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.     

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.     

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.     

The role of interferon-alpha in the treatment of multiple myeloma

Interferon-alpha (IFN-alpha) is an active therapeutic agent in multiple myeloma. IFN-alpha alone may induce complete or partial responses in approximately 20% of previously untreated patients. However, it remains less effective than conventional chemotherapy. Recently, it proved to be beneficial in some but not all studies, in combination with conventional chemotherapy, to improve the overall response rate and prolong the plateau phase in patients in remission. The Hanshin Hematological Neoplasia Study Group developed a regimen consisting of DMVM (dexamethasone, MCNU, VCR, melphalan) with IFN-alpha. This regimen yields an 69% response rate, including 26% complete remissions defined by disappearance of M-protein and morphological normalization of the bone marrow. The most effective strategy of administration has yet to be established.     

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.     

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.     

The efficacy of polychemotherapy programs in treating multiple myeloma patients

AIM: To compare efficiency of the programs MCVP, VCAP and ARA-COP in the treatment of multiple myeloma (MM) as regards completeness of the response, duration of the remission and toxicity. MATERIALS AND METHODS: A total of 41 MM patients entered the study (27 females, 14 males, age from 41 to 72 years, MM duration from 1 month to 8 years). 16, 10 and 15 patients were treated according to MCVP, VCAP and ARA-COP programs. RESULTS: Both in the resistant and primary patients the response was the highest to ARA-COP treatment. The remission or stabilization was achieved in 93.4% of patients. VCAP program was less effective. However, clinicohematological remission was achieved in 50% of patients. This program is rather heart toxic. MCVP program was the least effective. Survival was followed up in 16 patients (10 MCVP, 3 VCAP and 3 ARA-COP patients). The survival was 20-62, 16-36, 23.6-64.8 months for ARA-COP, VCAP and MCVP, respectively. CONCLUSION: ARA-COP program proved most effective of the three programs both in primary and drug-resistant patients. VCAP and MCVP programs are less effective but can be used in primary management of MM patients.     

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.     

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.     

Cytogenetics and molecular genetics in multiple myeloma

The striatum of the human brain has a highly differentiated neurochemical architecture visible in stains for many of the neurotransmitter-related molecules present in the striatum. The distributions for these chemical markers have never been analyzed comprehensively. We compared the distributions of multiple neurochemical markers in a serial-section analysis of the caudate nucleus, the putamen, and the ventral striatum in normal human brains. The cholinergic system was identified with choline acetyltransferase (ChAT). The organization of the cholinergic fiber system was compared with that of striatal systems expressing immunoreactivity for calbindin D28k, met-enkephalin, substance P, tyrosine hydroxylase, and parvalbumin. Each striatal region analyzed displayed a unique neurochemical organization. In the dorsal caudate nucleus, the distribution of all markers followed the classical striosome/matrix organization as previously reported. In the dorsal putamen, ChAT-staining was less intense, and striosomes were delineated primarily by unstained fiber bundles. In the ventral caudate nucleus/nucleus accumbens region, the boundaries of ChAT-stained regions were not always visible with stains for calbindin, enkephalin, and substance P. The ventral putamen displayed a similar organization, except in its lateral part, where ChAT-poor regions were often found adjacent to, rather than in register with, regions expressing low levels of the other markers (calbindin, enkephalin, substance P, and tyrosine hydroxylase). Our findings suggest that, in addition to the classical striosome-matrix organization visible in the dorsal caudate nucleus and putamen, there is further neurochemical differentiation in a large ventral part of the caudate nucleus and putamen and in the ventral striatum-nucleus accumbens proper. The more complex relationships among the different neurochemical systems in the ventral striatum may reflect the increase in size in the primate of striatal regions associated with association and limbic cortex.     

Bone manifestations of multiple myeloma and therapeutic possibilities

In the text are summarized the results of studies dealing with supportive therapy of multiple myeloma bone disease. The similarities of primary osteoporosis and osteoporosis in multiple myeloma raised a hope that sodium fluoride will help to prevent or to slow down the osteoporotic process in multiple myeloma patients. The first studies in small groups of patients reported some advantage for the patients with sodium fluoride, later in randomized studies no benefit of sodium fluoride was confirmed. The effect of calcitonin was studied in small groups of patients. All studies confirmed analgetic effect and some of them proved positive effect on the amount of bone hydroxyapatite by a histomorphometric examination. The contribution of bisphosphonate to the therapy of myeloma patients was confirmed in extensive studies. With the exception of a Canadian study with ethidronate, all studies reported good analgetic effects and the inhibitory influence on bone destruction. The advantage of bisphosphonates in comparison to calcitonin is the possibility of p.o. administration or in i.v. periodical administration several times a year.     

A case-control study of multiple myeloma and occupation

Lifetime job histories from a population-based, case-control study were analyzed to investigate the relationship between multiple myeloma and employment in various occupations and industries. Interviews were obtained from 89% (692) of eligible incident cases and 83% (1683) of eligible controls. An elevated risk was observed among persons ever employed as painters [odds ratio (OR) = 2.1, 95% confidence interval (CI) = 1.2-3.6], particularly for those employed for 10 or more years (OR = 4.1, 95% CI = 1.8-10.4). A small excess risk was observed among agricultural workers employed for 10 or more years (OR = 1.3, 95% CI = 1.0-2.2), with a higher relative risk observed among farm laborers (OR = 1.8, 95% CI = 1.0-4.0). Among agricultural workers who reported having been highly exposed to pesticides, the OR was 5.2 (95% CI = 1.6-21.1). Some evidence, based on smaller numbers, was also found to support an association with firefighting and employment in the petroleum- and coal-products manufacturing industries. Little evidence was found to support the previously noted association with wood exposure, and no evidence for an association with employment in the rubber or petroleum refining industries was found. This study lends further support to previously reported associations between multiple myeloma and employment among painters and agricultural workers.     

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.