerie L. White ◽  
Amy Johnson ◽  
Ching-Shih Chen ◽  
Sherif S. Farag
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Cell Lines ◽  
Plasma Cells ◽  
Parp Cleavage ◽  
Caspase Inhibitor ◽  
High Concentration ◽  
Down Regulation ◽  
Vitro Effect

Abstract Multiple myeloma (MM) is a clonal disorder affecting terminally differentiated B cells, with the accumulation of plasma cells in the bone marrow. Previous studies showed that OSU03012 is a novel celecoxib derivative lacking cyclooxygenase-2 inhibitory activity that induces apoptosis in various types of cancer cells and is being developed as an anti-cancer therapy in the NCI Rapid Access to Intervention Therapy (RAID). Here, we examined the in vitro effect of OSU03012 in MM cell lines (U266, ARH-77, IM-9 and RPMI8226). Cytotoxicity data indicated that mean LC50 (lethal concentration 50%) of OSU03012 was 6.25±0.86 μM at 24 hours and 4.23±0.87 μM at 72 hours in these four cell lines. Using annexin V/PI (propidium iodide) flow cytometry assay, OSU03012 was shown to induce apoptosis in MM cells. OSU03012 activated caspases-8, -9, and -3, induced PARP (POLY ADP-RIBOSE Polymerase) cleavage, and reduced survivin and XIAP expression after 6 and 24 hour exposure. Although the caspase inhibitor Q-VD-OPH treatment strongly blocked OSU03012-induced PARP cleavage, it did not inhibit OSU03012-induced apoptosis of MM cells. The pan-caspase inhibitor z-VAD-fmk did not prevent OSU03012 mediated cell death. Cell death with OSU03012 treatment was associated with significant down-regulation of phospho-Akt. Several substrates of AKT, including phospho-GSK-3 beta (Ser9), phospho-FoxO1a (Ser256) and phospho-MDM2 (Ser166) were also down-regulated by OSU03012 drug. OSU03012 triggered both early (6h) and late (24h) down-regulation of cyclin D1 expression, but cyclin A and B1 expression was down-regulated only at 24h. There was no induction of p21 or p27 protein levels by OSU03012. After 24-hour exposure, low concentration (1–5 μM) OSU03012 arrested MM cell lines in the G1 phase of the cell cycle while high concentration (10 μM) OSU03012 induced G2 phase arrested. OSU03012 decreased both phospho-Stat3 (Ser727) and Stat3 expression. OSU03012 has on effect on phosphorylated MAP kinase kinase1/2 (pMEK1/2) but it decreased MEK1/2 expression at 24h. The expression levels of Bcl-2 family proteins, Bcl-2, Mcl-1, BAX, and BIM did not alter with OSU03012 treatment suggesting that Bcl-2 members may not play direct or significant roles in inducing cell death. Taken together, we conclude that OSU03012 is potently active against MM cells by predominantly caspase-independent mechanisms, and may involve downstream pathways consequent to phopho-Akt down-regulation. These studies provide preclinical rationale for investigating OSU03012 in the treatment of MM.

Incorporation of Thalidomide-Dexamethasone (Thal-Dex) into up-Front Double Autologous Stem-Cell Transplantation (ASCT) for multiple Myeloma: Final analysis of phase II “Bologna 2002” Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 349-349
Author(s):  
Elena Zamagni ◽  
Nicoletta Testoni ◽  
Carolina Terragna ◽  
Paola Tacchetti ◽  
Chiara Nicci ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Induction Therapy ◽  
Plasma Cells ◽  
Final Analysis ◽  
Disease Stage ◽  
High Dose ◽  
Short Term ◽  
Cytogenetic Abnormalities ◽  
Intention To Treat

Abstract Abstract 349 We report here on the final analysis of the multicenter phase II “Bologna 2002” study which incorporated thal-dex into double ASCT with high-dose melphalan (200 mg/m2) as front-line therapy for younger patients with symptomatic multiple myeloma (MM). By study design, thal (200 mg/day) and pulsed low-dose dex (160 mg/month, with two added 4-day courses on the first and third cycle of induction therapy) were administered from the outset until the second ASCT. The analysis was performed on an intention-to-treat basis on a total of 357 patients who were followed for a median of 43 months. Their median age was 57 years, 86% had advanced disease stage. More than 80% of the patients were screened at diagnosis for the presence of cytogenetic abnormalities (FISH) on CD138+ bone marrow plasma cells, including del(13q) (45%), t(4;14) (14%) and del(17p) (6%). The rate of at least VGPR increased from 31% after thal-dex induction therapy to 60% after the second ASCT. The final CR rate was 33% for all the patients and 44% for those who actually received pre planned double ASCT. Median TTP and PFS were 68 and 47 months, respectively, with 5-year projected rates of 45% and 33%. The 5-year projected OS rate was 65%. TRM after the first and second ASCT was 0.5% and 2%, respectively. Median OS after relapse or progression was 30 months, suggesting that short-term thal exposure had no adverse influence on response to salvage therapies. The quality of response following ASCT(s) influenced clinical outcomes. In particular, patients achieving CR had significantly longer PFS and OS than patients in VGPR (PFS: median 68 vs 48 months, respectively, P=0.04; 5-year projected OS 84% vs 72%, respectively, P=0.02). Similarly, patients in VGPR had better outcomes compared with patients achieving PR (P=0.02 and 0.04 for PFS and OS comparisons, respectively). In a multivariate analysis, best response (at least VGPR) ever achieved and low beta2-m were the most important variables significantly extending TTP (P=0.04), PFS (P=0.000) and OS (P=0.003). Additional variables predicting for prolonged PFS were the absence of del(13q) (P=0.002) and del(17p) with or without t(4;14)(P=0.03). OS was favourably influenced also by IgG isotype (P=0.04) and absence of high-risk cytogenetic abnormalities [del (17p) +/- t(4;14)(P=0.03)]. A case match comparison of 135 patients enrolled in “Bologna 2002” study with an equal number of pair mates included in the previous “Bologna 96” study of double ASCT without thal confirmed the benefits from the addition of thal-dex to double autotransplantation in terms of rate (P=0.001) and duration (p<0.001) of at least VGPR, TTP (P<0.001) and PFS (P=0.001). In conclusion, attainment of CR and VGPR was a major determinant of favorable outcomes for patients treated with thal-dex and double ASCT. Poor prognosis conferred by del(13q) and del (17p)+/- t(4;14) was not overcome by thalidomide, consistently with previous data reported in refractory MM patients and with thal as maintenance therapy after double ASCT. Short-term thal therapy, as applied in “Bologna 2002” study, was generally well tolerated, with limited toxicities leading to less than 10% discontinuation rate due to drug-related adverse events, and had no adverse impact on OS after relapse. Disclosures: Off Label Use: Thalidomide was incorporated into up-front treatment for patients with newly diagnosed multiple myeloma.

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