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What's New In Research - January 8, 2003
01.08.03
Intradural recurrence of multiple myeloma during the hematological complete remission
Hayakawa H, Obama K, Tara M.
Department of Internal Medicine, Kagoshima City Hospital.
Rinsho Ketsueki 2002 Nov;43(11):1009-13
[Article in Japanese]

In December 1997, a 55-year-old man presented with left-sided back and arm pain. Pretreatment examination revealed IgG-lambda type M-protein, Bence-Jones protein and the posterior mediastinum tumor. Bone marrow examination revealed hypercellular marrow with 73.6% plasma cells. He was diagnosed as having multiple myeloma with extramedullary lesion. As a result of VAD, MP, interferon and radiation therapy, he had a hematological complete remission. After 21 months, he developed intradural relapse at cauda equina and cerebrum. Many plasma cells and IgG-lambda type M-protein were detected in the cerebrospinal fluid. Laboratory examinations showed a complete remission except for cerebral and meningeal involvement. The myeloma cells might have infiltrated the intradural space at diagnosis and expanded in the central nervous system despite chemotherapy. Because reported cases with cerebral and meningeal myeloma are increasing according to the recent advance of treatment, we must pay attention to the meningeal myeloma.


Response to first-line chemotherapy and long-term survival in patients with multiple myeloma. results of the MM87 prospective randomised protocol.
Riccardi A, Mora O, Tinelli C, Porta C, Danova M, Brugnatelli S, Grasso D, Tolca B, Spanedda R, De Paoli A, Barbarano L, Cavanna L, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E.
Medicina Interna e Oncologia Medica, Universita and Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, 27100, Pavia, Italy
Eur J Cancer 2003 Jan;39(1):31-7

In this study we evaluated whether a good response to conventional chemotherapy, i.e. a significant tumour reduction, is a prerequisite for improved survival in multiple myeloma (MM). Between January 1987 and March 1990, 341 consecutive previously untreated patients with MM received chemotherapy within the prospective, multicentre, randomised Protocol MM87. Of these, 258 patients were evaluable for both response and long-term survival and 244 (94.6%) have died. The median survival of all patients was 40 months (6-162 months). The median survival did not differ between patients who had complete response (CR) (50 months (9-162 months)), partial response (PR) (46 months (8-147 months)) or stable disease (SD) (41 months (7-135 months)). The median survival was shorter (13.6 months (6-135 months)) (P< 0.0001) in patients whose disease progressed while they were receiving first induction chemotherapy. Causes of death were more frequently (P=0.04) related to MM in patients who had progressive disease (PD) than in patients who had a CR or PR or SD. The main clinical and laboratory characteristics were similar in the four groups. These data indicate that patients who maintain SD during first-line chemotherapy have a prognosis similar to that of patients who attain a response. Only patients whose disease progresses have a distinctly worse outcome.


Pegylated Liposomal Doxorubicin Advantageous in Multiple Myeloma Treatment
NEW YORK (Reuters Health) Dec 19 - Substituting pegylated liposomal doxorubicin for doxorubicin in regimens for treating multiple myeloma improves safety and convenience without reducing efficacy, according to results of a phase II trial. A regimen that included vincristine and doxorubicin given over 4 days along with oral dexamethasone (VAD) has resulted in response rates of 50% to 80% in patients with newly diagnosed multiple myeloma, Dr. Mohamad A. Hussein and colleagues from the Cleveland Clinic, Ohio, note.

In the current study, the researchers treated 33 patients newly diagnosed with multiple myeloma with a regimen of pegylated liposomal doxorubicin (40 mg/m), vincristine (2.0 mg on day 1) and oral or intravenous dexamethasone (40 mg/day for 4 days). The duration of dexamethasone was reduced from that used in the phase I trial, because of steroid toxicity. The patients were treated every 4 weeks for six or more cycles and/or for two cycles after best response. The overall response rate was 88%, with four patients achieving a complete response, 18 having a major response and seven a minor response, the researchers report. Three patients had stable disease and one patient had progressive disease. Disease progression occurred at a median of 23.1 months. Progression-free survival was 42% at 2 years and 23% at 3 years, Dr. Hussein's team found. At 3 years the survival rate was 67%, they note in the November 15th issue of Cancer.

None of the patients stopped treatment due to adverse events andvmyelosuppression was manageable. The most common side effects included Grade 3 palmar-plantar erythrodysesthesia, mucositis, and neutropenia, but only one patient experienced cardiotoxicity, according to the report.

Dr. Hussein and colleagues add that "a randomized phase III study is now in progress" to directly compare this pegylated doxorubicin regimen with vincristine, doxorubicin and reduced-dose dexamethasone in patients with newly diagnosed multiple myeloma.
Cancer 2002;95:2160-2168


Delineation of the minimal region of loss at 13q14 in multiple myeloma
Manal O. Elnenaei, Rifat A. Hamoudi, John Swansbury, Alicja M. Gruszka-Westwood, Vasantha Brito-Babapulle, Estella Matutes, Daniel Catovsky
Department of Academic Haematology and Cytogenetics, The Institute of Cancer Research and Royal Marsden NHS Trust, London, United Kingdom
Genes, Chromosomes and Cancer, Volume 36, Issue 1, 2003. Pages: 99-106
Article Available Online in Advance of Print -- Published Online: 25 Sep 2002

Abstract: Previous studies have focused on the incidence and prognostic implications of 13q14 deletions in multiple myeloma (MM), but none has sought to delineate the minimal common deleted region (CDR). In an effort to do so, dual-color interphase fluorescence in situ hybridization (FISH) was applied on 82 myeloma cases, initially by use of three probes for 13q14 (RB1, D13S319, and D13S25). Deletions were detected in 29/82 (35.4%) cases, and all except one were monoallelic. Subsequently, contiguous YACs, PACs, and a BAC spanning the 13q14-q21 region were employed for deletion mapping in addition to a 13q telomere probe. Large deletions extending to the 13q34 region were found in 55% of the deleted cases, whereas an additional 13.8% showed loss of both 13q34 and 13q14 regions with retention of 13q21. A CDR of approximately 350 kb was identified at 13q14 with the proximal border approximately 120 kb centromeric from D13S319, encompassing an area rich in expressed sequence tagged sites and containing DLEU1, DLEU2, and RFP2 genes. Direct sequencing of the RFP2 gene revealed no mutations in six patients and four MM cell lines harboring deletions of the CDR. However, a role for RFP2 in the pathogenesis of MM cannot yet be excluded, given that alternative mechanisms such as haploinsufficiency remain possible. © 2002 Wiley-Liss, Inc.


Thalidomide alone or with dexamethasone for previously untreated multiple myeloma.
Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R.
The University of Texas MD Anderson Cancer Center, Houston, TX.
J Clin Oncol 2003 Jan 1;21(1):16-9

Purpose: To evaluate the activity of thalidomide in patients with asymptomatic multiple myeloma and of thalidomide-dexamethasone in patients with previously untreated symptomatic myeloma. Patients and Methods: Twenty-eight patients with previously untreated asymptomatic myeloma were treated with thalidomide 100 to 200 mg orally (PO) at bedtime (qhs) with serial increments of 50 to 100 mg at weekly intervals, as tolerated to a maximum of 600 mg PO qhs. Forty consecutive previously untreated patients with symptomatic myeloma were also treated as above (maximum dose 400 mg) and received dexamethasone 20 mg/m(2) for 4 days beginning on days 1, 9, and 17; the second and third cycles of repeated dexamethasone were begun on day 30. Both groups of patients were treated for at least 3 months. Results: The response rate was 36% for patients treated with thalidomide alone and 72% for patients treated with thalidomide-dexamethasone, the latter including complete remission in 16% of patients. The median time to remission was 4.2 months with thalidomide alone and 0.7 months with thalidomide-dexamethasone. Grade 3 toxicity included infections (nine patients) and thrombotic/embolic events (seven patients). Five deaths have occurred as a result of multiple myeloma (two patients), infection (one patient), unknown cause (one patient), and a possible thromboembolic event (one patient). Conclusion: Thalidomide alone was effective in patients with newly diagnosed myeloma. The combination with dexamethasone induced a high frequency of response, rapid onset of remission, and low incidence of serious irreversible toxicity. These observations support further studies of this promising combination for patients with newly diagnosed multiple myeloma.


Changing concepts in multiple myeloma: from conventional chemotherapy to high-dose treatment.
Sonneveld P, Segeren CM.
Erasmus M C, Department of Hematology, Room L407, PO Box 2040, 3000 CA, Rotterdam, The Netherlands

The treatment of Multiple Myeloma (MM), a malignant plasma cell disorder has changed considerably over the past decade. It has been convincingly shown that intensive treatment supported by autologous stem cell reinfusion is superior to conventional chemotherapy with alkylating agents or vincristine, doxorubicin and dexamethasone (VAD) alone in terms of a more rapid response and a longer disease-free survival. However, cure is not achieved in the majority of patients. Several trials have therefore focussed on repeated intensive treatments in order to improve the survival of these patients. Other approaches are aimed at identifying patients on the basis of prognostic factors, who may benefit from high-dose therapy. This review discusses the recent developments in intensive therapy for multiple myeloma.


Oral Drug Combination Proven as Effective as Standard Chemotherapy
HOUSTON, TX -- December 30, 2002 -- A recent study conducted at the University of Texas M. D. Anderson Cancer Center shows that patients with multiple myeloma, a cancer of the bone marrow, were more likely to achieve remission when treated with a combination of drugs that included thalidomide, a medicine that had previously been shelved for causing birth defects.

Donna Weber, MD, assistant professor of medicine, Raymond Alexanian, MD, professor of medicine, and their colleagues at M. D. Anderson report in the January 1, 2003 issue of the Journal of Clinical Oncology that 72 percent of 40 newly diagnosed patients with multiple myeloma who received a combination of thalidomide and the steroid dexamethasone achieved remission rapidly, usually within one month of treatment. Among these patients, 16 percent achieved complete remission.

The results were superior to a second set of patients in a parallel study treated with thalidomide alone. In these patients, about one-third (10 of 28 patients), achieved partial remission and none achieved complete remission.

"We found that even in patients with resistant disease where each of the two drugs didn't work alone, they were effective when taken together, which very rarely happens," says Dr. Weber, who was the principal investigator on both studies. "There was true synergy in terms of the anti-myeloma effect."

Researchers are not sure how thalidomide works to reduce the bone marrow tumors associated with multiple myeloma, but it may stop cancer cells from creating the network of blood vessels that provides oxygen and nutrients. As a result, the tumors starve to death. Since thalidomide is known to cause birth defects, women of childbearing age who take the medicine must use strict methods of birth control.

The results were as good as that achieved with intravenous combination chemotherapy, but without the side effects of nausea, vomiting and hair loss as well as low blood counts, the risk of infection and the need for a central venous catheter. An added benefit, says Weber, is that thalidomide-dexamethasone are taken orally, while previous chemotherapy has been given intravenously.

"This combination therapy achieved the highest frequency of response observed against myeloma for an oral regimen," says Dr. Alexanian. "This program appears to represent the new treatment of choice for patients as an initial program of therapy, provided side effects can be addressed and prevented."

The researchers noted that about 15 percent of patients treated with the thalidomide-dexamethasone combination developed blood clots in their legs or lungs. Subsequent studies showed that anti-coagulants prevent blood clots and could eliminate this side effect, Weber says.

The M. D. Anderson results were nearly identical to those found by researchers at the Mayo Clinic. In fact, says Weber, the two studies, which were conducted during the same time frame from 1999 to 2001, provide strong evidence of thalidomide's benefit for patients with multiple myeloma when combined with the intermittent high-dose dexamethasone. Previous studies had already shown that thalidomide could be safely and effectively used to treat patients with multiple myeloma who had failed to achieve remission after prior chemotherapy treatments.

The goal of treating patients with multiple myeloma is to reduce the number and size of bone marrow tumors as quickly as possible so that normal stem cells can be collected for use as an autologous bone marrow transplant, a transplant of a patient's own stem cells to repopulate the bone marrow after intensive treatment. For patients with multiple myeloma, the sequence of primary therapy followed by intensive treatment has become a standard of care for the majority of patients, in order to achieve the highest frequency of complete remission.

The American Cancer Society estimates that about 14,600 new cases of multiple myeloma will be diagnosed during 2002 and 10,800 people will die from the disease in the United States. The average survival time after diagnosis has been only three-and-a-half years, but new programs now under study are likely to improve this figure. Results from the M. D. Anderson study and others have spawned laboratory research into the mechanism of action of thalidomide, says Alexanian. These studies have led to the production of promising new drug candidates that are in the same chemical family as thalidomide and may produce even better results with less toxicity.

"We've waited a long time for an effective, convenient program with few side effects that would make an impact on the initial phase of treatment for multiple myeloma and that time has come," says Dr. Alexanian.


Continuous low dose of melphalan and prednisone in patients with multiple myeloma of very old age or severe associated disease.
Pulsoni A, Villiva N, Cavalieri E, Falcucci P, La Verde G, Matera R, Petrucci MT, Tosti ME, Mandelli F.
Department of Cellular Biotechnology and Hematology, "La Sapienza" University, Rome, Italy.

INTRODUCTION AND OBJECTIVE: The management of elderly patients with multiple myeloma is a relevant problem because it concerns a great number of patients. Patients with multiple myeloma who are very old or who have severe associated diseases have a dismal outcome. For these patients we retrospectively evaluated the effect of a mild approach with continuous low-dose melphalan and prednisone (cMP).

DESIGN AND METHODS: 109 patients with multiple myeloma, observed between 1985 and 2000, were treated with cMP; 67 were treated at time of diagnosis (group A; median age 78 years) and 42 as a second or subsequent line of therapy (group B; median age 72 years). The toxicity of the treatment was compared with a control group of 29 patients aged over 70 years, treated in the same institution with the conventional cyclical melphalan/prednisone regimen.

RESULTS: Major or minor responses were obtained in 32% of patients in group A and 13% of patients in group B. Disease was stabilised in 45% of group A and 47% of group B and progressed in 5 and 18%, respectively. Median survival was, respectively, 19 and 24 months in group A and B. Among the 42 patients who received cMP as a second-line therapy (group B), 36 (86%) had previously been treated according to the standard cyclical melphalan/prednisone schedule; of these 12 (33%) obtained a better M protein reduction after cMP compared with the previous response to first-line cyclical melphalan/prednisone. The cMP schedule was generally well tolerated, and the rate of haematological toxicity was lower than for a historical control group receiving cyclical melphalan/prednisone. CONCLUSION: The cMP treatment schedule is well tolerated and results in a high proportion of patients with stable disease, with acceptable survival even in patients with advanced disease.


Diagnostic utility of FDG PET in multiple myeloma
Hossein Jadvar1, and Peter S. Conti1
1PET Imaging Science Center, Division of Nuclear Medicine, Department of Radiology, Keck School of Medicine, University of Southern California, 1200 N. State Street, GNH 5250, Los Angeles, CA 90033, USA

Abstract
Objective. Very little information is available regarding the diagnostic utility of positron emission tomography with [18F]fluorodeoxyglucose (FDG PET) in multiple myeloma. Our objective was to further define the role of FDG PET in the clinical assessment of patients with multiple myeloma.

Design and patients.
Nine whole-body PET scans (45 min after intravenous administration of 370-555 MBq FDG) were performed in six patients (age 38-62 years, 5 males) with multiple myeloma for evaluation of the extent of disease at the time of initial diagnosis (n=3) and for assessment of therapy response (n=3). Three patients had PET scans both before and after therapy. Prior treatments included chemoradiation therapy (n=2) and chemotherapy with autologous bone marrow transplantation (n=1). Correlative imaging data were available in all patients and included skeletal radiographic survey (n=6), bone scan (n=3), and spinal CT or MRI (n=4), and were all obtained within 3 months of the PET study. Validation was by clinical or imaging follow-up.

Results.
In three patients with both pre- and post-therapy PET scans, PET demonstrated a favorable treatment response, by showing a decline in lesion metabolic activity (n=1), or progression of disease, by showing development of new lesions or higher lesion glucose metabolism (n=2), concordant with the clinical evaluation, while the other imaging studies showed no discernible interval changes. PET detected multiple hypermetabolic lesions in one patient with a negative bone scan and concordant positive skeletal radiographic survey. Bone scans underestimated the extent of disease in two other patients in comparison with PET. PET also detected a few early marrow lesions with subtle radiographic changes while all radiographically aggressive lytic lesions corresponded to intense hypermetabolism on PET.

Conclusion.
PET can detect early marrow involvement of multiple myeloma and is useful in assessing the extent of active disease at the time of initial presentation and in evaluating treatment response.


A pilot study on feasibility and efficacy of amifostine preceding high-dose melphalan with autologous stem cell support in myeloma patients.
Jantunen E, Kuittinen T, Nousiainen T.
Leuk Lymphoma 2002 Oct;43(10):1961-5

To evaluate feasibility and potential efficacy of amifostine (AMI) in the prevention of toxicities associated with high-dose melphalan (MEL), ten myeloma patients received AMI 910 mg/m2 in 15 min infusion preceding MEL 200 mg/m2 followed by stem cell infusion (AMI group). Hematologic and extra-hematologic toxicities as well as the need for supportive care observed in the AMI group were compared with ten myeloma patients treated in an identical protocol but without AMI. Hypotension was the most important adverse event of AMI infusion. No differences were observed in the time of engraftment between the AMI group and the control group neither was there any difference in the need for supportive care. Oral mucositis grade >2 was observed in 30% of the patients in both groups. Diarrhea grade >2 occurred only in two AMI patients but in five control patients. AMI preceding high-dose MEL is feasible, although adverse events are observed in some patients. Whether AMI could reduce the gastrointestinal toxicity associated with high-dose MEL can be reliably assessed only in prospective randomized trials


Correlation of sera TNF-alpha with percentage of bone marrow plasma cells, LDH, beta2-microglobulin, and clinical stage in multiple myeloma.
Jurisic V, Colovic M.
Pathophysiology Department, School of Medicine, University of Kragujevac, Serbia.
Med Oncol 2002;19(3):133-9

Tumor necrosis factor-alpha (TNF-alpha) is important for function, differentiation, and transformation of B-lymphocytes in multiple myeloma (MM) but can also induce apoptosis of myeloma cells. Based on this opposite effect, it is very crucial to analyze the correlation of the serum level of TNF-alpha with clinical parameters of the patients. In this article, we analyzed 18 MM patients, 48% male and 52% female, with a mean age of 52 yr (range: 35-81 yr), clinical stage I in 21.4%, stage II in 26.4%, and stage III in 52.2% of patients. Patients with advanced clinical stage, presence of osteolysis, and elevated lactate dehydrogenase (LDH) had a significant difference (Mann-Whitney U-test, p < 0.05) in the serum level of TNF-alpha in comparison with those in the early stage, without osteolysis, and normal LDH. The correlation of individual values of TNF-alpha with the percentage of plasma cells in the bone marrow, LDH, beta2-microglobulin, fibrinogen, and sedimentation rate was significant (p < 0.05). However, we have not found a significant correlation between TNF-alpha and concentration of hemoglobin, the number of white blood cells or platelets (p > 0.05). We concluded that our data indicate determination of TNF-alpha as a good parameter for estimation of tumor mass presence, among individual patients with MM, and may by used for monitoring during application of different therapy protocols.


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