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What's New In Research - May 16, 2003
Sickling trait may be associated with an increased risk for multiple myeloma.
(c) Copyright 2003 Cancer Weekly via NewsRx.com

"In the U.S., multiple myeloma (MM) rates have been disproportionately higher in states with high proportions of African Americans. Understanding this disparity may assist in developing new control/prevention strategies for MM," scientists in the United States report.

"Most of the known associated risk factors for MM are occupational and/or environmental. A possible chromosomal link between sickle cell disease and leukemia, a hematologic malignancy like MM, has been described," wrote O.J. Adegoke and colleagues, Meharry Medical College, School of Medicine.

"Interleukin-6 (IL-6) has been reported to be central to the pathogenesis of MM, inducing proliferation and inhibiting apoptosis in neoplastic plasma cells. IL-6 levels are also increased in healthy sickle cell disease patients," the researchers wrote.

"This role of IL-6 in the pathophysiology of MM and sickle cell disease makes it pertinent to ask whether persons with abnormal sickling erythrocytes are more at risk of developing MM than persons with no abnormal sickling erythrocytes," the researchers added.

"Abrogating the IL-6 signaling pathway will be of therapeutic interest for both MM and sickle cell disease," the researchers concluded.

Adegoke and colleagues published their study in Medical Hypotheses (Is sickling trait associated with an increased risk for multiple myeloma? Med Hypotheses, 2003;60(4):607-610).

For more information, contact O.J. Adegoke, Meharry Medical College, School of Medicine, Department of Surgery, 1005 Dr. D.B. Todd Jr. Blvd., Nashville, TN 37208, USA.

Basic fibroblast growth factor and interleukin-6 interact in myeloid cancer.
(c) Copyright 2003 Cancer Weekly via NewsRx.com

According to a study from Germany, "myeloma cells express basic fibroblast growth factor (bFGF), an angiogenic cytokine triggering marrow neovascularization in multiple myeloma (MM). In solid tumors and some lymphohematopoietic malignancies, angiogenic cytokines have also been shown to stimulate tumor growth via paracrine pathways. Since interleukin-6 (IL-6) is a potent growth and survival factor for myeloma cells, we have studied the effects of bFGF on IL-6 secretion by bone marrow stromal cells (BMSCs) and its potential reverse regulation in myeloma cells."

"Both myeloma-derived cell lines and myeloma cells isolated from the marrow of MM patients were shown to express and secrete bFGF. Cell-sorting studies identified myeloma cells as the predominant source of bFGF in MM marrow. BMSCs from MM patients and control subjects expressed high-affinity FGF receptors R1 through R4," reported G. Bisping and colleagues, University of Munster, Department of Hematology and Medical Oncology.

"Stimulation of BMSCs with bFGF induced a time- and dose-dependent increase in IL-6 secretion (median, 2-fold; p<0.001), which was completely abrogated by anti-bFGF antibodies. Conversely, stimulation with IL-6 enhanced bFGF expression and secretion by myeloma cell lines (2-fold; p=0.02) as well as MM patient cells (up to 3.6-fold; median, 1.5-fold; P =.002)," stated researchers.

"This effect was inhibited by anti-IL-6 antibody. When myeloma cells were cocultured with BMSCs in a noncontact transwell system, both IL-6 and bFGF concentrations in coculture supernatants increased 2- to 3-fold over the sum of basal concentrations in the monoculture controls. The IL-6 increase was again partially, but significantly, inhibited by anti-bFGF," said investigators.

"The data demonstrate a paracrine interaction between myeloma and marrow stromal cells triggered by mutual stimulation of bFGF and IL-6," researchers concluded.

Bisping and colleagues published their study in Blood (Paracrine interactions of basic fibroblast growth factor and interleukin-6 in multiple myeloma. Blood, 2003;101(7):2775-2783).

For more information, contact J. Kienast, University Munster, Department of Hematology and Medical Oncology, Albert Schweitzer Str 33, D-48129 Munster, Germany.

Transactivation of gp130 by interferon alpha can occur in myeloma cells, and may have implications for disease.
(c) Copyright 2003 Cancer Weekly via NewsRx.com

"Receptor transactivation, i.e, interaction between unrelated receptor systems, is a growing theme in cytokine and growth factor signaling.

"In this study we reveal for the first time the ability of IFN-alpha to transactivate gp130 in myeloma cells," investigators in the United States report.

"An epidermal growth factor receptor/gp130 chimeric receptor previously shown by us to transactivate endogenous gp130, provided a complementary tool to study the underlying mechanisms of receptor cross-talk. Further analysis revealed that transactivation of gp130 by IFN-alpha did not require the extracellular or trans-membrane domain of gp130.

"Moreover, transactivation of gp130 was critically dependent upon Janus kinase activation by the initiating receptor and correlated with rapid and sustained Janus kinase 1 and tyrosine kinase 2 tyrosine phosphorylation," wrote J.D. French and colleagues.

The researchers concluded: "Finally, transactivation of gp130 may be a common theme in myeloma cells, perhaps providing a mechanism for enhanced or qualitatively distinct cellular responses to specific stimuli."

French and colleagues published their study in Journal of Immunology (Transactivation of gp130 in myeloma cells. J Immunol, 2003;170(7):3717-3723).

For additional information, contact D.F. Jelinek, Mayo Clinic & Mayo Graduate School of Medicine, Department Immunology, 200 1st St. SW, Rochester, MN 55905, USA.

Johns Hopkins researchers have developed an inexpensive, reliable way to make large quantities of targeted immune cells that one day may provide a life-saving defense against cancers and viral infections.
(c) Copyright 2003 Immunotherapy Weekly via NewsRx.com

Using artificial antigen presenting cells, or aAPCs, the scientists converted run-of-the-mill immune cells into a horde of specific, targeted invader-fighting machines, they reported in the advance online version of Nature Medicine April 21, 2003.

"The ability to make vast quantities of targeted, antigen-specific immune cells in the lab broadens their potential in tackling a wide array of diseases, especially cancers," said Jonathan Schneck, PhD, professor of pathology and medicine at the Johns Hopkins School of Medicine. "Our technique provides an off-the-shelf way to create these cells."

The immune system normally defends the body against invaders. However, in cancer, tumor cells aren't recognized as "foreign," and after bone marrow and organ transplant the immune system has to be suppressed to avoid rejection of the transplant, opening the door to viral infections. Specially targeted immune cells that fill these defensive gaps are already being tested as experimental "cancer vaccines" in patients with melanoma and multiple myeloma and as virus fighters after bone marrow transplant.

However, the technological advance reported by the Johns Hopkins team overcomes a major weakness of current methods for making these targeted immune cells, known as antigen-specific cytotoxic T cells (CTLs) - namely the methods' reliance on a patient's own dendritic cells. Dendritic cells are immune system sentries that wave the proteins, or antigens, of foreign invaders like flags, teaching immune system T cells to recognize the invading cells and kill them.

"But dendritic cells vary in quality and number from patient to patient," said first author Mathias Oelke, PhD, a postdoctoral fellow in pathology at Johns Hopkins. "Many patients simply can't provide the number of dendritic cells needed to get a vaccine that would work."

The aAPCs made by the Hopkins team created twice as many specific, targeted CTLs as using dendritic cells, and could have made even more, said Oelke, who researched dendritic cell-derived CTLs in Germany. Both aAPCs and dendritic cells convert generic immune cells in the blood into targeted CTLs.

The aAPCs were made using a protein called HLA-Ig, which in 1998 Schneck showed could mimic the antigen-waving ability of dendritic cells. In the latest research, Oelke turned tiny magnetic beads into aAPCs by coating them with HLA-Ig and another protein that stimulates cell growth and exposing the beads to antigens from either melanoma or cytomegalovirus.

"Using the aAPCs, we were able to make a tremendous amount of CTLs while maintaining their specificity," said Schneck. "Losing specificity as CTL numbers rise has been a problem with other techniques."

Before aAPCs could be used to make CTLs for testing in patients, the production method must be modified to produce clinical grade cells, a process Oelke suggests could take two to four years.

Authors on the report are Oelke, Schneck and Dominic Didiano of Johns Hopkins; Marcela Maus and Carl June of the Abramson Family Cancer Research Institute at the University of Pennsylvania; and Andreas Mackensen of the University of Regensburg, Germany. The Johns Hopkins researchers were funded by the U.S. National Institutes of Health and the Dr. Mildred-Scheel-Stiftung Deutsche Krebshilfe Foundation.

Under a licensing agreement between Pharmingen and the Johns Hopkins University, Schneck is entitled to a share of royalty received by the University on sales of products related to technology described in this article. Schneck is a paid consultant to Pharmingen. The terms of this arrangement are being managed by Johns Hopkins University in accordance with its conflict-of-interest policies.

Increased angiogenesis can be found in many hematological cancers.
(c) Copyright 2003 Cancer Weekly via NewsRx.com

According to a study from Germany, "angiogenesis is defined as the formation of new capillaries from preexisting blood vessels and plays an important role in the progression of solid tumors. Recently a similar relationship has been described in several hematologic malignancies."

"Expression of the angiogenic peptides vascular endothelial growth factor (VEGF) and basic fibroblast growth factor correlates with clinical characteristics in leukemia and non-Hodgkin's-lymphoma and the serum/plasma concentrations serve as predictors of poor prognosis," stated T.M. Moehler and colleagues, University of Heidelberg.

"Increased bone marrow microvessels in multiple myeloma (MM) are correlated with decreased overall survival. Thalidomide, which has antiangiogenic effects and direct cytotoxic effects, was found to be effective in MM, myelodysplastic syndrome, and acute myeloid leukemia (AML)."

"Preliminary data indicate activity of VEGF-tyrosine kinase inhibitors in AML. Clinical research is now aimed at testing antiangiogenic treatment strategies in several hematologic neoplasms as well as identifying the best candidate patients for specific approaches," Moehler and coauthors advised.

Moehler and colleagues published their study in Critical Reviews in Oncology Hematology (Angiogenesis in hematologic malignancies. Crit Rev Oncol Hematol, 2003;45(3):227-244).

For more information, contact H. Goldschmidt, University Heidelberg, Department Med Hematology Oncology Rheumatol 5, Hospital Str 3, D-69115 Heidelberg, Germany.

Thalidomide improves AL amyloidosis but is poorly tolerated in this patient population because of its high toxicity, scientists in Boston report.
(c) Copyright 2003 Immunotherapy Weekly via NewsRx.com

"Thalidomide is an effective therapy for multiple myeloma, although its mechanisms of action remain unclear.

"Light chain-associated (AL) amyloidosis is a plasma cell disorder related to multiple myeloma, but in AL amyloidosis, fibrillar tissue deposits of clonal immunoglobulin light chains produce organ dysfunction.

"To test the toxicity and efficacy of thalidomide in AL amyloidosis we initiated a phase I/II trial for patients with AL amyloidosis, most of whom had failed prior therapy with high-dose melphalan and autologous stem cell transplantation," wrote D.C. Seldin and colleagues, Boston University, Boston Medical Center.

"This trial was designed as an individualized six-month dose-escalation study with re-evaluation of bone marrow plasmacytosis and serum and urine monoclonal proteins after 3 and 6 months. Sixteen patients were enrolled in the study with a median age of 62 years (range, 37-70 years).

"Fourteen patients had renal involvement, four had cardiac involvement, four had liver involvement, and two had predominant soft tissue or lymph node involvement. The median maximum tolerated dose was 300 mg, with fatigue and other central nervous system side effects being the major dose-limiting toxicities, the researchers wrote.

"Side effects not frequently reported for other patient populations included exacerbation of peripheral and pulmonary edema and worsening azotemia. In all, 50% of patients experienced grade 3/4 toxicity, and 25% had to discontinue the study drug.

No complete hematologic responses were seen, but 25% of patients had a significant reduction in Bence-Jones proteinuria. Thus, while thalidomide has activity in AL amyloidosis, it also has significant toxicity in this patient population," Seldin and colleagues concluded.

Seldin and colleagues published their study in Clinical Lymphoma (Tolerability and efficacy of thalidomide for the treatment of patients with light chain-associated (AL) amyloidosis. Clin Lymphoma, 2003;3(4):241-246).

For additional information, contact D. C. Seldin, Boston University, Boston Medical Center, 650 Albany St., Boston, MA 02118, USA.

Novel therapies in multiple myeloma.
IMF Scientific Advisors Singhal S, Mehta J.
Journal: Int J Hematol 2003 Apr;77(3):226-31

The discovery of the activity of thalidomide in myeloma in the late 1990s transformed the therapy of myeloma dramatically. Apart from providing a useful treatment option for patients with myeloma, it has spurred clinical investigation of several other nonchemotherapeutic agents for this disease. These active, promising agents include CC-5013 (a thalidomide analog) and bortezomib (a proteasome inhibitor), as well as other agents, such as arsenic trioxide, ENMD 0995 and 2-methoxyestradiol. Preliminary data show that a number of these agents are active in treating disease that has relapsed after conventional chemotherapy as well as after high-dose therapy and transplantation, and some agents are active even after other novel agents have failed. The only novel drug that is commercially available currently is thalidomide, which has a therapeutically relevant benefit at all stages of the disease. A therapeutic trial of thalidomide is essential for all patients with myeloma. There are in vitro and in vivo data showing synergy between some of the novel agents. Although these novel drugs are typically used for treating disease that is refractory to or has relapsed after cytotoxic therapy, it is likely that they will start being used as part of frontline therapy, either by themselves or in combination with chemotherapy.

Treatment of relapsed and refractory multiple myeloma.
IMF Scientific Advisors Singhal S, Mehta J.
Journal: Curr Treat Options Oncol 2003 Jun;4(3):229-37

The definition of relapsed and refractory myeloma was straightforward when melphalan-prednisone constituted the mainstay of treatment and high-dose therapy with transplantation was rarely used in myeloma. However, several advances have occurred in the treatment of myeloma over the past decade. Most notably, high-dose therapy and transplantation have become broadly applicable, thalidomide has become available as effective salvage therapy, and several investigational agents with novel mechanisms of action appear to be very promising. Because of the differing properties of some of these agents, it is often possible to control the disease with an alternative treatment approach after the failure of one therapy. Some data indicate that combinations of these agents work when the drugs have failed individually. Therefore, refractory myeloma indicates disease unresponsive to the most recent therapy administered. Broadly, the salvage approaches that are used in patients with refractory or relapsed disease include high-dose dexamethasone, high-dose chemotherapy with autotransplantation, allogeneic hematopoietic stem cell transplantation, thalidomide-based therapies, and novel/investigational agents. The appropriate therapy for a given situation depends on the nature of the disease, age, organ function, bone marrow function, prior treatment, the availability of stem cell donors, and access to novel agents. A therapeutic trial of thalidomide is essential at some stage of the disease in all patients. High-dose therapy with autotransplantation is needed at some stage of the disease in most patients younger than 65 to 70 years.

Aetiology of bone disease and the role of bisphosphonates in multiple myeloma.
Ashcroft AJ, Davies FE, IMF Scientific Advisor and co-chair of the Bank on a Cure™ research initiative Morgan GJ.
Journal: Lancet Oncol 2003 May;4(5):284-92

Osteolytic bone disease is a major cause of morbidity in patients with multiple myeloma. Our understanding of the pathophysiology of multiple myeloma has increased substantially during the past decade. However the underlying mechanisms of bone destruction and the treatments available have, until recently, received relatively little specific attention. In this review, we provide an overview of the RANK/RANKL/osteoprotegerin system; we describe its interaction with other cellular mechanisms, through which malignant plasma cells drive osteolysis, and explain how bisphosphonates can be used to block this action. We also review the supporting evidence for bisphosphonates as the treatment of choice for patients with bone complications related to multiple myeloma, and discuss possible developments for targeted therapy in the future.

Global gene expression profiling in the study of multiple myeloma.
Shaughnessy JD Jr.
Journal: Int J Hematol 2003 Apr;77(3):213-25

Multiple myeloma (MM) is a rare but uniformly fatal malignancy of antibody-secreting plasma cells. Although several key molecular events in disease initiation or progression have been confirmed (eg, FGFR3/MMSET activation) or implicated (e.g., chromosome 13 deletion), the mechanisms of MM development remain enigmatic. Although it is generally indistinguishable morphologically, MM importantly exhibits a tremendous degree of variability in its clinical course, with some patients surviving only months and others for many years. However, measures of current laboratory parameters can account for no more than 20% of this outcome variability. Furthermore, the means by which current drugs impart their anti-MM effect are mostly unknown. The development of serious comorbidities, such as osteopenia and/or focal lytic lesions of bone, is also poorly understood. Finally, very little knowledge exists concerning the molecular triggers for the conversion of benign monoclonal gammopathy of undetermined significance (MGUS) to overt MM. Given that abnormal gene expression lies at the heart of most if not all cancers, high-throughput global gene expression profiling has become a powerful tool for investigating the molecular biology and clinical behaviors. Here I discuss recent progress made in addressing many of these issues through the molecular dissection of the transcriptome of normal plasma cells, MGUS, and MM.

Management of multiple myeloma: a systematic review and critical appraisal of published studies.
Kumar A, Loughran T, Alsina M, IMF Chairman of the Board Durie BG, Djulbegovic B.
Journal: Lancet Oncol 2003 May;4(5):293-304

We have done a systematic review of all randomised studies in myeloma, identified through a comprehensive search. Our aim was to investigate and critically examine the effects of various treatment modalities on outcome in patients with multiple myeloma and address 22 specific clinical questions in the management of this disease. As a result of our analysis we identified two therapeutic advances in the management of myeloma that, according to the evidence, are most important for improving outcome. These advances were: introduction of high dose chemotherapy, which appears to be superior to conventional chemotherapy, and the use of bisphosphonates, which decrease the probability of pathological vertebral fractures. However, the overall quality of the body of evidence for myeloma management was poor. Many trials were done with small sample sizes, and did not include reporting power analysis. The majority of studies had inadequate allocation concealment, and few were analysed according to intention to treat principle. We conclude that the quality of total evidence supporting treatment recommendations in myeloma is modest at best and has an ample scope for improvement.

Reduced-intensity transplantation with in vivo T-cell depletion and adjuvant dose-escalating donor lymphocyte infusions for chemotherapy-sensitive myeloma: Limited efficacy of graft-versus-tumor activity
1Department of Haematology, University College London Hospitals, London, and 2Therapeutic Antibody Centre, Oxford University, Oxford, United Kingdom
Journal: Biology of Blood and Marrow Transplantation 9:257-265 (2003) April 2003 € Volume 9 € Number 4

Reduced-intensity conditioning regimens allow application of allogeneic stem cell transplantation to greater numbers of patients with myeloma by reducing transplantation-related mortality. We prospectively evaluated the role of an approach incorporating in vivo T-cell depletion and subsequent adjuvant donor lymphocyte infusions (DLIs) as part of front-line therapy for chemotherapy-sensitive multiple myeloma. Twenty patients with HLA-matched related (n = 12) or unrelated (n = 8) donors entered the study. None had previously undergone autologous transplantation. Acute graft-versus-host disease (GVHD) following transplantation was minimal (3 grade II and no grade III or IV). Nonrelapse mortality rate was relatively low (15%) compared with conventional myeloablative allogeneic transplantation series, although it remained significantly higher than in the autologous setting. Disease responses by 6 months posttransplantation were modest (2 in complete remission, 4 in partial remission, 2 were minimally responsive, 6 had no change, 3 had progressive disease, and 3 were not evaluable). Fourteen patients received escalating-dose DLI for residual/progressive disease. Three developed acute GVHD and 2 developed limited chronic GVHD. Seven demonstrated further disease responses, which appeared to be more common in those developing GVHD (5 of 5 versus 2 of 9; P = .02). All responses were associated with conversion from mixed to full donor T-cell chimerism. Response durations were disappointing (5 <12 months) and progression often occurred despite persisting full donor chimerism. Two-year estimated overall survival and current progression-free survival rates (intention to treat with DLI from 6 months) were 71% and 30%, respectively. The current approach incorporating T-cell depletion appears excessively immunosuppressive despite attempts to restore immune function with DLI. Dose escalation failed to allow convincing dissociation of graft-versus-myeloma from GVHD. Attempts to hasten immune reconstitution and to focus and amplify appropriate components of allogeneic T-cell responses will be required to increase complete remission rates and response durations.

© 2003 American Society for Blood and Marrow Transplantation

Myeloma of the jaw bones: A clinicopathologic study of 33 cases
Marick E. Lae, MD 1, Eneida F. Vencio, MD 1, Carrie Y. Inwards, MD 2, K. Krishnan Unni, MD 2, Antonio G. Nascimento, MD 2 *
Visiting Resident at the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905
Journal: Head Neck 25: 000-000, 2003

Background. A clinicopathologic study of 33 cases of plasma cell neoplasm of the jaw bones was performed.

Methods. The Mayo Clinic's pathology files through 1995 were reviewed for cases of plasma cell neoplasia involving the jaw bones. Clinical data, radiologic features, and follow-up data were obtained from the hospitals of origin, referring physicians, and Mayo Clinic files. The histopathologic features of the 33 tumors were studied.

Results. There were 21 (64%) male and 12 (36%) female patients, ranging in age from 25 to 81 years (mean, 57.7 years). Twenty-one tumors (64%) were classified as solitary plasmacytoma of bone (SPB) and 12 (36%) as multiple myeloma (MM). Among the SPB cases, 15 (71%) involved the maxilla, and 14 patients were men, with a mean age of 57.1 years. Abnormal serum protein was found in 22% of patients, and in nine patients (43%) the SPB converted to MM after a median of 20.7 months. Among the MM cases, seven (58%) affected the maxilla, seven patients were men with mean age of 58.3 years, and abnormal serum protein and Bence-Jones protein were found in 42% and 73% of the patients, respectively. Anaplastic histology was identified in seven (33%) SPB and six (50%) MM tumors, and amyloid was present in eight (38%) SPB and three (25%) MM tumors. Twelve (57%) SPB patients died of the disease after a median disease-free survival of 6.75 years, and the overall and disease-free survival rates at 5 and 10 years were 52%, 33%, 33%, and 24%, respectively. All MM patients died of the disease after a median survival of 17.6 months, and the 5-year and 10-year survival rates were 8% and zero. Eighty-six percent of the SPB patients with anaplastic histologic findings died of the disease (average survival, 3.8 years), whereas only 43% of those with classic histologic findings died of the disease (average survival, 11.75 years). Among MM patients, anaplastic histologic findings were associated with a 9-month average survival (26-month average survival for MM patients with classic histologic findings).

Conclusions. SPB patients seem to have a better prognosis than MM patients, and 43% of SPB tumors convert to MM after an average of 20.7 months. Anaplastic histologic findings seem to be associated with lower survival rates and periods for SPB patients and lower survival periods for MM patients.
© 2003 Wiley Periodicals, Inc. Head Neck 25: 000-000, 2003

Clinical Implications of Abnormalities of Chromosomes 1 and 13 in Multiple Myeloma
Yasunori Nakagawaa, Masakazu Sawanoboria, Hiroshi Amayaa, Isao Matsudaa, Yasuyuki Inouea, Kenshi Suzukia, Sachiko Hashimotob, Keiko Kanno
Journal: Acta Haematol Volume 109 No. 3, 2003

Stratification of patients with multiple myeloma according to clinical severity was attempted by chromosomal analysis of 180 bone marrow specimens from 79 patients. The 79 patients were hospitalized and treated between 1994 and 1999. Abnormalities of chromosome 1 were detected at the initial medical examination in 8 (10%) of the 79 patients and were found during follow-up in additional 3 patients. Abnormalities of chromosome 1 were often detected in IgA (4/17) and IgD (2/4) multiple myeloma, while detection in IgG myeloma was relatively rare (4/42). The relevant break points were 1q12 in 5 patients and 1q42 and 1q21 in 3 patients, while 3 patients had trisomy 1. Deficiency of the long arm of chromosome 13 was detected in 6 patients, and this was believed to imply a prognosis. The long arm was completely deleted in 2 patients and part of the arm (13q10-14) was deleted in 4 patients. It is interesting that all 6 patients had concomitant abnormalities of chromosome 1. Although the initial response to treatment of patients having abnormal chromosomes 1 and 13 was comparable to that of patients having other chromosomal abnormalities or patients who were karyotypically normal, the median survival time was only 18 months (p < 0.02). Consequently, aggressive treatment such as early stem cell transplantation and so on is needed to improve their survival.

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