Oral low-dose etoposide therapy for refractory multiple myeloma with extramedullary involvement

A 65-year-old man was hospitalized with IgG kappa-type multiple myeloma (MM) and enormous subcutaneous plasmacytomas. Two different combination chemotherapy regimens (MMCP and AVPP) and alpha-interferon therapy were ineffectual. Oral administration of etoposide at 50 mg/day was subsequently started, the tumors completely disappeared after 5 months. The blood level of monoclonal protein became undetectable after 8 months of continuous treatment. The side effect noted was loss of hair. The course in this patient suggests that long-term daily low-dose administration of etoposide should be attempted in patients with refractory MM and extramedullary plasmacytoma.     

Nitrosoureas in multiple myeloma

A number of cooperative-group and single-institution studies have shown that BCNU used in combination with prednisone alone or with melphalan,cyclophosphamide, and prednisone is useful for remission induction in patients with previously untreated multiple myeloma. In this setting, results with BCNU (and probably CCNU) are as good as (but not superior to)the results obtained to the frequency of remission induction, duration of remission, and survival. BCNU plus prednisone also appears to be equal to melphalan plus prednisone for remission-maintenance therapy, although it is still unclear whether maintenance therapy is superior to discontinuation of therapy during remission. At the present time, the major use of the nitrosoureas in multiple myeloma appears to be for patients who enter remission with conventional alkylating-agent therapy and later relapse. BCNU and CCNU are occasionally effective when used as single agents or in combination with other alkylating agents for relapsing patients. Results of a pilot study at the University of Arizona with low doses of BCNU and adriamycin for patients relapsing on alkylating-agent therapy have been encouraging, with a 54% (seven of 13 patients) incidence of CRs and PRs. The use of this combination in conjunction with vincristine and prednisone for relapsing patients is under investigation by the Southwest Oncology Group.     

Imaging of multiple myeloma

Multiple myeloma (MM) is characterized by a proliferation of plasma cells responsible for osteolytic lesions. Imaging studies are performed in MM to establish diagnosis and prognosis, and may also be used to judge the efficacy of treatment and to detect complications. TO ESTABLISH THE DIAGNOSIS: Conventional radiography demonstrates, at the time of diagnosis, characteristic features in 80% of cases. These lytic lesions involve more often the sites of red marrow. More rarely the only abnormal finding is diffuse osteopenia. Tomodensitometry and, above all, magnetic resonance imaging (MRI), which is a reference method for bone marrow disorders, can be useful for diagnosis in some difficult cases. But the lesions observed, hyposignals on spin echo T1 sequences and hyposignals on T2-weighted gradient echo, are not specific and usually do not allow to distinguish MM from osteolytic metastasis or other bone marrow disorders. TO DETERMINE EXTENT OF DISEASE AND TO EVALUATE PROGNOSIS: According to Durie and Salmon, the extension of home lesions at diagnosis is strongly correlated with the myelomatous measured cellular mass and with survival of patients. But this relation is denied by some authors who have noted that the shortest survival was seen in patients with normal X-rays. TO JUDGE THE EFFICACY OF TREATMENT: Improvement of the radiological abnormalities is observed in nearly 30% of patients responding to a conventional chemotherapy and appears to be an adverse pronostic sign. A good correlation between MRI and the biological response to treatment has also been reported. TO RECOGNIZE COMPLICATIONS OF DISEASE: Conventional radiography is also very important in diagnosis of complications like fractures or vertebral compression. Lastly, MRI is the investigation of first choice in the evaluation of patients with suspected spinal cord compression.     

Hyperammonemic encephalopathy in multiple myeloma

We report two cases of hyperammonemic encephalopathy in patients with multiple myeloma. This rare complication, whose pathophysiology remains unknown, is associated with disease progression and so with a very bad prognosis. We believe that this complication should be included in the differential diagnosis of encephalopathy occurring in multiple myeloma.     

Immunochemical studies in multiple myeloma

Many hospitals are converting to electronic records and allied health professionals are required to modify their traditional documentation practices to accommodate this new technology. This paper discusses a study conducted to determine the computer anxiety and attitudes of physical, occupational, and speech therapists in a large urban teaching hospital before and after the implementation of a computerized documentation system. Fifty-three therapists surveyed with a preinstallation questionnaire reported mild computer anxiety and generally good attitudes about the planned computer system. A greater amount of previous computer use and better self-related computer skills were consistent with less computer anxiety. Seven of the original sample became the first to use the computer system. After their six month trial period, surveys revealed a reduction in computer anxieties. Manual time logs completed before and after the system implementation revealed a significant decrease in total documentation time when using computers.     

Glomerular lesions in multiple myeloma

An autopsy case of multiple myeloma (IgG, lambda type), clinically characterized by decreased glomerular filtration rate, is reported with particular emphasis on changes in the glomeruli of kidneys. Histologically, the glomeruli revealed slight increase in mesangial matrix and focal thickening of tuft capillary wall. Electron-microscopically, deposits were observed in a subendothelial location in the glomerular capillary walls, and inclusions were noted in the cytoplasm of the visceral epithelial cells. Histoimmunofluorescent study of the kidney demonstrated intense focal and slight diffuse positivity against labelled antisera of anti-IgG and anti-lambda type of light chain on the capillary wall of the glomerular tufts. Other immunoglobulins were not demonstrable in capillary walls. These findings represent the intraglomerular deposition of paraprotein of multiple myeloma without amyloidosis.     

Immunoregulatory mechanisms in multiple myeloma

This review presents current experimental data regarding immunologic changes associated with multiple myeloma (Table 1). It is becoming increasingly clear that some of the immunologic changes are host responses to the malignant plasma cell clone and monoclonal immunoglobulin. In the last 2 to 3 years an anti-idiotypic response has been clearly documented, and cells expressing CD16 and soluble CD16 have been identified as modulators of myeloma cell growth and differentiation. Abnormalities in B- and T-cell differentiation have been observed, most consistently the deficiency of T4 helper cells. Differences in the immunologic changes point to the provocative hypothesis that, in MGUS and the initial stages of myeloma, immunologic responses play an important role in controlling proliferation of the malignant clone, and at some point the system is overwhelmed or fails, leading to an overt or more aggressive disease. The quest is to understand the genesis of the autoregulatory circuits operative in myeloma. Novel strategies for immunotherapy in management of myeloma will arise through improved understanding of host immune response and its cause-and-effect relationship with myeloma cell growth.     

Prognostic factors of multiple myeloma

Multiple myeloma is a heterogeneous disease with survival ranging from a few months to many years. Several clinical parameters (S beta 2-M) are a direct expression of the tumor burden and have been shown by univariate analysis to be related to patient survival. Durie and Salmon developed a myeloma staging system that analyzed the presenting clinical features, response to treatment and survival duration. But this classification is not related to the intrinsic malignancy (labeling index). Many new parameters (genetic alterations, plasma cell evaluation; serum marqueurs, immune dysregulation) related to patient response to chemotherapy and survival duration have been identified. However, they have not yet been included in standard staging and compared with the recognized prognostic parameters in multivariate analysis. There is a need to create a new international myeloma staging system based on biological features of the disease.     

Growth control mechanisms in multiple myeloma

Neo red cells (NRCs) are a blood substitute representing stroma free hemolysate (SFHL) encapsulated in liposomes and containing NAD, glucose, adenine, and inosine, etc. as substrates or coenzymes of the Embden-Meyerhof pathway in RBCs and inositol hexaphosphate (IHP) as an allosteric effector. The oxygen transport efficiency (OTE) of NRCs was increased to > 45% when the oxygen partial pressure in arterial blood increased. We carried out exchange transfusion with NRCs in rats, monitored their functioning as a blood substitute in vivo, and demonstrated that NRCs worked sufficiently. First, we confirmed that the OTE of NRCs was augmented by increasing the oxygen supply to the rats by using oxygen masks. Second, we carried out 70% blood exchange with NRCs (with hemoglobin concentrations of 4, 5, 6, or 7 g/dl), and compared these experimental groups with control groups (RBC and saline). Each sample was contained bovine albumin (final volume of 5% (w/v)). As a result, the NRC groups with hemoglobin concentrations of 5, 6, and 7 g/dl showed stability after the exchange transfusion. On the other hand, the NRC group with hemoglobin concentration of 4 g/dl and the saline group showed respiratory acidosis and a drop of blood pressure and heart rate, and thus did not maintain an adequate oxygen supply. We concluded that a hemoglobin concentration of > 5 g/dl was sufficient in the NRC solution, and demonstrated in an experiment on animals that the OTE of NRCs was increased by using oxygen masks.     

Spinal cord injury in multiple myeloma

Myelomic spinal cord damage may be a result of both its compression and vascular disorders (squeezing of an artery, disorders of venous outflow). Diagnosis is based on evaluation of the following signs: normochromic anemia; increase of ESR, total protein and calcium levels; discovery of M-gradient in protein fractions of gamma-zone; multiple regions of destruction in spondylogramme. In doubtful cases magneto-resonance and computer tomography were the most informative. Highly effective was therapy with intensive chemoprogramme including either a range of preparations (alkeran, BGNU, cyclophosphan, adriblastina, prednisolon) or a combination of polychemotherapy with irradiation. The operation was indicated in both insufficiency of conservative therapy and increasing of the symptoms of the damage.     

Current role of immunotherapy in multiple myeloma

Myeloablative chemotherapy improved the results of multiple myeloma treatment but the disease remains incurable. Residual disease eradication is one of the main clues for further improvement of the prognosis of myeloma patients. Interferon alpha maintenance therapy has controversial results. New methods, such as consolidation therapy, antibodies, gene therapy, interleukins, immunotoxins, dendritic cells, vaccines and induction of graft-versus-tumor effect, are tested in the phase I/II clinical trials. This article briefly reviews the new treatment modalities of immunotherapy. Progress in adoptive cellular immunotherapy and progress in induction of graft versus myeloma effect are very promising. We are still not able to transfer very good preclinical results of immunotherapy into clinical results in vivo measured by event free and long-term survivals. Combination of myeloablative therapy followed a new type of immunotherapy focusing on residual disease eradication evaluated in the setting of sensitive disease may be optimal. Such approach could improve the current controversial status of immunotherapy in MM.     

Mechanisms of multiple myeloma cell growth

The mechanism of human multiple myeloma cell growth was studied utilizing eleven myeloma cell lines established in vitro or in vivo (Scid mouse). Four bone marrow derived cell lines grew dependently on IL-6 or bone marrow stromal cells. Seven extramedullary lesion derived cell lines grew spontaneously and additively proliferated in response to IL-6. All cell lines expressed the IL-6 receptor (IL-6R) and IL-6RmRNA, but none expressed IL-6mRNA. No IL-6 activity was detected in the myeloma cell culture supernatant. Both the anti-IL-6 antibody and anti-IL-6R antibody neutralized IL-6-induced proliferation, but did not inhibit spontaneous proliferation of extramedullary lesion derived cell lines. While establishing cell lines, it was found that the proliferating fraction was primarily included in a fraction which was non-adherent to stromal cells and composed of undifferentiated plasmablasts. Undifferentiated plasmablasts proliferated in response to IL-6, in contrast to the adherent, mature form of myeloma cells which did not proliferate in response to IL-6. Innoculation of myeloma cells into Scid mice induced subcutaneous tumor formation. These tumors were composed of undifferentiated plasmablasts, which also proliferated in response to IL-6. These results imply that the growth of bone marrow derived myeloma cell lines are dependent on the IL-6 paracrine mechanism and that the growth of extramedullary lesion derived cell lines primarily autonomous and additively dependent on the IL-6 paracrine mechanism.