Chromosome findings in multiple myeloma

Cytogenetic studies were performed on six patients with multiple myeloma in which G-banding allowed the identification of clonal chromosome abnormalities. Normal cells and random chromosome gains and losses were seen in all cases. Numerical clonal aberrations were observed in two cases. Among the remaining cases, clonal chromosome rearrangements were seen in two cases, whereas, the other two patients revealed both numerical and structural clonal anomalies. The following marker chromosomes were identified: 1q-, 2p+, 2q+, 7q-, 17p-, and five unidentified abnormal chromosomes.     

Clinical feature and laboratory findings of multiple organ failure

The pathology of multiple organ failure consists of tissue-cell damage (disruption of energy metabolism) and severe infections (host exhaustion). The impairment of the TCA cycle was mild in two-organ disease but was nearly arrested in three-organ disease, and the cells are considered to have been in lactic acidosis with a shift of the glycolytic system from pyruvate to lactate. Significant differences were observed also in the number and the function of lymphocytes between two-organ and three-organ diseases. Therefore, in multiple organ failure, infections are considered to worsen as the ability of antigen recognition is impaired and differentiation of B cells into antibody-producing cells is inhibited with a decrease in lymphocytes. The phagocytic activity of neutrophils did not decrease unless leukocytes were reduced.     

Initial bone marrow findings in multiple myeloma. Significance of plasma cell nodules

A retrospective review of bone marrow specimens from 235 patients with multiple myeloma and 148 patients with reactive plasmacytosis was performed in an attempt to evaluate the usefulness of bone marrow sections in distinguishing between these conditions. Although the presence of large homogeneous nodules and/or infiltrates of plasma cells in bone marrow sections remains the best criterion for the diagnosis of myeloma, a few specimens (2%) from patients with reactive plasmacytosis also showed this feature. In addition, 26% of the patients with myeloma had bone marrow sections that were considered nondiagnostic in that they lacked recognizable homogeneous nodules and/or infiltrates of plasma cells. Finally, distinguishing multiple myeloma from bone marrow involvement by lymphoplasmacytic lymphomas can be very difficult, if not impossible, based on findings in the sections alone.     

Bisphosphonates in multiple myeloma

Bone disease is a frequent manifestation of multiple myeloma, and results in considerable morbidity. In this review we summarise the current theories as to the mechanism of bony destruction in this disease and discuss the interrelationships between the malignant plasma cells and those cells responsible for bone remodelling, i.e. the osteoclasts and osteoblasts. The bisphosphonates are a long established group of drugs known to have inhibitory effects on osteoclast activity, and in common use for osteoporosis and Paget's disease. Their role in myeloma is less clear. Several clinical studies, including phase III randomised placebo controlled trials, have been reported in recent years. Although these have tended to show a benefit for bisphosphonate treatment, we have not yet identified the most appropriate use of these agents. Two of the clinical trials have suggested that bisphosphonates may also have a beneficial effect on the underlying disease, a tantalizing theory which has been supported with some early laboratory data.     

Anti-immunoglobulins in multiple myeloma

Human myeloma cells isolated from bone marrow aspirates by sucrose density gradients and cultured in vitro were shown to undergo proliferation and increased DNA synthesis upon incubation with anti-immunoglobulin (anti-Ig) antisera directed against the immunoglobulin that these cells carry or secrete. A circulating anti-Ig could be detected in the sera of the majority of these patients. In a γ-globulin-free medium, the isolated anti-Ig could stimulate the patient's own plasma cells to undergo proliferation in vitro. The possible role of circulating anti-Ig in the in vivo continued proliferation of a specific clone of bone marrow cells is discussed.     

Amylase-producing multiple myeloma

Summary The first autopsy case of amylase-producing IgA--type multiple myeloma is described. Immunohistochemically, amylase and and chains of immunoglobulin were demonstrated in the cytoplasm of the myeloma cells. Secretion of amylase by cultured myeloma cells obtained from the patient's pleural effusion was clearly demonstrated by the starch film method. Immunoelectron microscopically, positive reaction products for amylase and the chain of immunoglobulin were observed in the well developed endoplasmic reticulum. Since no secretory granules were observed, we postulated that the secretory process of amylase was not via the zymogen granules but via a mechanism similar to that for immunoglobulin.     

Interferon in the treatment of multiple myeloma

The effect of recombinant interferon-alpha-2C monotherapy was compared with the efficacy of VMCP-polychemotherapy in 42 patients with multiple myeloma in a prospective randomized multicenter trial. IFN-treatment induced remissions (R) in 2 (14%) and partial remissions (PR) in 4 (29%) out of 14 evaluable patients. 7 patients remained stable. Polychemotherapy induced R in 11 (57%) and PR in 6 (32%) of 19 evaluable patients. 2 (11%) patients remained stable. IFN was preferentially active in patients with low tumor burden and patients with IgA paraprotein. The proportion of responders (R + PR) was significantly lower in the IFN-arm (43%) compared to the polychemotherapy group (89%; p less than 0,001).     

Conventional chemotherapy in multiple myeloma

Multiple myeloma is a disease, mainly affecting elderly individuals, for which no curative therapy is available today. The most important aim of the treatment given to such patients should therefore be to improve the quality of life and prolong the period of non-progressive disease. A concise review is given of the therapeutic options in patients, for whom high-dose cytostatic therapy with stem cell support is not an alternative. Traditional intermittent courses of melphalan and prednisone still holds its role as standard induction therapy. This regimen has convincingly in a recent large world-wide overview been shown to be able to induce a length of overall and progression-free survival, that is comparable to what can be achieved with different forms of combination chemotherapy. For patients refractory to alkylating agents a combination of vincristine, doxorubicin and prednisone (VAD) or intermittent courses of high-dose steroids alone are well proven alternatives. Several new drugs are under evaluation, but their therapeutic role is not yet established.     

Drug resistance in multiple myeloma

Multidrug resistance (MDR) is a pleiotropic resistance against several unrelated drugs. It may be induced by prolonged exposure of cells to drugs such as doxorubicin, etoposide and vinca alkaloids. Once MDR develops in clinical tumors, it is a major obstacle for the improvement of treatment of multiple myeloma (MM). Several specific mechanisms have been identified in clinical refractory MM patients including typical MDR, which is associated with P-glycoprotein (Pgp) and Lung Resistance Protein (LRP). The expression of the proteins associated with these genes seems to depend on exposure to chemotherapeutic agents. Recently, reversal of MDR by non-cytotoxic agents such as verapamil, cyclosporin A and PSC 833 (Valdospar) was explored in acute leukemia and multiple myeloma. Preliminary results from clinical phase I/II trials indicate that reversal of MDR is possible and that it may lead to alterations of the plasma pharmacokinetics of the cytostatic agents, in addition to P-glycoprotein inhibition in tumor cells. The potential implications of P-glycoprotein reversal are discussed.