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What's New in Research - October 15, 2002
10.15.02

Recovery of renal function after autologous stem cell transplantation in myeloma patients with end-stage renal failure.
Tauro S, Clark FJ, Duncan N, Lipkin G, Richards N, Mahendra P.
Bone Marrow Transplant Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK.
Bone Marrow Transplant 2002 Oct;30(7):471-3

Abstract
The disease-free survival of patients with myeloma and severe renal failure after high-dose melphalan and autologous stem cell rescue is similar to those with normal renal function at the time of the autograft. However, recovery of renal function after intensive treatment is uncommon and patients with end-stage renal failure continue to be dialysis-dependent. We report two patients with myeloma who required regular haemodialysis from diagnosis, but became dialysis-independent after a high-dose melphalan autograft. Thus, in some patients, renal function may be partially salvageable despite the requirement for dialysis at the time of autografting.


Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma.
Fassas AB, Spencer T, Sawyer J, Zangari M, Lee CK, Anaissie E, Muwalla F, Morris C, Barlogie B, Tricot G.
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Br J Haematol 2002 Sep;118(4):1041-7

Abstract
Complete or partial deletion of chromosome 13 or translocations involving 13q (Delta13) by conventional cytogenetic analysis confers a poor prognosis in multiple myeloma (MM) patients, even with timely application of tandem autologous transplants. It was recently suggested that the prognostic significance of Delta13 is related to its frequent association with hypodiploidy but by itself does not have a poor prognostic significance. We therefore analysed our experience in 1475 consecutive MM patients in whom we intended treatment with tandem transplants after a melphalan-based conditioning regimen. Patients with abnormal cytogenetic analysis were grouped into hypodiploid/hypotetraploid, pseudodiploid and hyperdiploid groups, according to their modal chromosome number. Their event-free and overall survival were compared with those of patients with a normalkaryotype. Both hypodiploidy and Delta13 were found to independently confer poor prognosis in MM patients. Furthermore, these parameters in combination with easily obtained pretransplant levels of beta-2 microglobulin and albumin define three groups of MM patients with clearly distinct outcomes.


Cytotoxic chemotherapy following tandem autotransplants in multiple myeloma patients.
Fassas AB, Spencer T, Desikan R, Zangari M, Anaissie E, Barlogie B, Tricot G.
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Br J Haematol 2002 Oct;119(1):164-8

High-dose treatment (HDT) with autologous stem cell transplant (ASCT) is superior to conventional chemotherapy in multiple myeloma. However, relapses eventually occur, especially in the presence of unfavourable cytogenetic abnormalities, high beta-2 microglobulin levels prior to transplant and extensive prior treatment. Cytotoxic consolidation chemotherapy, following tandem transplants (TT), was given to 75 myeloma patients with at least one poor prognostic factor. When their outcome was compared with that of 75 matched controls who received dexamethasone +/- interferon post TT, no event-free or overall survival advantage was observed. Other approaches may be required to improve survival in multiple myeloma.


Natural cytotoxicity to autologous antigen-pulsed dendritic cells in multiple myeloma.
Zheng C, Ostad M, Andersson M, Celsing F, Holm G, Sundblad A.
Division of Hematology, Centre for Molecular Medicine, Karolinska Institutet and Hospital, Stockholm, Sweden.
Br J Haematol 2002 Sep;118(3):778-85

Abstract
To analyse autologous lymphocyte cytolytic activities of potential importance for cell-based immunotherapy in multiple myeloma (MM), in vitro differentiated dendritic cells (DCs) loaded with patient-specific monoclonal immunoglobulin (mIg) were used as autologous target cellsin cytotoxicity assays. Effector populations consisted of purified natural killer (NK) cells (CD56+, CD3-) and T cells (CD3+). The MM patients' NK cells cultured in the presence of interleukin 2 (IL-2) showed pronounced cytotoxic activity towards autologous mature DCs. Autologous MM DC targets displayed similar susceptibility to NK cell lysis, compared with allogeneic control DC targets, despite high surface expression of self major histocompatibility complex (MHC) antigens. However, some degree of classic MHC class I-mediated negative regulation was implicated in the NK-DC interactions, as indicated by class I blocking experiments. NK-mediated lysis was also discerned towards primary autologous MM cells. The results indicated that the major effector mechanism was mediated through the perforin-granzyme exocytosis pathway. In conclusion, NK cells from MM patients displayed significant and consistent cytotoxicity towards autologous mature DCs, suggesting that innate immunity could be implicated in MM and may influence the outcome of the administration of tumour antigen-pulsed DCs in treatment trials.


Farnesyl transferase inhibitor R115777 induces apoptosis of human myeloma cells.
Le Gouill S, Pellat-Deceunynck C, Harousseau JL, Rapp MJ, Robillard N, Bataille R, Amiot M.
Institut National de la Sante et de la Recherche Medicale Unite 463, Institut de Biologie, Nantes, France.
Leukemia 2002 Sep;16(9):1664-7

Abstract
R115777, a nonpeptidomimetic farnesyl transferase inhibitor has recently demonstrated a significant antileukemic activity in vivo in acute myeloid leukemia. Multiple myeloma (MM) is a fatal hematological malignancy characterized by an accumulation of long-lived plasma cells within the bone marrow. In the present study, we have investigated the effect of the R115777 on growth and survival of myeloma cells. We have found that R115777 induced (1) a significant and dose-dependent growth inhibition of the three myeloma cell lines tested; and (2) a significant and time-dependent apoptosis. R115777 also induced apoptosis in the bone marrow mononuclear cell population of four MM patients, being almost restricted to the malignant plasma cells. Finally, we have investigated the effect of the R115777 in the Ras/MAPK and JAK/STAT pathways which are implicated in survival and/or proliferation in MM. The phosphorylation of both STAT3 and ERK1/2 induced by IL-6 was totally blocked at 15 microM of R115777 and partially blocked when R115777 was used at 10 and 5 microM. The induction of apoptosis by R115777 in myeloma cells and its implication in the regulation of JAK/STAT signalling suggest that R115777 might be an interesting therapeutical approach in MM.


Strontium-89: a novel treatment for a case of osteosclerotic myeloma associated with life-threatening neuropathy.
Sternberg AJ, Davies P, Macmillan C, Abdul-Cader A, Swart S.
Department of Haematology, John Radcliffe Hospital, Headington, Oxford, UK.
Br J Haematol 2002 Sep;118(3):821-4

Abstract
Osteosclerotic myeloma is a rare disorder characterized by paraproteinaemia and osteosclerosis, and may be associated with a progressive peripheral neuropathy. Patients with widespread osteosclerotic lesions can succumb from neurological complications despite systemic chemotherapy. We present a case of disseminated osteosclerotic myeloma associated with POEMS (peripheral neuropathy, organomegaly, endocrinopathy, M band, skin changes) syndrome, which was complicated by a rapidly progressive, life-threatening neuropathy. The patient's symptoms remained unchanged in the face of combination chemotherapy. However, a substantial improvement was seen following outpatient treatment with the commonly available radioisotope strontium 89 in combination with steroids.


Long-term results (12 years) of high-dose therapy in 127 patients with de novo multiple myeloma.
Moreau P, Misbahi R, Milpied N, Morineau N, Mahe B, Vigier M, Rapp MJ, Bataille R, Harousseau JL.
Department of Hematology, University Hospital, Nantes, France.
Leukemia 2002 Sep;16(9):1838-43

Abstract
This report describes the long-term outcome of a cohort of 127 de novo multiple myeloma patients treated with at least one course of high-dose therapy (HDT) in a single institution between June 1985 and December 1995, for whom the minimum follow-up duration for survivors is 6 years. The 12-year overall survival (OS) and event-free survival (EFS) rates are 24.9% and 3.1%, respectively, and the median survival and EFS are 49 and 17 months, respectively. Only four patients are alive and disease-free 79, 90, 132 and 153 after the first HDT, respectively. Three of them received a subsequent allogeneic bone marrow transplantation. Three factors significantly influence OS in this series: B2M at diagnosis, age, and the completion of a second HDT. The 10-year survival is 18.9% for the group of patients with B2M level >3 mg/l at diagnosis as compared with 41% for patients with B2M < or =3, with a median survival of 31 months vs 73 (P = 0.01). The 10-year survival is 23.4% for the group of patients aged >55 years as compared with 36.5% for patients aged 55.


Clinical activity of arsenic trioxide for the treatment of multiple myeloma.
Munshi NC, Tricot G, Desikan R, Badros A, Zangari M, Toor A, Morris C, Anaissie E, Barlogie B.
University of Arkansas for Medical Sciences, Myeloma and Transplantation Medical Center, Little Rock, AR, USA.
Leukemia 2002 Sep;16(9):1835-7

Abstract
Arsenic has been used since ancient times as a therapeutic agent. However, until recently its use in modern medicine has been restricted to the treatment of a limited number of parasitic infections. In the early 1990s, reports from China described impressive results with arsenic trioxide in patients with de novo, relapsed, and refractory acute promyelocytic leukemia (APL). Other investigators subsequently confirmed these results leading to approval of its use for relapsed or refractory APL in the United States. Investigations of this agent have demonstrated that its efficacy in APL and preclinical tumor models is dependent upon a number of mechanisms, including induction of apoptosis, effects on cellular differentiation, cell cycling, and tumor angiogenesis. Subsequent preclinical studies showed significant activity of arsenic trioxide in multiple myeloma (MM). Based on this, in a phase II trial, we have evaluated the activity of arsenic trioxide in 14 patients with relapsed MM, refractory to conventional salvage therapy. With the dose and schedule used, treatment with arsenic trioxide produced responses in three patients and prolonged stable disease in a fourth patient, with the longest response lasting 6 weeks. Although treatment was reasonably well tolerated, in these patients with extensive prior therapy, 11 developed cytopenia, five associated with infectious complications and three developed deep vein thromboses. The results of this small trial support further investigation of this novel drug for the treatment of patients with relapsed or refractory MM.


Cytotoxic chemotherapy following tandem autotransplants in multiple myeloma patients.
Fassas AB, Spencer T, Desikan R, Zangari M, Anaissie E, Barlogie B, Tricot G.
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Br J Haematol 2002 Oct;119(1):164-8

Abstract
High-dose treatment (HDT) with autologous stem cell transplant (ASCT) is superior to conventional chemotherapy in multiple myeloma. However, relapses eventually occur, especially in the presence of unfavourable cytogenetic abnormalities, high beta-2 microglobulin levels prior to transplant and extensive prior treatment. Cytotoxic consolidation chemotherapy, following tandem transplants (TT), was given to 75 myeloma patients with at least one poor prognostic factor. When their outcome was compared with that of 75 matched controls who received dexamethasone +/- interferon post TT, no event-free or overall survival advantage was observed. Other approaches may be required to improve survival in multiple myeloma.


Methylation is an inactivating mechanism of the p16 gene in multiple myeloma associated with high plasma cell proliferation and short survival.
Mateos MV, Garcia-Sanz R, Lopez-Perez R, Moro MJ, Ocio E, Hernandez J, Megido M, Caballero MD, Fernandez-Calvo J, Barez A, Almeida J, Orfao A, Gonzalez M, IMF Scientific Advisor San Miguel JF.
Servicio de Hematologia, Hospital Universitario de Salamanca, Spain.
Br J Haematol 2002 Sep;118(4):1034-40

Abstract
In order to gain further insights into the role of the p16 gene in cell cycle regulation and the prognostic implications of its inactivation, we investigated the methylation status of the p16 gene in 98 untreated patients using a polymerase chain reaction assay based on the inability of some restriction enzymes to digest methylated sequences. Forty-one patients showed a p16 methylated gene (42%). The percentage of S-phase plasma cells (PC) in these patients was almost three times higher than in those with an unmethylated p16 gene (4.16% +/- 3.37%vs 1.5% +/- 1.41%, P < 0.001). The presence of p16 methylation also correlated with both elevated beta2-microglobulin serum levels and high C-reactive protein values. Patients with a p16 methylated gene had shorter overall and progression-free survival than those patients without p16 methylation. However, this feature did not retain independent prognostic influence on multivariate analysis, probably due to its association with the S-phase PC, which had more potent statistical significance in the Cox model. These findings showed methylation of the p16 gene was a frequent event inMM patients at diagnosis, and was associated with an increased proliferative rate of plasma cells and a poor prognosis, indicating an important role for p16 gene in the cell cycle regulation of multiple myeloma tumour cells, and thus in the clinical outcome of the disease.


Microvessel density, a surrogate marker of angiogenesis, is significantly related to survival in multiple myeloma patients.
Pruneri G, Ponzoni M, Ferreri AJ, Decarli N, Tresoldi M, Raggi F, Baldessari C, Freschi M, Baldini L, Goldaniga M, Neri A, Carboni N, Bertolini F, Viale G.
Division of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan, School of Medicine, Italy.
Br J Haematol 2002 Sep;118(3):817-20

Abstract
We evaluated microvessel density (MVD) in bone marrow biopsies (BM) from multiple myeloma (MM) patients after staining with anti-CD34 and anti-CD105 antibodies (mAbs). The anti-CD105 mAb was significantly more sensitive than the anti-CD34 mAb in visualizing blood vessels both in controls and MM samples. MVD was significantly higher in MM than in controls with both anti-CD34 and anti-CD105 mAbs. Patients with low CD34+ MVD survived longer than patients with higher MVD (P = 0.01), whereas there was no difference in survival between patients with low and high CD105+ MVD. Multivariate analysis confirmed the independent significant association between CD34+ MVD and survival (P = 0.001).


Alterations of the cyclin D1/pRb/p16(INK4A) pathway in multiple myeloma.
Kramer A, Schultheis B, Bergmann J, Willer A, Hegenbart U, Ho AD, IMF Scientific Advisor Goldschmidt H, Hehlmann R.
Medizinische Klinik und Poliklinik V, Universitat Heidelberg, Heidelberg, Germany.
Leukemia 2002 Sep;16(9):1844-51

Abstract
The retinoblastoma protein (pRb), p16(INK4A), D-type cyclins, and their partners cyclin-dependent kinase (CDK) 4 and 6 constitute a G(1) regulatory pathway commonly targeted in tumorigenesis. Several malignancies show a reciprocal correlation between genetic alterations of single members of the pRb pathway. Therefore, we determined the frequency of Rb deletions and cyclin D1 alterations by fluorescence in situ hybridization as well as 5' CpG island hypermethylation of the p16(INK4A)gene using methylation-specific polymerase chain reaction in bone marrow mononuclear cells from 82 individuals with plasma cell disorders. Alterations in at least one of the components of the pathway were found in 75%. Cyclin D1 translocations or amplifications were detected in 14/82 (17.1%), Rb deletions at 13q14 in 23/82 (28%) of the cases, including three (3.6%) homozygous deletions. p16(INK4A) was hypermethylated in 33/57 (57.9%) of the samples. Further analysis revealed a highly significant correlation between cyclin D1 alterations and extramedullar or leukemic myeloma manifestations (P = 0.014; Fisher's test). Whereas Rb deletions seemed to occur alternatively to cyclin D1 alterations, no reciprocal correlation was found between p16(INK4A) hypermethylations and cyclin D1 or Rb locus aberrations. Cyclin D1 locus alterations and Rb deletions were associated with a significantly worse prognosis whereas p16(INK4A) hypermethylation had no impact on survival. We conclude that cyclin D1 and Rb aberrations seem to occur as alternative events in plasma cell malignancies and contribute to clinical course and prognosis. In contrast, although p16(INK4A) hypermethylation is frequent, inactivation of p16(INK4A) seems not to be involved in the pathogenesis of plasma cell disorders.


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