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E Terpos,
M A Dimopoulos,
O Sezer,
D Roodman,
N Abildgaard, R Vescio,
P Tosi,
R Garcia-Sanz,
F Davies,
A Chanan-Khan,
A Palumbo,
P Sonneveld,
M T Drake,
J-L Harousseau,
K C Anderson,
B G M Durie
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ABSTRACT: Lytic bone disease is a frequent complication of multiple myeloma (MM). Lytic lesions rarely heal and X-rays are of limited value in monitoring bone destruction during anti-myeloma or anti-resorptive treatment. Biochemical markers of bone resorption (amino- and carboxy-terminal cross-linking telopeptide of type I collagen (NTX and CTX, respectively) or CTX generated by matrix metalloproteinases (ICTP)) and bone formation provide information on bone dynamics and reflect disease activity in bone. These markers have been investigated as tools for evaluating the extent of bone disease, risk of skeletal morbidity and response to anti-resorptive treatment in MM. Urinary NTX, serum CTX and serum ICTP are elevated in myeloma patients with osteolytic lesions and correlate with advanced disease stage. Furthermore, urinary NTX and serum ICTP correlate with risk for skeletal complications, disease progression and overall survival. Bone markers have also been used for the early diagnosis of bone lesions. This International Myeloma Working Group report summarizes the existing data for the role of bone markers in assessing the extent of MM bone disease and in monitoring bone turnover during anti-myeloma therapies and provides information on novel markers that may be of particular interest in the near future.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2010; 24(10):1700-12. · 8.30 Impact Factor
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R A Kyle,
B G M Durie,
S V Rajkumar,
O Landgren,
J Blade,
G Merlini,
N Kröger,
H Einsele,
D H Vesole,
M Dimopoulos, [......],
P Sonneveld,
S Pavlovsky,
A Palumbo,
P G Richardson,
B Barlogie,
P Greipp, R Vescio,
I Turesson,
J Westin,
M Boccadoro
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ABSTRACT: Monoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is approximately 1% per year. Low-risk MGUS is characterized by having an M protein <15 g/l, IgG type and a normal free light chain (FLC) ratio. Patients should be followed with serum protein electrophoresis at six months and, if stable, can be followed every 2-3 years or when symptoms suggestive of a plasma cell malignancy arise. Patients with intermediate and high-risk MGUS should be followed in 6 months and then annually for life. The risk of smoldering (asymptomatic) multiple myeloma (SMM) progressing to multiple myeloma or a related disorder is 10% per year for the first 5 years, 3% per year for the next 5 years and 1-2% per year for the next 10 years. Testing should be done 2-3 months after the initial recognition of SMM. If the results are stable, the patient should be followed every 4-6 months for 1 year and, if stable, every 6-12 months.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2010; 24(6):1121-7. · 8.30 Impact Factor
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M A Hussein,
F D Vrionis,
R Allison,
J Berenson,
S Berven,
E Erdem,
S Giralt,
S Jagannath,
R A Kyle,
S Legrand,
R Pflugmacher,
N Raje,
S V Rajkumar,
R L Randall,
D Roodman,
D Siegel, R Vescio,
J Zonder,
B G M Durie
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2008; 22(8):1649. · 8.30 Impact Factor
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M A Hussein,
F D Vrionis,
R Allison,
J Berenson,
S Berven,
E Erdem,
S Giralt,
S Jagannath,
R A Kyle,
S LeGrand,
R Pflugmacher,
N Raje,
S V Rajkumar,
R L Randall,
L Randall,
D Roodman,
D Siegel, R Vescio,
J Zonder,
B G M Durie
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2008; 22(8):1479-84. · 8.30 Impact Factor
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ABSTRACT: Increased nuclear factor (NF)-kappaB activity is associated with enhanced tumor cell survival in multiple myeloma (MM). The function of NF-kappaB is inhibited through binding to its inhibitor, IkappaB. Release of activated NF-kappaB follows proteasome-mediated degradation of IkappaBalpha resulting from phosphorylation of the inhibitor and finally conjugation with ubiquitin. We report that myeloma tumor cells show enhanced NF-kappaB activity. In addition, these patients possess polymorphisms of IkappaBalpha at sites important in the degradation of the inhibitor protein. Exposure of myeloma cells to chemotherapy leads to an increase in IkappaBalpha phosphorylation and reduces the levels of this inhibitor of NF-kappaB function. Chemoresistant myeloma cell-lines have increased NF-kappaB activity compared to sensitive lines. An inhibitor of NF-kappaB activity, the proteasome inhibitor PS-341 (Millenium Inc, Boston, MA), showed consistent antitumor activity against chemoresistant and sensitive myeloma cells. The sensitivity of chemoresistant myeloma cells to chemotherapeutic agents was markedly increased (100,000- to 1,000,000-fold) when combined with a noncytotoxic dose of PS-341. In contrast, this combination had little growth inhibitory effect on normal hematopoietic cells. Similar effects were observed using a dominant negative super-repressor for IkappaBalpha. These results suggest that inhibition of NF-kappaB with PS-341 may overcome chemoresistance and allow doses of chemotherapeutic agents to be markedly reduced with antitumor effects without significant toxicity.
Seminars in Oncology 01/2002; 28(6):626-33. · 3.50 Impact Factor
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A K Stewart, R Vescio,
G Schiller,
O Ballester,
S Noga,
H Rugo,
C Freytes,
E Stadtmauer,
S Tarantolo,
F Sahebi, [......],
R Schlossman,
R Brown,
H Tully,
M Benyunes,
C Jacobs,
R Berenson,
M White,
J DiPersio,
K C Anderson,
J Berenson
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ABSTRACT: Although high-dose chemotherapy supported by autologous peripheral-blood progenitor-cell (PBPC) transplantation improves response rates and survival for patients with multiple myeloma, all patients eventually develop progressive disease after transplantation. It has been hypothesized that depletion of malignant plasma cells from autografts may improve outcome by reducing infused cells contributing to relapse.
A randomized phase III study using the CEPRATE SC System (Cellpro, Bothell, WA) to enrich CD34(+) autograft cells and passively purge malignant plasma cells was completed in 190 myeloma patients randomized to receive an autograft of CD34-selected or unselected PBPCs.
After CD34 selection, tumor burden was reduced by 1.6 to 6.0 logs (median, 3.1), with 54% of CD34-enriched products having no detectable tumor. Median time to count recovery, number of transfusions, transplantation-related mortality, and days in hospital were equivalent between the two transplantation arms. With a median follow-up of 37 months, 33 patients (36%) in the selected and 34 patients (35%) in the unselected arm had died (P =.784). Median overall survival in the selected arm was reached at 50 months and is not reached at this time in the unselected arm (P =.78). Median disease-free survival was 100 versus 104 weeks (P =.82), with 67% of patients in the selected arm and 66% of patients in the unselected arm relapsing.
This phase III trial demonstrates that although CD34 selection significantly reduces myeloma cell contamination in PBPC collections, no improvement in disease-free or overall survival was achieved.
Journal of Clinical Oncology 10/2001; 19(17):3771-9. · 18.37 Impact Factor
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M Beksac,
M Ma,
C Akyerli,
M DerDanielian,
L Zhang,
J Liu,
M Arat,
N Konuk,
H Koc,
T Ozcelik, R Vescio,
J R Berenson
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ABSTRACT: In order to investigate the frequency of HHV-8 in MM patients from another geographic location, we obtained fresh bone marrow (BM) biopsies from Turkish patients with MM (n = 21), monoclonal gammopathy of undetermined significance (MGUS) (n = 2), plasmacytoma (n = 1) with BM plasma cell infiltration, various hematological disorders (n = 6), and five healthy Turkish controls. The frequency of HHV-8 was analyzed by polymerase chain reaction (PCR) in two independent laboratories in the USA and in Turkey. Using fresh BM biopsies, 17/21 MM patients were positive for HHV-8 whereas all five healthy controls, and six patients with other hematological disorders were negative. Two patients with MGUS, and one patient with a solitary plasmacytoma were also negative. The data from the two laboratories were completely concordant. Also using primer pairs for v IRF and v IL-8R confirmed the results observed with the KS330233 primers. Furthermore, sequence analysis demonstrated a C3 strain pattern in the ORF26 region which was also found in MM patients from the US. Thus, HHV-8 is present in the majority of Turkish MM patients, and the absence of the virus in healthy controls further supports its role in the pathogenesis of MM.
Leukemia 09/2001; 15(8):1268-73. · 9.56 Impact Factor
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ABSTRACT: Bone metastases typically are associated with osteolytic bone destruction, resulting in bone pain, pathologic fractures, spinal cord compression, and hypercalcemia. Bisphosphonates are potent inhibitors of normal and pathologic bone resorption and represent a significant therapeutic improvement in the management of patients with lytic bone metastases. Zoledronic acid is a new-generation, highly potent, nitrogen-containing bisphosphonate that to the authors knowledge is the most potent inhibitor of bone resorption currently in clinical trials. The objectives of the current study were to assess the safety and tolerability of increasing doses of zoledronic acid and to determine its activity with respect to reducing biochemical markers of bone resorption in cancer patients with bone metastases.
Forty-four cancer patients with bone metastases or primary bone lesions were enrolled sequentially into 1 of 5 fixed ascending-dose treatment groups. Each patient received a single intravenous bolus injection of 1, 2, 4, 8, or 16 mg of zoledronic acid over 30-60 seconds. Patients were monitored for 8 weeks for the evaluation of clinical findings, adverse events, vital signs, electrocardiograms, markers of bone resorption, and urinary N-acetyl-beta-D-glucosaminidase.
Zoledronic acid was safe and well tolerated at all dose levels tested. Commonly reported adverse events included bone pain, fever, anorexia, constipation, and nausea, which were experienced by a similar proportion of patients in each treatment group. Seven patients reported serious adverse events, none of which appeared to be related to the study drug. Zoledronic acid effectively suppressed biochemical markers of bone resorption, including the highly specific markers N-telopeptide and deoxypyridinoline, for up to 8 weeks in the 2-16-mg dose groups and for a shorter duration in the 1-mg group.
In the current study, zoledronic acid was safe and well tolerated and demonstrated potent inhibition of bone resorption. The authors believe it may improve the treatment of metastatic bone disease.
Cancer 02/2001; 91(1):144-54. · 4.77 Impact Factor
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Blood 09/2000; 96(3):1194. · 9.90 Impact Factor
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ABSTRACT: Without a randomized trial any benefit of purging on patient survival will remain theoretical. Although molecular techniques may document that the autograft tumor burden is substantial when compared with the patient tumor load following conditioning therapy, a theoretical benefit may not be sufficient to persuade third-party payers to expend additional money for the purging procedure. For insurers, the equation to determine product usefulness does not consider risk as the only negative component, but a combination of risk and cost. When the amount that can be spent is limited, a demonstration that these additional costs will garner a true patient benefit becomes more important. Because it is difficult to assign a dollar amount for a theoretical benefit, third-party payers may be unwilling to accept the potential but unproven benefit from a purging procedure. Nevertheless, if the time to engraftment remains unchanged, the added costs of the purging procedure should be relatively minimal and, in the authors' view, should not be a major impediment to its widespread use. Educated patients and physicians will probably demand that these procedures be performed in cases where autograft purging adds little if any risk and provides at least a significant potential for benefit.
Hematology/Oncology Clinics of North America 11/1999; 13(5):969-86. · 2.64 Impact Factor
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R Vescio,
G Schiller,
A K Stewart,
O Ballester,
S Noga,
H Rugo,
C Freytes,
E Stadtmauer,
S Tarantolo,
F Sahebi, [......],
J Meharchard,
R Schlossman,
R Brown,
H Tully,
M Benyunes,
C Jacobs,
R Berenson,
J DiPersio,
K Anderson,
J Berenson
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[hide abstract]
ABSTRACT: High-dose chemotherapy followed by autologous transplantation has been shown to improve response rates and survival in multiple myeloma and other malignancies. However, autografts frequently contain detectable tumor cells. Enrichment for stem cells using anti-CD34 antibodies has been shown to reduce autograft tumor contamination in phase I/II studies. To more definitively assess the safety and efficacy of CD34 selection, a phase III study was completed in 131 multiple myeloma patients randomized to receive an autologous transplant with either CD34-selected or unselected peripheral blood progenitor cells after myeloablative therapy. Tumor contamination in the autografts was assessed by a quantitative polymerase chain reaction detection assay using patient-specific, complementarity-determining region (CDR) Ig gene primers before and after CD34 selection. A median 3.1 log reduction in contaminating tumor cells was achieved in the CD34 selected product using the CEPRATE SC System (CellPro, Inc, Bothell, WA). Successful neutrophil engraftment was achieved in all patients by day 15 and no significant between-arm difference for time to platelet engraftment occurred in patients who received an infused dose of at least 2.0 x 10(6) CD34(+) cells/kg. In conclusion, this phase III trial demonstrates that CD34-selection of peripheral blood progenitor cells significantly reduces tumor cell contamination yet provides safe and rapid hematologic recovery for patients receiving myeloablative therapy.
Blood 04/1999; 93(6):1858-68. · 9.90 Impact Factor
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Y Tu,
S Renner,
F Xu,
A Fleishman,
J Taylor,
J Weisz, R Vescio,
M Rettig,
J Berenson,
S Krajewski,
J C Reed,
A Lichtenstein
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ABSTRACT: Because murine myeloma plasma cells and normal human lymph node plasma cells express BCL-X, we evaluated BCL-X expression in malignant human plasma cells. BCL-X expression was detected in several human myeloma cell lines, as well as in CD38-sorted bone marrow cells obtained from some patients. Only the antiapoptotic long form of BCL-X (BCL-X-L), was detected. Because BCL-X-L expression can protect tumor cells from apoptotic death induced by chemotherapeutic agents, we tested the clinical relevance of expression in 55 archival bone marrow biopsies. The biopsies were stained by immunohistochemistry, and BCL-X expression was correlated with the subsequent response to treatment. BCL-X expression in malignant plasma cells strongly correlated with decreased response rates in patient groups treated with either melphalan and prednisone or vincristine, Adriamycin, and dexamethasone. Response rates were 83-87% in non-BCL-X-expressing cases and 20-31% in BCL-X-expressing cases. In addition, BCL-X expression was more frequent in specimens taken from patients at relapse (77%), when compared to those at initial diagnosis (29%). Further support for the association of drug resistance with BCL-X-L expression came from studies of the 8226 dox-40 cell line. This line, which expresses p-glycoprotein and serves as a model of multidrug resistance in multiple myeloma cells, demonstrated an up-regulated expression of BCL-X-L, which was relatively specific, in that BCL-2 or BAX expression was not altered. In addition, dox-40 cells demonstrated a generalized resistance to apoptosis that was induced by several different agents. These results indicate that malignant plasma cells can express BCL-X-L and that such expression may be a marker of chemoresistant disease.
Cancer Research 02/1998; 58(2):256-62. · 7.86 Impact Factor
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G Schiller, R Vescio,
C Freytes,
G Spitzer,
M Lee,
C H Wu,
J Cao,
J C Lee,
A Lichtenstein,
M Lill,
R Berenson,
J Berenson
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ABSTRACT: Fifty-five patients with advanced multiple myeloma received purified CD34-selected peripheral blood progenitor cell transplants following myeloablative chemotherapy. A median of 4.1 x 10(6) CD34 cells/kg (range 1.2-30.7) were infused after busulfan (14 mg/kg) and cyclophosphamide (120 mg/kg); granulocyte-macrophage colony-stimulating factor was used until hematopoietic recovery. Median time to neutrophils >0.5 x 10(9)/l and platelets >20 x 10(9)/l were 12 days (range 10-16 and 8-184 days, respectively). Median follow-up of survivors from the time of transplantation is 33 months (range 7 to 44 months). Thirty-one patients are alive, 19 progression-free. Median progression-free survival is 14 months. Actuarial 3-year progression-free and overall survival are 29+/-14% and 47+/-17%. CD34-selection of peripheral blood progenitor cells provides effective hematopoietic support with significant progression-free and overall survival.
Bone Marrow Transplantation 01/1998; 21(2):141-5. · 3.75 Impact Factor
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ABSTRACT: Pamidronate is a second-generation bisphosphonate that undergoes negligible biodegradation and is eliminated exclusively by renal excretions. Nineteen cancer patients were stratified according to baseline creatinine clearance (Clcr): group I, Clcr > 90 mL/min (n = 6); group II, Clcr 61 mL/min to 90 mL/min (n = 6); group III, Clcr 30 mL/min to 60 mL/min (n = 3); group IV, Clcr < 30 mL/min (n = 4). All patients received a single, 90-mg dose of pamidronate disodium administered in a 4-hour intravenous infusion. Plasma and urine samples were collected at intervals up to 36 and 120 hours, respectively, after the start of infusion and were assayed for pamidronate, using validated high-performance liquid chromatography. Pamidronate's pharmacokinetics were characterized by a short distribution phase (2-3 hours) followed by rapid elimination of the drug in urine. Elimination of pamidronate was slower in patients in group IV with a mean +/- standard deviation area under the plasma concentration-time curve (AUC0-36) of 19.0 +/- 4.60 micrograms.hr/mL compared with 8.1 +/- 3.13 micrograms.hr/mL in patients in group I. A linear relationship in Clcr was observed for AUC0-36 (r = 0.67), urinary excretion (r = 0.69), and renal clearance (r = 0.81). Renal clearance was proportional to Clcr for patients in all four renal-function groups. In the treatment of bone metastases of malignancy, successive doses of pamidronate are generally separated by weeks; thus, plasma accumulation in patients with renal impairment is not expected to be clinically relevant. A reduction in dose of pamidronate disodium should not be necessary in cancer patients with renal impairment.
The Journal of Clinical Pharmacology 04/1997; 37(4):285-90. · 2.91 Impact Factor
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ABSTRACT: To study the structural integrity of the cyclin-dependent kinase inhibitors known as INK4A (p16), INK4B (p15) and INK4C (p18) in multiple myeloma, we examined 20 primary myeloma samples (including one case of plasma cell leukaemia) using polymerase chain reaction-single strand conformation polymorphism, and 17 samples were examined by Southern blot analysis. The plasma cell leukaemia sample had homozygous deletions of the p15 and p16 genes (6%). One myeloma case had a p15 gene homozygous deletion (6%) with an intact p16 gene. This sample also had a p18 homozygous deletion, suggesting that the deletion of both genes may be important in either the development or progression of myeloma. No point mutations of these INK4 genes were found in the 20 samples. This is the first report that indicates that deletions of p15, p16 and p18 genes occur in some individuals with multiple myeloma (2/17 cases).
British Journal of Haematology 02/1997; 96(1):98-102. · 4.94 Impact Factor
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ABSTRACT: Enhanced expression of the antiapoptotic gene BCL-2 may participate in chemoresistance. To ascertain if multiple myeloma cells surviving exposure to chemotherapy alter their BCL-2 expression, we treated the myeloma cell lines 8226, IM-9, and U266 as well as a primary myeloma cell culture with various injurious agents. Doxorubicin, etoposide, and hydrogen peroxide consistently induced a concentration- and time-dependent upregulation of BCL-2 expression in all myeloma target cell types assayed by flow cytometry and Western blot analysis. In contrast, serum starvation, dexamethasone, and anti-fas antibodies had no effect on expression. Enhanced expression of BCL-2 was relatively selective as treatments had no effect on expression of Ig light chains, BCL-X, or actin. An reverse transcriptase-polymerase chain reaction assay showed increased levels of BCL-2 RNA in 8226 cells as early as 4 hours after treatment with doxorubicin at a time when cell recoveries were not decreased. Thus, doxorubicin stimulates BCL-2 expression in individual 8226 cells rather than simply allowing a selected survival of high BCL-2-expressing cells in culture. Doxorubicin-treated 8226 cells with upregulated BCL-2 expression were relatively resistant to a second exposure of doxorubicin. In addition, BCL-2-transfected IM-9 cells, with enhanced expression of BCL-2 which was comparable to that achieved by initial exposure to doxorubicin, were resistant to doxorubicin and etoposide cytotoxicity. These data suggest that exposure to chemotherapeutic agents may enhance BCL-2 expression in surviving myeloma cells and contribute to acquired chemoresistance.
Blood 10/1996; 88(5):1805-12. · 9.90 Impact Factor
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ABSTRACT: Much progress has been made in delineating the pathogenesis of multiple myeloma and chronic lymphocytic leukemia. The cell of origin in both diseases has been better defined, which has led to important clinical treatments. For myeloma, reduction of tumor burden in autografts has been accomplished and been associated with favorable outcome. The importance of interleukin-6 in maintaining this tumor and causing skeletal disease has been more clearly defined and has led to treatment with antibodies that block this cytokine's action. The bisphosphonate pamidronate decreases skeletal complications and improves quality of life for these patients. For chronic lymphocytic leukemia, further definition of common cytogenetic and gene abnormalities have been made and associated with patient outcome. The nucleoside analogues continue to produce excellent responses and the use of myeloablative chemotherapy with hematopoietic support shows promise in early studies.
Current Opinion in Hematology 08/1996; 3(4):288-96. · 4.52 Impact Factor
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Current topics in microbiology and immunology 02/1996; 210:367-74. · 4.93 Impact Factor
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Annals of the New York Academy of Sciences 10/1995; 764:519-22. · 3.15 Impact Factor
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ABSTRACT: A major potential problem of autologous transplantation in the treatment of advanced malignancy is the infusion of tumor cells. A multi-institutional study of purified CD34-selected peripheral blood progenitor cell (PBPC) transplantation was conducted in 37 patients with advanced multiple myeloma receiving myeloablative chemotherapy. Fourteen days after intermediate-dose cyclophosphamide, prednisone, and granulocyte colony-stimulating factor (G-CSF), a median of 3 (range, 2 to 5) 10-L leukaphereses yielded 9.8 x 10(8)/kg (range, 3.7 to 28.3) mononuclear cells. The adsorbed (column-bound) fraction contained 5.9 x 10(6) cells/kg (range, 1.6 to 25.5) with 4.65 x 10(6) CD34 cells/kg (range, 1.2 to 23.3). Using Poisson distribution analysis of positive polymerase chain reactions with patient-specific complementarity-determining region 1 (CDR1) and CDR3 Ig-gene primers, tumor was detected in leukapheresis products from 8 to 14 unselected patients and ranged from 1.13 x 10(4) to 2.14 x 10(6) malignant cells/kg. After CD34 selection, residual tumor was detected in only three patients' products. Overall, a greater than 2.7- to 4.5-log reduction in contaminating multiple myeloma cells was achieved. CD34 PBPCs were infused 1 day after busulfan (14 mg/kg) and cyclophosphamide (120 mg/kg), and granulocyte-macrophage colony-stimulating factor was used until hematologic recovery. The median time to both neutrophil and platelet recovery was 12 days (range, 11 to 16 days and 9 to 52 days, respectively). The median number of erythrocyte and platelet transfusions was 7 (range, 2 to 37) and 3 (range, 0 to 85), respectively. Patients receiving fewer than 2 x 10(6) CD34 cells/kg had significantly prolonged neutropenia, thrombocytopenia, and an increased red blood cell and platelet transfusion requirement. Thus, CD34 selection of PBPCs markedly reduces tumor contamination in multiple myeloma and provides effective hematopoietic support for patients receiving myeloablative therapy.
Blood 08/1995; 86(1):390-7. · 9.90 Impact Factor
