National Cancer Institute®
Last Modified: June 1, 2002
UI - 12011126
AU - Osterborg A; Brandberg Y; Molostova V; Iosava G; Abdulkadyrov K; Hedenus
TI - M; Messinger D; Epoetin Beta Hematology Study Group Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies.
SO - J Clin Oncol 2002 May 15;20(10):2486-94
AD - Department of Oncology (Radiumhemmet), Karolinska Hospital, S-17176 Stockholm, Sweden. firstname.lastname@example.org
PURPOSE: To investigate the effect of recombinant human erythropoietin (epoetin beta) on anemia, transfusion need, and quality of life (QOL) in severely anemic patients with low-grade non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or multiple myeloma (MM). PATIENTS AND METHODS: Transfusion-dependent patients with NHL (n = 106), CLL (n = 126), or MM (n = 117) and a low serum erythropoietin concentration were randomized to receive epoetin beta 150 IU/kg or placebo subcutaneously three times a week for 16 weeks. Primary efficacy criteria were transfusion-free and transfusion- and severe anemia-free survival (hemoglobin [Hb] > 8.5 g/dL) between weeks 5 to 16. Response was defined as an increase in Hb > or = 2 g/dL with elimination of transfusion need. QOL was assessed by the Functional Assessment of Cancer Therapy scale. RESULTS: Transfusion-free (P =.0012) survival and transfusion- and severe anemia-free survival (P =.0001) were significantly greater in the epoetin beta group versus placebo (Wald chi(2) test), giving a relative risk reduction of 43% and 51%, respectively. The response rate was 67% and 27% in the epoetin beta versus the placebo group, respectively (P <.0001). After 12 and 16 weeks of treatment, QOL significantly improved in the epoetin beta group compared with placebo (P <.05); this improvement correlated with an increase in Hb concentration (> or = 2 g/dL). A target Hb that could be generally recommended could not be identified. CONCLUSION: Many severely anemic and transfusion-dependent patients with advanced MM, NHL, and CLL and a low performance status benefited from epoetin therapy, with elimination of severe anemia and transfusion need, and improvement in QOL.
UI - 11904738
AU - Dierlamm T; Laack E; Dierlamm J; Fiedler W; Hossfeld DK
TI - IgM myeloma: a report of four cases.
SO - Ann Hematol 2002 Mar;81(3):136-9
AD - University Hospital Hamburg-Eppendorf, Department of Oncology and Hematology, Martinistrasse 52, 20246 Hamburg, Germany. email@example.com
IgM myeloma is a rare disease, accounting for approximately 0.5% of multiple myelomas (MM). Here we report four cases of IgM multiple myeloma. Two were diagnosed in advanced clinical stages with multiple osteolytic lesions, leading to hypercalcemia in one patient. Bone marrow morphology showed a variable degree of infiltration with mainly mature plasma cells. An immunophenotypic analysis performed in one case showed expression of CD38 and monoclonal cytoplasmatic immunoglobulin. Interphase fluorescence in situ hybridization performed in one case did not reveal any aneuploidies or deletions of the retinoblastoma, P16, or P53 tumor suppressor genes. While one patient with a smoldering IgM myeloma did not need specific therapy, the others received cytotoxic treatment based on standard chemotherapy for MM. The outcomes were one stable disease, one sustained complete remission, and one progressive disease. All four patients were alive 1 year after diagnosis. One died due to progressive disease after 31 months. We conclude that IgM myeloma shares clinical and histological features with other MM rather than with Waldenstrom's macroglobulinemia, which is most commonly diagnosed in cases with IgM monoclonal gammopathy. Since MM and Waldenstrom's macroglobulinemia differ in prognosis and treatment strategies, the two disease entities should be distinguished based on clinical criteria, bone marrow morphology, and immunophenotypic analysis.
UI - 11900061
AU - Gregersen H; Pedersen G; Svendsen N; Thulstrup AM; Sorensen HT;
TI - Schonheyder HC Multiple myeloma following an episode of community-acquired pneumococcal bacteraemia or meningitis.
SO - APMIS 2001 Nov;109(11):797-800
AD - Department of Medicine B, Aalborg Hospital, Denmark. firstname.lastname@example.org
The risk of multiple myeloma subsequent to an episode of serious pneumococcal infection has not been ascertained. We identified 328 episodes of community-acquired pneumococcal bacteraemia and 77 episodes of pneumococcal meningitis in 227,000 persons over 40 years of age in the County of North Jutland, Denmark, in the period 1981 to 1996. The incidence rate of a subsequent diagnosis of multiple myeloma was determined by linkage to the Danish Cancer Registry. During 1,218 patient-years of follow-up in the bacteraemia cohort, 7 cases of multiple myeloma were diagnosed compared with 0.13 cases expected (standardized incidence ratio (SIR) 53.5, 95% confidence interval 21.4-111.4). During 444 patient-years of follow-up in the meningitis cohort, 4 cases of multiple myeloma were diagnosed compared with 0.05 cases expected (SIR 83.2, 95% confidence interval 22.6-214.8). Patients who survive an episode of community-acquired pneumococcal bacteraemia or meningitis are at increased risk of being diagnosed with multiple myeloma, but the absolute risk is low.
UI - 11920223
AU - Rodjer S; Nilsson B; Westin J; The Nordic Myeloma Study Group
TI - Do anthracyclines have a role in the therapy of multiple myeloma?
SO - Hematol J 2000;1(6):422-6
AD - Department of Medicine, Sahlgrenska University Hospital/Ostra, S-41685 Goteborg, Sweden. email@example.com
INTRODUCTION: There is a great need for alternative treatments for patients with relapsing and refractory multiple myeloma. The new anthracycline idarubicin has the advantage of oral administration and has been suggested as part of new orally based chemotherapeutic combination regimens. The evidence of its own efficacy in this disorder is, however, insufficient. MATERIALS AND METHODS: In a multi-centre phase II study we administered oral idarubicin as a single drug in a dose of 10 mg/m(2) days 1-4 every four weeks to a total of 30 patients with relapsing (n=18) or refractory (n=12) multiple myeloma. RESULTS: Of 28 evaluable patients only one achieved a partial response of 15 months' duration. Other patients showed a very short minor response (n=1), "no change" (n=11) or progression (n=15) during the therapy. Toxicity was mostly mild and the drug was fairly well tolerated. None the less, half of the patients experienced WHO grade 3 and 4 toxicity in the form of granulocytopenia (n=10) or thrombocytopenia (n=4). CONCLUSION: Based on our experience and available data from three previously published reports, we consider idarubicin to have only a marginal effect in relapsing and refractory myeloma. A review of the literature on studies of anthracylines as single-agent therapy shows that only 5% of patients (19 out of 377) show a partial response. In our opinion the regular inclusion of an anthracycline in drug combinations for refractory myeloma should be reconsidered.
UI - 11986230
AU - Fonseca R; Blood EA; Oken MM; Kyle RA; Dewald GW; Bailey RJ; Van Wier
TI - SA; Henderson KJ; Hoyer JD; Harrington D; Kay NE; Van Ness B; Greipp PR Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients.
SO - Blood 2002 May 15;99(10):3735-41
AD - Mayo Clinic Department of Hematology and Internal Medicine, Minneapolis, MN 55905, USA. firstname.lastname@example.org
The t(11;14)(q13;q32) results in up-regulation of cyclin D1 and is the most common translocation detected in multiple myeloma, where it is also associated with a lymphoplasmacytic morphology. We performed an interphase fluorescent in situ hybridization (FISH) study to determine the clinical and biologic significance of the abnormality when testing a large cohort of myeloma patients. Bone marrow slides from multiple myeloma patients entered into the Eastern Cooperative Oncology Group phase III clinical trial E9486 and associated laboratory correlative study E9487 were analyzed using interphase FISH combined with immune-fluorescent (cytoplasmic immunoglobulin-FISH) detection of clonal plasma cells. We used FISH probes that hybridize to the 14q32 and 11q13 chromosomal loci. The t(11;14)(q13;q32) was correlated with known biologic and prognostic factors. Of 336 evaluable patients, 53 (16%) had abnormal FISH patterns compatible with the t(11;14)(q13;q32). These patients appeared to be more likely to have a serum monoclonal protein of less than 10 g/L (1 g/dL) (28% vs 15%, P =.029) and a lower plasma cell labeling index (P =.09). More strikingly, patients were less likely to be hyperdiploid by DNA content analysis (n = 251, 14% vs 62%, P <.001). Patients with the t(11;14)(q13;q32) appeared to have better survival and response to treatment, although this did not reach statistical significance. Multiple myeloma with the t(11;14)(q13;q32) is a unique subset of patients, not only characterized by cyclin D1 up-regulation and a lymphoplasmacytic morphology, but is also more frequently associated with small serum monoclonal proteins and is much less likely to be hyperdiploid. These patients do not have a worsened prognosis as previously thought.
UI - 11986233
AU - Brenne AT; Baade Ro T; Waage A; Sundan A; Borset M; Hjorth-Hansen H
TI - Interleukin-21 is a growth and survival factor for human myeloma cells.
SO - Blood 2002 May 15;99(10):3756-62
AD - Department of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Trondheim, Norway.
Interleukin-21 (IL-21) is a recently cloned cytokine with homology to IL-2, IL-4, and IL-15. In this study we examined the effects of IL-21 on human myeloma cells. We found that IL-21 induced proliferation and inhibited apoptosis of the IL-6-dependent human myeloma cell lines ANBL-6, IH-1, and OH-2. The potency of IL-21 was close to that of IL-6 in the OH-2 cell line. Neutralizing antibodies to IL-6 or the IL-6 receptor transducer chain (gp130) did not affect IL-21-induced DNA synthesis, indicating that IL-21-induced proliferation was not mediated through these proteins. Tumor necrosis factor (TNF), another stimulator of myeloma cell growth, up-regulated the expression level of IL-21 receptor (IL-21R), and combinations of TNF and IL-21 gave synergistic effects on myeloma cell proliferation. Furthermore, 4 of 9 purified samples of primary myeloma cells showed a significant increase in DNA synthesis on stimulation of the cells by IL-21. By Western blot analysis, we demonstrated that the intracellular signaling pathways of IL-21 in myeloma cells involved phosphorylation of Jak1, Stat3, and Erk1/2 (p44/42 mitogen-activated protein kinase). IL-21 is a novel growth and survival factor in multiple myeloma and may represent a target for future therapy.
UI - 12033193
AU - Kamel NS; Banks MC; Dosik A; Ursea D; Yarilina AA; Posnett DN
TI - Lack of muco-cutaneous signs of toxic shock syndrome when T cells are absent: S. aureus shock in immunodeficient adults with multiple myeloma.
SO - Clin Exp Immunol 2002 Apr;128(1):131-9
AD - Department of Medicine, Weill Medical College, Cornell University, New York, NY 10021, USA.
Staphylococcal toxic shock syndrome (TSS) is an acute life threatening disease. The diagnosis can be made clinically based on diagnostic criteria. The clinical manifestations are caused in large part by there lease of high levels of T-cell-derived cytokines as a result of potent toxins, also called superantigens (SAg), produced by Staphylococcus aureus, but it is not clear which clinical symptoms/signs are strictly T-cell dependent. Here, we report on three adults with multiple myeloma (MM) presenting with S.aureus sepsis/shock, and two patients with typical TSS. The MM patients had compromised humoral immunity because of depression of normal immunoglobulin (Ig) levels at the expense of the M protein.In addition, their T cells were absent due to high dose chemotherapy initiated for bone marrow trans-plantation. The MM cases lacked mucosal hyperemia, erythroderma and desquamation, but were otherwise indistinguishable from the TSS cases. All patients grew S. aureus and in each case, SAg genes were detected by PCR. In several cases, the plasma contained biological SAg activity resulting in VP specific proliferation of indicator T cells in vitro. The same specific activity was observed with the supernatant fluids of S. aureus broth cultures from the respective bacterial isolates. This confirms the presence of bio-active toxins in the plasma but did not lead to full blown TSS when T cells were lacking.Thus, S. aureus sepsis/shock can be clinically distinguished from typical TSS, and we suggest that mucocutaneous manifestations of TSS are the most telling signs of massive T-cell-dependent cytokine release.
UI - 12014021
AU - Oita T; Yamashiro A; Sakizono K; Etoh M; Mizutani F; Imoto S; Nagai K;
TI - Kasakura S [A case with multiple myeloma in which serum forms gel precipitation upon exposure to air]
SO - Rinsho Byori 2002 Apr;50(4):404-9
AD - Department of Clinical Laboratory, Kobe City General Hospital, Kobe 650-0046.
We present the case of a 69-years-old man who was admitted to hospital with multiple myeloma. IgG-kappa type monoclonal protein was detected in the serum. When we separated the serum obtained from blood sample of the patient and the lid of the collecting tube was opened, the patient's serum became gelled immediately. When the lid of the collecting tube remained closed, the patient's serum did not become gelled even at 4 degrees C. Moreover, the gelled serum of the patient did not resolve at 56 degrees C. Taken together, these results indicated that gel formation of the patient's serum may not be due to cryoglobulin. It was found that the pH of the patient's serum elevated to pH 8.0 quickly after exposed to air. It was also found that the patient's serum, but not the sera of other IgG-kappa multiple myeloma patients, became gelled as soon as PBS of pH 8.0 was added. These results highly suggest that the patient's serum becomes gelled at pH 8.0. However, the isoelectric focusing of isolated precipitation in the patient showed fractions around the pH 8.5-8.7 zone, which was different from the pH at which the precipitation began to form. We think that this may be the first report of a multiple myeloma patient whose serum becomes gelled after exposed to air.
UI - 11994983
AU - Hogan MC; Lee A; Solberg LA; Thome SD
TI - Unusual presentation of multiple myeloma with unilateral visual loss and numb chin syndrome in a young adult.
SO - Am J Hematol 2002 May;70(1):55-9
AD - Internal Medicine, Division of Nephrology, Mayo Graduate School of Medicine and Clinic, 200 First Street SW, Rochester, MN 55905, USA. email@example.com
A 39-year-old man presented with unilateral visual loss as the first sign of multiple myeloma (MM). His visual loss was due to a plasmacytoma in the sphenoid sinus compressing the optic nerve with resultant optic nerve atrophy. Shortly after this presentation he developed numb chin syndrome due to a mandibular plasmocytoma compressing the mental nerve. His MM progressed rapidly despite treatment with high-dose steroids and alkylating agents and he required allogeneic bone marrow transplantation in order to achieve a remission. We reviewed the published medical literature on the presentation of MM with visual impairment and present a summary in tabular form in this paper. This is the first reported case of MM presenting with isolated complete visual loss due to intracranial extrinsic compression of the optic nerve since the advent of modern cross-sectional imaging. Multiple myeloma needs to be included in the differential diagnosis of cranial neuropathies and skull base neoplasms even in adults under 40 years of age.
UI - 12030445
AU - Yasuda S; Hoshikawa T; Yazawa N; Fukumitsu H; Ishikawa K; Suzuki T;
TI - Sadahiro S; Shimakura Y; Shibuya M; Nasu S; Tajima T; Makuuchi H A case of duodenal involvement of multiple myeloma imaged by positron emission tomography with 18F-fluorodeoxyglucose.
SO - Tokai J Exp Clin Med 2001 Dec;26(4-6):147-51
AD - Department of Surgery, Tokai University School of Medicine, Isehara, Kanagawa, Japan. firstname.lastname@example.org
A 61-year-old woman had been treated for multiple myeloma for 4 years when she developed abdominal pain. Ultrasonography and computed tomography revealed a tumor in the abdomen. Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) showed increased FDG uptake in the tumor. In previous bone marrow lesions, which were in clinical remission after chemotherapy and radiotherapy, abnormal FDG uptake was not recognized. Pathological examination after surgery revealed the tumor to be a plasmacytoma of the duodenum. Plasmacytoma of the duodenum is rare but can be seen during the clinical course of multiple myeloma. A few reports have described FDG PET findings of plasmacytoma. Those previous reports and our present case suggest a potential value of FDG PET in the evaluation of multiple myeloma.
UI - 12001122
AU - Shiratsuchi M; Muta K; Abe Y; Motomura S; Taguchi F; Takatsuki H; Uike
TI - N; Umemura T; Nawata H; Nishimura J Clinical significance of telomerase activity in multiple myeloma.
SO - Cancer 2002 Apr 15;94(8):2232-8
AD - Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
BACKGROUND: The clinical course of patients with multiple myeloma varies, and therefore it is important to evaluate the disease state. We studied the telomerase activity of myeloma cells as a possible prognostic factor in such patients. METHODS: Twenty five samples from patients with multiple myeloma were studied. We purified myeloma cells in bone marrow samples according to the expression of surface antigens, CD38 and CD45. CD38+/CD45- or dim cells had morphologic characteristics of myeloma cells, with a purity exceeding 95%. The telomerase activity of myeloma cells was determined by a polymerase chain reaction-based telomeric repeat amplification protocol assay. Ki-67 positivity of the purified cells was determined by flow cytometry using anti-Ki-67 antibody. The relationship between telomerase activity and prognostic factors was also examined. RESULTS: A significantly high degree of telomerase activity was detected in subjects with a serum beta2-microglobulin level > or = 6 mg/dL or at Stage III (P = 0.002). The serum C-reactive protein, lactate dehydrogenase, and creatinine levels did not correlate with the telomerase activity, but this activity did significantly correlate with Ki-67 positivity and the percentage of plasma cells in the bone marrow (r = 0.561, P = 0.004, and r = 0.397, P = 0.049, respectively). The patients with high levels of telomerase activity were thus found to have a significantly short survival time after sampling (P = 0.035). CONCLUSIONS: The measurement of the telomerase activity in myeloma cells was found to be a reliable marker for the proliferating capacity and tumor mass in myeloma patients. The telomerase activity of myeloma cells may therefore be useful as a prognostic factor. Copyright 2002 American Cancer Society.
UI - 12018742
AU - Porche R; Levy V; Fermand JP; Katsahian S; Chevret S; Ravaud P
TI - Evaluating high dose therapy in Multiple Myeloma: use of quality-adjusted survival analysis.
SO - Qual Life Res 2002 Mar;11(2):91-9
AD - Departement de Biostatistique et Informatique Medicale, Hjpital Saint Louis, U444-INSERM, Universite Paris, France. email@example.com
PURPOSE: To incorporate quality-of-life considerations in assessing high dose therapy (HDT) for patients with Multiple Myeloma (MM). PATIENTS AND METHODS: A quality-adjusted survival analysis. using the quality-adjusted time without symptoms or toxicity (Q-TWiST) method, was applied to two randomized clinical trials conducted in patients with MM which compared randomized assignment to HDT vs. conventional chemotherapy (CCT) alone (MAG91) or followed by HDT (MAG90). Treatment benefit in terms of mean Q-TWiST was assessed through threshold utility analyses, i.e., sensitivity analyses of the choice of the utility coefficients over all possible values of utility weights. RESULTS: In both trials, results slightly favored the first-line HDT group over the first-line CCT group, with an average gain in TWiST of about 5.5 months over the 58 month-median follow-up period (27.8 vs. 22.3 months, respectively) in the MAG90 trial and 5.8 months over the 56 month-median follow-up period (19.1 vs. 13.3 months, respectively) in the MAG91 trial. The utility threshold analyses revealed that the first-line HDT group had a statistically increased mean quality-of-life adjusted time compared to the other group for a broad range of utility coefficient values. CONCLUSION: The development of such understandable and intuitive measures of expressing the relative benefit of complex treatment strategies is expected to be used in clinical decision making in the near future.
UI - 11868870
AU - Neki NS; Sharma RK; Sharma N; Multani LS
TI - Multiple myeloma presenting as proptosis and sixth nerve palsy.
SO - J Assoc Physicians India 2001 Nov;49():1116-7
AD - Department of Medicine, Government Medical College/GND Hospital, Amritsar.
Cranial and intracranial locations are rare in multiple myeloma (MM). But their occurrence has a particular significance. Proptosis and 6th nerve palsy is very uncommon presentation. We report a case of MM with presenting features as proptosis and 6th nerve palsy.
UI - 11920260
AU - Blade J; San Miguel JF; Fontanillas M; Esteve J; Maldonado J; Alcala A;
TI - Brunet S; Garcia-Conde J; Besalduch J; Moro MJ; Fernandez-Calvo J; Conde E; Font L; Gardella S; Carnero M; Carbonell F; Marti JM; Hernandez-Martin J; Ortega F; Besses C; Ribera JM; Trujillo J; Escudero ML; Rozman C; Estape J; Montserrat E Increased conventional chemotherapy does not improve survival in multiple myeloma: long-term results of two PETHEMA trials including 914 patients.
SO - Hematol J 2001;2(4):272-8
AD - Spanish Cooperative Group for Hematological Malignancies Treatment (PETHEMA), Spanish Society of Hematology. Institut de Investigacions Biomediques August Pi i Sunyer. Hospital Clinico. Barcelona. Spain. firstname.lastname@example.org
BACKGROUND: Melphalan and prednisone (MP) has been the standard treatment for multiple myeloma (MM) for the last 30 years. Combination chemotherapy at conventional doses has not shown a significant prolongation of survival when compared to MP. There are few data comparing conventional chemotherapy at standard doses with conventional treatment at higher doses. We present the long-term outcome of 914 patients from two randomized trials comparing three different dose intensity regimens. METHODS: From 1 January, 1985 to 31 December, 1989, 487 patients were randomized between MP (melphalan 9 mg/m(2) p.o. and prednisone 60 mg/m(2) days 1-4) and alternating VCMP (vincristine 1 mg i.v. on day 1, cyclophosphamide 500 mg/m(2) i.v. on day 1, melphalan 6 mg/m(2) p.o. on days 1-4, and prednisone 60 mg/m(2) on days 1-4) and VBAP (vincristine 1 mg i.v. on day 1, BCNU and doxorubicin 30 mg/m(2) i.v. each on day 1, and prednisone 60 mg/m(2) on days 1-4). From 1 January, 1990 to 31 May, 1994, 427 patients were randomized between VCMP/VBAP at the above detailed doses (VCMP/VBAP 'SD') and the same regimen increasing the doses of cyclophosphamide and doxorubicin from 500 to 1200 mg/m(2) and from 30 to 50 mg/m(2), respectively (VCMP/VBAP 'HD'). RESULTS: Increasing dose intensity produced a significantly higher partial response rate (31% vs 45% vs 51% for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P < 0.01). However, a significantly early death rate was observed in the HD arm (7.7, 7.5 and 12.1% for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = 0.05). Median duration of response (20 vs 18 vs 19 months for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = NS) and median survival (25 vs 31 vs 29 months for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = NS) were similar in the three groups. MP produced a higher degree of thrombocytopenia than combination chemotherapy at standard (P = 0.002) or high dose (P = 0.01), this leading to a significantly higher dose reduction in the MP arm (P < 0.001 and P = 0.003 for VCMP/VBAP 'SD' and VCMP/VBAP 'HD', respectively). CONCLUSION: In these trials the response rate significantly correlated with the regimen intensity. However, no significant differences in response duration and survival were found. This highlights the limited role of conventional chemotherapy in MM and the need for further trials, aimed at determining the impact of new treatment approaches such as high-dose therapy/autotransplantation.
UI - 11872748
AU - Hideshima T; Chauhan D; Richardson P; Mitsiades C; Mitsiades N; Hayashi
TI - T; Munshi N; Dang L; Castro A; Palombella V; Adams J; Anderson KC NF-kappa B as a therapeutic target in multiple myeloma.
SO - J Biol Chem 2002 May 10;277(19):16639-47
AD - Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
We have shown that thalidomide (Thal) and its immunomodulatory derivatives (IMiDs), proteasome inhibitor PS-341, and As(2)O(3) act directly on multiple myeloma (MM) cells and in the bone marrow (BM) milieu to overcome drug resistance. Although Thal/IMiDs, PS-341, and As(2)O(3) inhibit nuclear factor (NF)-kappaB activation, they also have multiple and varied other actions. In this study, we therefore specifically address the role of NF-kappaB blockade in mediating anti-MM activity. To characterize the effect of specific NF-kappaB blockade on MM cell growth and survival in vitro, we used an IkappaB kinase (IKK) inhibitor (PS-1145). Our studies demonstrate that PS-1145 and PS-341 block TNFalpha-induced NF-kappaB activation in a dose- and time-dependent fashion in MM cells through inhibition of IkappaBalpha phosphorylation and degradation of IkappaBalpha, respectively. Dexamethasone (Dex), which up-regulates IkappaBalpha protein, enhances blockade of NF-kappaB activation by PS-1145. Moreover, PS-1145 blocks the protective effect of IL-6 against Dex-induced apotosis. TNFalpha-induced intracellular adhesion molecule (ICAM)-1 expression on both RPMI8226 and MM.1S cells is also inhibited by PS-1145. Moreover, PS-1145 inhibits both IL-6 secretion from BMSCs triggered by MM cell adhesion and proliferation of MM cells adherent to BMSCs. However, in contrast to PS-341, PS-1145 only partially (20-50%) inhibits MM cell proliferation, suggesting that NF-kappaB blockade cannot account for all of the anti-MM activity of PS-341. Importantly, however, TNFalpha induces MM cell toxicity in the presence of PS-1145. These studies demonstrate that specific targeting of NF-kappaB can overcome the growth and survival advantage conferred both by tumor cell binding to BMSCs and cytokine secretion in the BM milieu. Furthermore, they provide the framework for clinical evaluation of novel MM therapies based upon targeting NF-kappaB.
UI - 11928568
AU - Grzasko N; Dmoszynska A; Krawczyk S; Hus M; Soroka-Wojtaszko M; Ciepluch
TI - H; Hellmann A [Evaluation of blood morphology in patients with refractory multiple myeloma treated with thalidomide]
SO - Pol Arch Med Wewn 2001 Jul;106(1):573-9
AD - Klinika Hematoonkologii i Transplantacji Szpiku AM w Lublinie.
Thalidomide, a derivative of alpha-N-phthalimidoglutarimide acid, was withdrawn from the market in the 1960s because of severe birth defects. Recent reports have suggested antiangiogenic and antitumor activity of this drug. We have treated 52 patients with refractory multiple myeloma at age from 32 to 79 years (mean 63) with thalidomide at a dose of 200-400 mg daily. Out of the group of 52 patients, 27 patients (52%) responded to the therapy, in 25 patients (48%) a response was not achieved (decline in monoclonal protein was smaller than 25%). There was a systematic improvement in haemoglobin concentration, erythrocyte count and thrombocyte count during thalidomide therapy. Leukocyte count showed an inclination to decrease, however observed changes were not statistically significant. The improvement in morphotic parameters of blood was observed both in responder and nonresponder patients.
UI - 12043184
AU - Ogasawara T; Yasuyama M; Kawauchi K
TI - [Biclonal light chain gammopathy in multiple myeloma--a case report]
SO - Nihon Rinsho Meneki Gakkai Kaishi 2002 Apr;25(2):170-6
AD - Department of Medicine, Tokyo Women's Medical University Daini Hospital. low-back pain. In 1990, she had a chemotherapy for diffuse mixed cell lymphoma. Biochemical and serologic assays revealed a total protein level of 9.7 g/dl and an IgG level of 4,530 mg/dl. Immunoelectrophoresis showed monoclonal IgG protein associated with two monoclonal kappa and lambda light chain components. Bone marrow examination showed proliferation of myeloma cells comprising up to 25% of all nucleated cells. Myeloma cells were immunohistochemically positive for IgG and kappa and lambda light chains. IgG contained equal amounts of IgG 1 and IgG 2 subtypes and the complementarity determining region 3 (CDR 3) of myeloma cells showed oligoclonality by polymerase chain reaction, suggesting the myeloma cells may have two components. The patient received melphalan and prednisone in combination, resulting in only a minor response. She eventually developed angioimmunoblastic T-cell lymphoma. Biclonal gammopathy associated with malignant lymphoma is rare in case of multiple myeloma and may provide some insight into the pathogenesis of plasma cell tumors.
UI - 11949632
AU - Schmidt HH
TI - Multiple myeloma: illegitimate switch recombinations and their relation to chromosomal translocations.
SO - Blood 2002 Apr 15;99(8):3072-3; discussion 3073-4
UI - 12038663
AU - Das T; Chaudhuri U
TI - Solitary plasmacytoma of the skull bone.
SO - J Assoc Physicians India 2002 Feb;50():270-2
AD - Department of Medicine, Medical College, Calcutta.
Solitary plasmacytoma of the bone is an uncommon variety of plasma cell tumour. Here an interesting case of solitary plasmacytoma of the skull bone, which is extremely rare, is being reported.
UI - 11924912
AU - Treon SP; Pilarski LM; Belch AR; Kelliher A; Preffer FI; Shima Y;
TI - Mitsiades CS; Mitsiades NS; Szczepek AJ; Ellman L; Harmon D; Grossbard ML; Anderson KC CD20-directed serotherapy in patients with multiple myeloma: biologic considerations and therapeutic applications.
SO - J Immunother 2002 Jan-Feb;25(1):72-81
AD - Department of Adult Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Clonotypic B cells circulating in patients with multiple myeloma (MM) express CD20, and it has been suggested that these cells may be clonogenic. Furthermore, 20% of patients with MM express CD20 on their bone marrow plasma cells (BMPCs). Therefore, the authors began a phase II clinical study to determine the activity of the anti-CD20 monoclonal antibody rituximab in MM patients. Nineteen previously treated MM patients received 375 mg/m2 rituximab per week for 4 weeks. Three months after initiation of treatment, patients were assessed for response and received a second course of therapy if their disease was stable (SD) or they achieved a partial response (PR). Six of 19 (32%) patients had either a PR (n = 1) or SD (n = 5), with a median time to treatment failure of 5.5 months (mean, 10.3 months; range, 3-27+ months). All six patients who had a PR or SD had CD20+ BMPC. Overall, rituximab therapy was well tolerated. Because most patients with MM poorly express CD20 on their BMPCs, the authors evaluated agents for their ability to induce CD20 expression and thereby facilitate rituximab binding on MM cells. These studies show that interferon-gamma (IFN-y) induced CD20 expression on MM BMPCs, MM B cells, and healthy donor BMPCs. In contrast, CD20 expression on chronic lymphocytic leukemia, follicular non-Hodgkin's lymphoma, healthy donor B cells, and progenitor cells was unaffected by IFN-y. Rituximab binding to the BMPCs of MM patients was also increased after culture with pharmacologically attainable levels of IFN-gamma (1-100 U/mL). In conclusion, these studies suggest that MM patients with CD20+ BMPCs may benefit from rituximab therapy. Furthermore, IFN-gamma induces CD20 expression on MM BMPCs and B cells and facilitates rituximab binding to MM BMPCs, providing the rationale for clinical trials to examine its use with CD20-directed serotherapies in MM.
UI - 11167810
AU - Fassas AB; Bolanos-Meade J; Buddharaju LN; Rapoport A; Cottler-Fox M;
TI - Chen T; Lovchik JC; Cross A; Tricot G Cytomegalovirus infection and non-neutropenic fever after autologous stem cell transplantation: high rates of reactivation in patients with multiple myeloma and lymphoma.
SO - Br J Haematol 2001 Jan;112(1):237-41
AD - Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA. FassasAthanasios@exchange.uams.edu
In a retrospective study, we examined the association between cytomegalovirus (CMV) infection and non-neutropenic fever immediately following autologous peripheral blood stem cell transplantation for a variety of haematological malignancies and solid tumours. Sixty non-neutropenic febrile episodes (41 in CMV-seropositive and 19 in CMV-seronegative patients) were evaluated. CMV reactivation, documented by CMV antigenaemia, was detected in 16 out of 41 (39%) seropositive patients compared with 0 out of 19 seronegative patients. In 12 of these 16 patients, CMV infection was considered the sole cause of fever. Thirteen patients had maximum antigenaemia levels > 5 cells/slide. Specific antiviral treatment led to the resolution of the fever in all, but two, patients, who developed fatal CMV pneumonia. Patients with multiple myeloma and lymphoma, possibly owing to a combination of disease-related characteristics and prior immunosuppressive treatment, had high rates of CMV reactivation and may require more frequent diagnostic evaluation and prompt therapeutic intervention.
UI - 11418482
AU - Davies FE; Raje N; Hideshima T; Lentzsch S; Young G; Tai YT; Lin B;
TI - Podar K; Gupta D; Chauhan D; Treon SP; Richardson PG; Schlossman RL; Morgan GJ; Muller GW; Stirling DI; Anderson KC Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma.
SO - Blood 2001 Jul 1;98(1):210-6
AD - Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
The antiangiogenic activity of thalidomide (Thal), coupled with an increase in bone marrow angiogenesis in multiple myeloma (MM), provided the rationale for the use of Thal in MM. Previously, the direct anti-MM activity of Thal and its analogues (immunomodulatory drugs, IMiDs) on MM cells was demonstrated, suggesting multiple mechanisms of action. In this study, the potential immunomodulatory effects of Thal/IMiDs in MM were examined. It was demonstrated that Thal/IMiDs do not induce T-cell proliferation alone but act as costimulators to trigger proliferation of anti-CD3-stimulated T cells from patients with MM, accompanied by an increase in interferon-gamma and IL-2 secretion. However, an increase in autologous T-cell killing of patient MM cells could not be demonstrated. A role for natural killer (NK)- and LAK-cell-mediated killing is suggested because IL-2-primed peripheral blood mononuclear cells (PBMCs) treated with Thal/IMiDs demonstrated significantly increased lysis of MM cell lines. Cold target inhibition assays suggested NK- rather than LAK-cell-mediated killing. Furthermore, this killing was not major histocompatibility complex-class restricted, and the depletion of CD56(+) cells blocked the drug-induced MM cell lysis. It was significant that increased killing of patient MM cells by autologous PBMCs treated with Thal/IMiDs was also observed. Although the in vivo relevance of NK-cell-mediated MM cell killing is unknown, phenotypic analysis performed in MM patients receiving Thal therapy demonstrated an increase in CD3(-)CD56(+) cells in patients responding to therapy. Thus in vitro and in vivo data support the hypothesis that Thal may mediate its anti-MM effect, at least in part, by modulating NK cell number and function.
UI - 11964279
AU - Berenson JR; Crowley JJ; Grogan TM; Zangmeister J; Briggs AD; Mills GM;
TI - Barlogie B; Salmon SE Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients.
SO - Blood 2002 May 1;99(9):3163-8
AD - Cedars Sinai Medical Center and the Jonsson Comprehensive Cancer Center, University of California-Los Angeles, USA.
The role of maintenance therapy in multiple myeloma is controversial. Recent studies have shown an improvement in both progression-free and overall survival for patients receiving maintenance treatment with a combination of interferon and glucocorticoids, compared with interferon alone. The role of glucocorticoids alone as maintenance therapy has not been previously addressed. We compared alternate-day, oral prednisone at 2 different dose levels (10 mg versus 50 mg) for remission maintenance among previously untreated myeloma patients following a response to induction with standard-dose vincristine, doxorubicin, and dexamethasone with prednisone (VAD-P) or VAD-P plus quinine (VAD-P/Q). There were 250 eligible patients registered on Southwest Oncology Group study 9210 and randomized to receive VAD-P or VAD-P/Q. There were 125 patients achieving at least a 25% tumor reduction following induction therapy who were randomized to either physiologic (10 mg) or pharmacologic (50 mg) doses of alternate-day, oral prednisone until disease progression. At the time of study entry, patient characteristics were similar in VAD-P and VAD-P/Q patients and in the 2 arms randomized to maintenance therapy. After a median follow-up of 53 months, there was no difference in either progression-free or overall survival between the 2 induction regimens. However, from the time of maintenance randomization, both progression-free (14 versus 5 months; P =.003) and overall survival (37 versus 26 months; P =.05) were significantly improved in patients receiving 50 mg as compared with 10 mg alternate-day prednisone. There was no difference in treatment-related adverse events between the groups. Thus, 50 mg, oral, alternate-day prednisone is effective maintenance treatment for multiple myeloma patients who achieve a response to induction chemotherapy. (Blood. 2002;99:3163-3168)
UI - 11964294
AU - Wen YJ; Min R; Tricot G; Barlogie B; Yi Q
TI - Tumor lysate-specific cytotoxic T lymphocytes in multiple myeloma: promising effector cells for immunotherapy.
SO - Blood 2002 May 1;99(9):3280-5
AD - Myeloma and Transplantation Research Center, University of Arkansas for Medical Science, Little Rock 72205, USA.
The idiotype protein, secreted by myeloma plasma cells, is a tumor-specific but weak antigen. Idiotype-based immunotherapy has been explored in myeloma patients with disappointing results. It is conceivable that myeloma cells contain a multitude of tumor antigens that can more effectively stimulate antitumor T cells. To explore the possibility of using whole myeloma cells as a source of tumor antigens for immunotherapy, the current study was undertaken to generate and examine the function of myeloma-specific cytotoxic T lymphocytes (CTLs) by using dendritic cells (DCs) pulsed with myeloma cell lysates as stimulating cells. After repeated stimulation, specific CTL lines, containing CD4(+) and CD8(+) T cells, were generated from myeloma patients. Our results show that these T cells not only recognized and lysed autologous myeloma protein-pulsed DCs, they also killed autologous primary myeloma cells. Occasionally, CTLs responded to autologous idiotype-pulsed DCs and to allogeneic primary myeloma cells. No cytolytic activity, however, was detected against autologous lymphocytes including B cells, suggesting that the T cells acted specifically against myeloma cells. Cytotoxicity against target cells was major histocompatibility complex class 1 and, to a lesser extent, class 2 restricted and was dependent mainly on the perforin-mediated pathway. CTLs secreted predominantly interferon-gamma and tumor necrosis factor-alpha on antigenic stimulation, indicating a type 1 T-cell subset. These findings represent the first demonstration that tumor cell lysate-primed CTLs kill only myeloma cells, not autologous lymphocytes. This provides a rationale for myeloma cell-based immunotherapy in multiple myeloma.
UI - 12041852
AU - Chen BH
TI - Monoclonal gammopathy of undetermined significance: new insights.
SO - CMAJ 2002 May 14;166(10):1309
AD - Division of General Internal Medicine, Queen's University, Kingston, Ont.
UI - 12038950
AU - Mueller PS; Terrell CL; Gertz MA
TI - Fever of unknown origin caused by multiple myeloma: a report of 9 cases.
SO - Arch Intern Med 2002 Jun 10;162(11):1305-9
AD - Division of General Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
BACKGROUND: Most authorities regard multiple myeloma as a rare cause of fever and not a cause of fever of unknown origin (FUO). OBJECTIVE: To describe a series of patients with FUO caused by multiple myeloma. METHODS: We reviewed the clinical features of 9 patients seen at Mayo Clinic from January 1, 1975, to February 1, 2001, with FUO caused by multiple myeloma. RESULTS: Fever of unknown origin caused by multiple myeloma was found in 9 patients (6 men and 3 women). All patients satisfied accepted criteria for FUO. The mean +/- SD time from the onset of fevers to the initial physician evaluation was 4.8 +/- 2.0 weeks. The mean time from the initial physician evaluation to the diagnosis of multiple myeloma was 11.4 +/- 6.5 weeks. The mean age at diagnosis of multiple myeloma was 55.9 +/- 6.9 years. All 9 patients were anemic. Peripheral blood smears were available for 8 patients, and all had rouleaux formations. All 9 patients underwent exhaustive testing to determine the cause of fevers. Further testing was done in 6 patients subsequent to the diagnosis of multiple myeloma. Acetaminophen or nonsteroidal anti-inflammatory drugs or both relieved fevers in all patients who received them. All 8 patients who received chemotherapy experienced resolution of fevers. The median actuarial survival of the patient cohort was 38 months. CONCLUSIONS: Multiple myeloma can cause FUO. When appropriate, clinicians should include multiple myeloma in the differential diagnosis of FUO to reduce unnecessary testing, rapidly establish the diagnosis, and initiate effective treatments.
UI - 12040451
AU - Cheung WC; Van Ness B
TI - Distinct IL-6 signal transduction leads to growth arrest and death in B cells or growth promotion and cell survival in myeloma cells.
SO - Leukemia 2002 Jun;16(6):1182-8
AD - Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
In B cell development, interleukin-6 (IL-6) induces terminal maturation of B lymphocytes into antibody producing plasma cells. Terminal differentiated B cells cell cycle arrest and death follows. In contrast, IL-6 acts as a growth factor for malignant myeloma plasma cells and in some cases protects them from therapeutic treatment. In this study, we examined two cell lines that show different responses to IL-6. Lymphoblastoid CESS cells respond to IL-6 by terminally differentiating into antibody producing plasma cells, cell cycle arrest, and undergo cell death. Continuous addition of IL-6 to these cells induces transient activation of STAT3, SHP-2 phosphorylation, and does not alter bcl-X(L) and c-myc expression. In contrast, the myeloma line ANBL6 proliferates when stimulated with IL-6 and this correlates with prolonged STAT3 activation and up-regulation of bcl-X(L) and c-myc. Interestingly, gp130-associated SHP-2 phosphorylation was detected in the IL-6-induced CESS cells but not myeloma cell lines. The data show a very distinct IL-6 signal transduction and kinetics in these cell lines and the distinct molecular events correlate closely to the cell fate of the lymphoblast and myeloma cell lines.
UI - 12040452
AU - French JD; Tschumper RC; Jelinek DF
TI - Analysis of IL-6-mediated growth control of myeloma cells using a gp130 chimeric receptor approach.
SO - Leukemia 2002 Jun;16(6):1189-96
AD - Dept of Immunology, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, MN 55905, USA.
Interleukin 6 (IL-6) has been shown to be a key growth factor for myeloma cells. To study IL-6 signal transduction in multiple myeloma (MM), we employed chimeric receptors composed of the epidermal growth factor receptor (EGFR) extracellular domain, gp130 transmembrane domain, and full-length or truncated gp130 cytoplasmic domains lacking regions previously shown to be necessary for MAPK, STAT1, and STAT3 activation. The IL-6-dependent KAS-6/1 MM cell line was transfected with various chimeric receptor constructs and assayed for EGF responsiveness. EGF stimulation surprisingly stimulated DNA synthesis in all transfectants, regardless of receptor length. When cell proliferation was assayed instead, only transfectants capable of inducing high levels of STAT3 activation proliferated in response to EGF. Additional studies revealed that EGF stimulation resulted in tyrosine phosphorylation of endogenous gp130 in cells expressing the chimeric receptor. Replacing the gp130 transmembrane region with the EGFR transmembrane domain diminished but did not disrupt this interaction. This receptor interaction was also observed in the IL-6-dependent MM cell line ANBL-6. In summary, although our results suggest that STAT activation is crucial in gp130-mediated proliferation of myeloma cells, these results must be interpreted with caution given our demonstration of the interaction between chimeric and endogenous receptors in myeloma cells. Importantly, this interaction has not been noted in studies utilizing the same gp130 chimeric receptor system in non-MM cells.