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What's New In Research - February 26, 2003
Chromosome abnormalities clustering and its implications for pathogenesis and prognosis in myeloma."
Debes-Marun CS, Dewlap GW, Bryant S, Picken E, Santana-Davila R, Gonzalez-Paz N, Winkler JM, Kyle RA, Gertz MA, Witzig TE, Dispenzieri A, Lacy MQ, Rajkumar SV, Lust JA, Greipp PR, Fonseca R.
Mayo Clinic Division of Hematology, Mayo Clinic, Rochester, MN, USA.
Leukemia 2003 Feb;17(2):427-36

ABSTRACT The nonrandom recurrent nature of chromosome abnormalities in myeloma suggests a role for them in disease pathogenesis. We performed a careful cytogenetic analysis of patients with abnormal karyotypes (n = 254), to discern patterns of association, search for novel abnormalities and elucidate clinical implications. Patients with karyotypic abnormalities suggestive of myelodysplasia/acute leukemia were excluded. In this study we compared survival by abnormality only between patients with abnormal karyotypes. Patients with abnormalities were more likely to have features of aggressive disease as compared to all other patients without abnormalities entered into the myeloma database (lower hemoglobin, higher beta(2)-microglobulin, labeling-index and plasmocytosis; all P < 0.0001). Several groups of patients could be readily identified; hypodiploid (22%), pseudodiploid (36%), hyperdiploid (31%) and near-tetraploid (11%). Clustering associations were seen among several trisomies and monosomy of chromosome 13 and 14. Several monosomies (-2, -3, -13, -14 and -19), 1p translocations/ deletions, and hypodiploidy were associated with a significantly shorter survival. Trisomy of chromosome 13 was rare ( <2%). Even among patients with abnormal karyotypes, specific chromosome abnormalities can impart biologic variability in myeloma, including several monosomies, hypodiploidy and abnormalities of 1p.

High dose chemotherapy and allogenic peripheral blood stem cell transplantation for multiple myeloma evolving from intra-abdominal plasmacytoma.
Chung KM, Chuang SS, Hwang WS, Lee PS, Li CY.
Division of Hematology and Oncology, Department of Internal Medicine, Tainan, Taiwan, ROC.
Zhonghua Yi Xue Za Zhi (Taipei) 2002 Nov;65(11):557-60

Solitary plasmacytomas include extramedullary plasmacytomas and those found in the bone. Seventy percent of patients are male and the median age is 50-55 years, younger than that for plasma cell myeloma. Most solitary plasmacytomas of bone eventually evolve to plasma cell myeloma within 2-10 years, while the extramedullary ones do so infrequently. We present an unusual case of intra-abdominal plasmacytoma in a young woman which was misdiagnosed and treated as T cell lymphoma initially. Typical manifestations of plasma cell myeloma appeared one year later. High dose chemotherapy followed by allogeneic peripheral stem cell blood transplantation (allo-PBSCT) was given. Relapse in skin occurred one year after allo-PBSCT, and was treated with wide excision and local irradiation. The patient was well and alive without evidence of disease 4 years after wide excision of the recurrence of chest wall solitary plasmacytoma and local radiotherapy.

Hypercalcemia due to sun exposure in a patient with multiple myeloma and elevated parathyroid hormone-related protein
Peter D Papapetrou, Marina Bergi-Stamatelou1, Helen Karga and Stavroula Thanou
Second Division of Endocrinology and Metabolism, Alexandra Hospital, Athens , Greece, and 1Division of Hematology, St Savvas Hospital, Athens, Greece
European Journal of Endocrinology


A patient with multiple myeloma who developed hypercalcemia during three different stages of his disease, with a different hypercalcemic agent elevated in his serum on each occasion , is described. The initial episode of hypercalcemia was associated with high serum IL-6. After treatment for myeloma normocalcemia was achieved. Subsequently, a relapse of hypercalcemia occurred ,this time characterized by frankly elevated plasma PTHrP, but normal IL-6. Monotherapy with pamidronate infusions resulted in remission of the hypercalcemia and a significant fall of PTHrP. A third spell of hypercalcemia characterized by an acute rise of serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D to abnormally high levels occurred during the summer season, after prolonged and intense exposure to the sun.

Amyloid arthropathy resembling seronegative rheumatoid arthritis in a patient with IgD-kappa multiple myeloma."
Fujishima M, Komatsuda A, Imai H, Wakui H, Watanabe W, Sawada K.
Third Department of Internal Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543.
Intern Med 2003 Jan;42(1):121-4

A 67-year-old woman suffered from symmetrical polyarthralgia and multiple joint swelling simulating rheumatoid arthritis (RA). Laboratory examination showed negative results for rheumatoid factor, decreased levels of IgG, IgA, and IgM, and an increased level of IgD. Immunoelectrophoresis in her serum and urine revealed an IgD-kappa monoclonal component and Bence Jones protein (kappa), respectively. A bone marrow biopsy showed an excess of atypical plasma cells. A synovial biopsy revealed amyloid deposition composed of IgD-kappa. She was diagnosed with amyloid arthropathy (AmyA) secondary to IgD-kappa multiple myeloma. It is important to pay attention to AmyA due to multiple myeloma in patients with seronegative RA.

Intermediate-dose (25mg/m2) IV melphalan for multiple myeloma with renal failure
Cécile Vigneau1, Claude Ardiet2, Monique Bret4, Maurice Laville1, Denis Fiere3, Brigitte Tranchand2, Denis Fouque1
Services of Nephrology1, Intensive Care4 and Hematology3, Edouard Herriot Hospital, and Service of Pharmacology2, Léon Bérard Centre, Lyon - France
J NEPHROL 2002; 15: 684-689

ABSTRACT: Background: Multiple myeloma is a malignant plasma cell disorder which still bears a dramatic prognosis. Renal insufficiency is a frequent and severe complication directly related to prognosis. The aim of our study was to establish whether an intermediate dose of intravenous melphalan, 25 mg/m2, could be safely and efficiently administered to patients with multiple myeloma and renal impairment.

Methods: Between January 1990 and April 2000, 45 patients with multiple myeloma received a single intravenous dose of melphalan, 25 mg/m2. Survival was analysed, as well as the duration of response and potential toxicity. In addition, a melphalan pharmacokinetic study was performed.

Results: The overall median survival was 45 ± 43 months after diagnosis. Based on the Cockcroft and Gault formula, 79% patients had renal impairment. For the 28 stage III patients, survival was no different whether renal insufficiency was present or not. Twenty-five out of 34 patients had leukopenia for an average of 13.8 ± 12 days, and the most frequent adverse effect was infection. The pharmacokinetic study showed that the melphalan area under the curve was positively correlated to the degree of renal insufficiency. However, this was not clinically relevant since patients with the most altered renal function, including those undergoing dialysis, did not present more episodes of leukopenia.

Discussion: The present study shows that renal impairment is not a contraindication for aggressive myeloma chemotherapy, even for patients undergoing dialysis. Intravenous melphalan, 25 mg/m2, is associated with good survival and acceptable side-effects. A randomised trial seems needed to compare this melphalan dose with standard melphalan/prednisone or combination chemotherapies.

Introduction: Multiple myeloma is a malignant plasma cell disorder accounting for about 10% of hematological malignancies. About 2500 new cases are diagnosed in France every year. The prognosis is still deadly: a few months survival without treatment and mean survival of three years under standard chemotherapy (1).

Renal insufficiency is a severe complication of myeloma, and is directly related to prognosis (2). It is present in about 50% of patients with myeloma and is an important limiting factor for therapeutic choices. Ten percent of these patients will even require temporary or chronic hemodialysis. Renal insufficiency is viewed as a bad prognostic factor and contraindicates many chemotherapies.

In 1969, Alexanian reported that an association of oral melphalan and prednisone could improve the prognosis of multiple myeloma (3). Other studies have described combination chemotherapies such as VAD (vincristine, adriamycine and dexamethasone) which improved survival. However, none of them were superior to the Alexanian protocol (4, 5). High-dose intravenous melphalan with bone marrow transplantation now somewhat improves survival rates ( 6, 7, 8, 9) but this treatment is often limited to young patients without renal insufficiency. Indeed, until the 90's, renal insufficiency was associated with such a bad prognosis that these patients did not benefit from the most efficient treatments available.

When Salmon and Durie classifed myeloma and prognosis factors in 1975, treatment of renal failure was not as sophisticated as now (10). Alexanian et al and more recently Cavo et al found comparable results, however, even without dialysis (4, 11). A recent literature survey did not find major improvement in survival with the main chemotherapies and hemodialysis as compared with studies ten years ago (12-14). Some younger patients were treated by bone marrow transplantation, besides dialysis or renal transplantation (15-19). In 1989, Petrucci showed that an intermediate dose of IV melphalan, 25 mg/m2, improved survival with an acceptable range of adverse effects (20). Those patients did not have renal insufficiency.

The aim of this study was to establish whether an intermediate dose of IV melphalan, 25 mg/m2, could be safely and efficiently administered to patients with multiple myeloma and renal impairment. We report on 45 patients and their clinical and biological responses. We also ran a pharmacokinetic study to see if the dose needs to be adapted when renal insufficiency is present.

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