Novel therapies in monoclonal gammopathies

Multiple myeloma (MM) is a plasma cell malignancy with an incidence of approximately 20 000 cases per year. Over the past decade, the advent of novel therapies has resulted in a positive shift in survival for patients with advanced MM. Over the last decade progress has been made in the understanding of the mechanisms involved in myeloma cell proliferation, trafficking and survival. Through this understanding, molecular therapeutic targets have been identified and treatment programs which incorporate these concepts are beginning to appear. The current review does not intend to be a comprehensive compendium of available treatments rather to highlight the most exciting avenues of research in myeloma therapeutics. Novel immunomodulating drugs, proteasome inhibitors and monoclonal antibodies will be highlighted.     

Evaluation of hyperviscosity in monoclonal gammopathies

The serum or plasma hyperviscosity syndrome has been described in both monoclonal and polyclonal immunoglobulin disorders. The usefulness of initial and serial plasma viscosity measurements by an automated viscometer technique was evaluated and compared with serum protein electrophoresis data in 107 patients without monoclonal gammopathies and 153 patients with monoclonal gammopathies. In patients without monoclonal gammopathies, plasma viscosity correlated best with the concentration of gamma globulins. In patients with monoclonal gammopathies, plasma viscosity correlated best with the serum monoclonal protein concentration, but individual patient variations in the ratio of plasma viscosity to monoclonal protein concentration made accurate prediction of plasma viscosity difficult without direct measurement. Six of eight patients with plasma viscosity above 5.0 cp had classic symptoms of hyperviscosity syndrome, and four of the six had recurrent episodes. Six other patients with plasma viscosity above 4.0 cp had more subtle presentations of hyperviscosity but responded equally well to therapeutic lowering of plasma viscosity. These patients are part of a larger subset of 27 patients in whom initial plasma viscosity was above 3.0 cp. No patient with an initial plasma viscosity below 3.0 cp subsequently showed hyperviscosity symptoms. Plasma viscosity measured by this technique is a useful tool in screening patients with dysproteinemias to identify and monitor those with and at risk for the hyperviscosity syndrome.     

Current concepts on monoclonal gammopathies

This is a review of the monoclonal gammopathies, including a discussion of cause. The role of T lymphocytes and B lymphocytes is presented. The recognition of a monoclonal protein in the serum and urine is presented in detail.
The frequency of benign and malignant monoclonal gammopathies is provided. A long-term follow-up of 241 patients with apparently benign monoclonal gammopathy is examined closely. In this series, multiple myeloma, macroglobulinaemia, amyloidosis, or related disorders developed in 22% of the 241 patients with long-term disease. The median duration from the recognition of the monoclonal protein until the development of serious disease was approximately eight to ten years.
The differentiation of benign from malignant monoclonal gammopathics is examinad in detail. The point is made that paticnu must be folld indefinitely because malignancy may develop more than 20 years later. The association of monoclonal gammopathies with other apparently unrelated diseases discussed. (Aust NZ J Med 1992; 22: 291–302.)     

Ploidy and proliferative characteristics in monoclonal gammopathies

Measurements were performed in 143 patients with monoclonal gammopathy of the cellular substrate in the bone marrow, including analysis of DNA and RNA content and tritiated thymidine labeling index. Aneuploidy by DNA content was present in 80% of 115 patients with active multiple myeloma and in 4 of 9 patients with benign monoclonal gammopathy, but was absent in all 12 patients with myeloma in remission and in 7 individuals with Waldenstrom's macroglobulinemia. With regard to prognosis in multiple myeloma, a low pretreatment plasma cell labeling index of less than or equal to 1% heralded longer survival than that observed in patients with a labeling index less than 1%, independent of myeloma tumor burden and ploidy pattern, except for a subset of 17 patients with a low-degree hyperdiploid abnormality whose survival was not affected by the magnitude of the pretreatment labeling index. Thus, besides tumor burden, tumor proliferative activity and ploidy both appear to have additional prognostic importance for patients with multiple myeloma.     

Ankylosing spondylitis and monoclonal gammopathies.

From 1960 to 1990, 557 patients with ankylosing spondylitis (428 men, 129 women) were diagnosed and indexed in the department of rheumatology. Monoclonal gammopathies were found in seven (five men, two women) patients (1.3%). With one exception, ankylosing spondylitis preceded monoclonal gammopathies by many years. The distribution of the isotypes of the mIg found in these seven patients was striking when compared either with previous reports of an association between ankylosing spondylitis and monoclonal gammopathies or with local data on the epidemiology of monoclonal gammopathies: five patients with IgG, four of them of the lambda (lambda) type, and two IgM, both of the kappa (kappa) type were found; no patients with mIgA were recorded. Two patients were HLA-B27 positive and had slight and transient monoclonal gammopathies, whereas three subjects were HLA-B27 negative and had important spikes, corresponding in two subjects to malignant diseases. This observation raises the question of whether the coexistence of HLA-B27 and ankylosing spondylitis might provide a protective action. Epidemiological studies are required to clarify such points.     

Characterization of the colony-forming cell in monoclonal gammopathies

The nature of the colony-forming cell in the bone marrow of patients with monoclonal gammopathy, as defined in the stem cell assay described by Hamburger and Salmon, has been studied. It could be shown that the colony-forming cells produce immunoglobulins of the same idiotype, heavy chain and light chain, as the monoclonal bone marrow cells in the patient. Data regarding the presence or absence of J chain in the colonies, the failure to observe isotype-switch in the growing colonies, as well as the lack of inhibition of colony formation using antiidiotypic antibodies, strongly suggest that colony formation in vitro reflects proliferation of the clonogenic stem cell in the bone marrow without apparent differentiation. The stem cell may be of plasma cell nature.     

T-cell subsets in malignant lymphomas and monoclonal gammopathies

159 patients with malignant lymphomas or monoclonal gammopathies were investigated for lymphocytes and their subsets using conventional surface markers and a panel of monoclonal antibodies. In untreated patients with Hodgkin's disease, non-Hodgkin lymphomas and multiple myeloma, (MM) a reduction of T-cells and especially of the "helper/inducer" subset (OKT4+) was found to be a common phenomenon. The major abnormalities occurred in advanced stages of disease. Patients previously treated by chemo- and/or radiotherapy had a further decrease of T-cells, whereas the loss of OKT4+ cells was more pronounced than that of the "suppressor/cytotoxic" lymphocytes (OKT8+). The alterations of lymphocyte subsets persisted even in long-term remitters. Comparing the lymphocyte subsets in MM and benign monoclonal gammopathies (BMG), patients with BMG showed a significant reduction in OKT8+ cells, whereas the OKT4+ population was within normal range, resulting in a significant elevation of the OKT4/OKT8-ratio compared to the controls and untreated multiple myeloma.     

Prospective follow-up of monoclonal gammopathies in HIV-infected individuals

Summary. A cohort of 341 symptomless anti-human immunodeficiency virus (HIV)-1 positive individuals was screened over a 6-year period to detect a serum monoclonal gammopathy (MG) and to approach the prognostic significance of such anomaly in HIV infection. Eleven individuals with a MG were followed-up over a mean period of 50 months from the date of discovery of the MG. At the end of this period, the MG had disappeared in seven individuals, was still present in the four others. The appearance of a second MG was noticed in two cases, and of a third in one case. Immunoglobulin (Ig) typing identified eleven IgG kappa and three IgG lambda. Mean serum concentration of MG of individuals with persistent MG (14 · 3 g/l) and of individuals without (4 · 2 g/l) was significantly different ( P < 0 · 05). The discovery of a MG was without prognosis value on the disease progression and did not appear as a primary event in the subsequent development of lymphoma.     

Overview of monoclonal gammopathies of undetermined significance

Among the B-cell lymphoproliferative disorders, monoclonal gammopathy of undetermined significance (MGUS) is the humoral counterpart to monoclonal B-cell lymphocytosis. This review introduces the papers from the section devoted to MGUS at the International Workshop entitled 'Monoclonal B-cell lymphocytosis and chronic lymphocytic leukaemia: environmental and genetic risk factors.'     

Idiotype-reactive T-cell subsets and tumor load in monoclonal gammopathies

The presence of idiotype-reactive T-cell subsets and their relation to the tumor load were analyzed in 9 patients with monoclonal gammopathy of undetermined significance (MGUS), in 12 patients with multiple myeloma (MM) clinical stage I, and in 9 patients with MM stage II/III. An enzyme-linked immunospot assay was used to identify interferon-gamma (IFN-gamma)-, interleukin-2 (IL-2)-, or IL-4-secreting T cells after stimulation by F(ab')2 fragments of monoclonal IgG. The response to autologous IgG was significantly higher than that induced by isotypic monoclonal IgG. Comparable results were obtained in a proliferation assay (3H-thymidine incorporation). A total of 8 of 9 patients with MGUS, 7 of 12 patients with MM stage I, and 3 of 9 with MM stage II/III had T cells secreting IFN-gamma and/or IL-2 (T helper [Th1] type-1 cells), whereas cells secreting both Th1 and Th2 or Th0 types of cytokines were more frequent in patients with MM, particularly in those with MM stage II/III. The number and frequency of Th1-type cells were significantly higher in MGUS patients as compared with those of MM stage II/III. The results indicate that idiotype-reactive T cells of the Th1 and Th2 or Th0 subsets were present in MGs and might provide indirect evidence that idiotype-reactive Th1-type cells may have a regulatory impact on the human tumor B cells.     

Kidney damage in multiple myeloma and other monoclonal gammopathies

Multiple myeloma typically damages the skeleton in the form of osteolytic lesions or diffuse osteoporosis and causes a decrease in blood production. Renal insufficiency is diagnosed immediately at the onset of illness when establishing diagnosis in up to 20% of patients. Where patients suffer from an advanced form of the illness, it occurs in up to 40%. The predominant cause of damage to the kidneys is the monoclonal light chains. Most frequently, nephropathy is caused by the precipitation of light chains with the Tamm-Horsfall protein in the distal part of the loop of Henle and subsequent tubular ruptures and the creation of fibrous changes in the interstitium. Less frequently, there is clinically serious damage to tubular functions without indication of renal insufficiency. In some patients monoclonal immunoglobulin induces changes in the glomeruli. A rare type of damage is deposits of light chains in the form of AL-amyloid and subsequent nephritic syndrome. A very rare form is the deposition of monoclonal immunoglobulin in the form of amorphous matter (light-chain deposition disease) or in the form of crystals within tissue histiocytes (crystal storing histiocytosis). Both of these disorders cause renal insufficiency and less frequently nephritic syndrome such as AL amyloidosis. With timely and intensive treatment of multiple myeloma, which quickly suppresses the creation of light chains, a significant proportion of patients experience reparative changes and improved kidney function. The benefit of plasmapheresis for patients with severe kidney damage has not been confirmed by randomised studies. At the present time the first positive results are becoming available from tests of the use of pre-emptive haemodialysis with special columns that are permeable for light chains. The aim of the text is to provide information on the various forms of nephropathy whose closer analysis can reveal multiple myeloma and contribute to the timely diagnosis of the cause of the nephropathy.     

Evaluation of monoclonal gammopathies in the "well" elderly

The study of monoclonal gammopathies in the elderly provides an opportunity to define immunologic and neoplastic changes with aging. Previous reports using paper and cellulose acetate electrophoresis have documented an age-related increase in monoclonal gammopathies. In this study, the more sensitive techniques of high-resolution agarose gel electrophoresis and immunofixation were used, in conjunction with other protein studies, to further evaluate the prevalence of monoclonal gammopathies in 111 ambulatory residents (aged 62 to 95) of a retirement home. Eleven of the 111 residents (10 percent) were found to have a monoclonal gammopathy, ranging in concentration from 0.2 to 1.8 g/dl. All monoclonal gammopathies were confirmed by immunofixation, which also documented the presence of additional unsuspected monoclonal components in three of the 11 residents. The prevalence of monoclonal gammopathies by age ranged from 6 percent in the group younger than 80 years of age to 14 percent in the group older than 90 years of age. Only one of the 11 residents had any clinical or routine laboratory suggestion of a monoclonal gammopathy. The other 10 had normal ratios of total protein and albumin to globulin. Five of the 11 (45 percent) had an otherwise clinically unexplained erythrocyte sedimentation rate of more than 20 mm/hour, compared with only two of 100 in the group without monoclonal gammopathies. Follow-up studies one to three years after initial evaluation revealed that five of the 11 patients had died, two with evidence of disease progression. In the other six patients, monoclonal protein concentration and other protein values remained stable. An unexplained elevation of the erythrocyte sedimentation rate in the elderly warrants investigation for the presence of a monoclonal gammopathy. Agarose gel electrophoresis and immunofixation identify a higher percent of monoclonal gammopathies in the elderly than has previously been recognized. Identification of monoclonal components in this population is useful for the subsequent study of plasma cell dyscrasias, neoplastic disease, or other immune dysfunction in the aged.     

Is there any significance for intracellular crystals in plasma cells from patients with monoclonal gammopathies?

Several plasma cells morphological changes have been described in monoclonal gammopathies, including intracytoplasmic crystals. We report one case of indolent kappa-chain multiple myeloma with renal insufficiency, featuring plasma cells with Auer-rod-like intracytoplasmic inclusions. The relationship between such aberrations and those found in multiple-myeloma-associated adult Fanconi syndrome is discussed. The significance of intracellular storage and crystallisation of immunoglobulin within plasma cells remains partially unknown.     

Renal involvement in benign monoclonal gammopathies: an underdiagnosed condition

Renal involvement is observed frequently in association with malignant gammopathies, mainly those related to light chain deposition, although has also been described in non-malignant monoclonal gammopathy. This study reports the clinicopathological findings and outcome in 9 patients with nephropaty secondary to monoclonal immunoglobulin deposit in absence of malignancy. They were three men and six women and they were 59.2+/-12 years old. All patients presented proteinuria and different levels of renal insufficiency (mean creatinin = 315+/-187 micromol/L) at the moment of diagnostic. Two patients required dialysis at the time of renal biopsy. The pathology studies revealed a nodular sclerosing glomerulopathy in four cases, mesangiocapilary glomerulonephritis in three cases, only tubular lesions in one and mesangial lesions in the other one. The treatment applied was: Prednisone alone (two cases), with chemotherapy associated (melfalan in two, clorambucil in one and ciclophosphamide in another one). One patient received plasmapheresis and mycophenolate and another patient undergone a bone marrow authotransplant associated to mycophenolate and prednisone. One of the two patients who required dialysis at the moment of presentation was not treated. After a follow-up of more than 4 years (4.89 +/-DE: 3.69) renal function improved or remained stable in three patients and proteinuria was disappeared in more than 50% of patients. Four patients had a worsening of renal function and they required dialysis during the time of follow-up (in 2,4 years +/- DE: 4,3). In any case malignitation was observed. Chemotherapy stabilized or improved renal function in 3 of nine patients (33%) with non-malignant monoclonal gammopathy. Non-malignant monoclonal gammopathy could go unnoticed. Appearance of abnormalities in renal routine tests deserves more in-depth diagnostic procedures, including renal biopsy. Evolution to end stage renal disease could probably be avoided or reduced in severity with early detection and treatment of this entity.     

Diagnostic value of serum IL-6 level in monoclonal gammopathies

Summary. The serum level of IL-6 was reported to reflect disease severity in patients with multiple myeloma. We used a specific radioimmunoassay to measure the level of IL-6 in 239 serum samples in which a monoclonal gammopathy was identified for the first time. The same sample was used for the measurement of serum C reactive protein and serum albumin. Then, an inventory of clinical and biological features allowed us to classify these patients into five groups: monoclonal gammopathy of undetermined significance (MGUS: 128), multiple myeloma (MM:66), Waldenström's macroglobulinaemia (WM:27), non-Hodgkin's lymphoma (NHL: 11) and chronic lymphocytic leukaemia (CLL: 7). The number of patients with serum IL-6 (S-IL-6) level >0.335 ng/ml (upper limit in normal sera) was significantly higher in the MM group (35%; Confidence Interval (CI) 23.5–46.5) compared with the MGUS group (15%; CI 8.8–21.2). The distribution of S-IL-6 levels was also significantly different between the groups (Mann-Whitney test: P< 0.01). High S-IL-6 levels were measured in 5/11 patients with NHL and 9/27 patients with WM. The distribution of S-IL-6 levels in these groups was the same as that in MGUS or MM groups. In patients with MM, elevated S-IL-6 levels were associated with haemoglobin level <100 g/l (P< 0.005). bone marrow plasmocytosis >50% (P<0.05) and stages II and III in the Durie & Salmon staging system (P< 0.005). The S-IL-6 level was also related to light chain component excretion in urine (P<0.01) and M component serum level for IgA (P<0.01). In patients with MGUS, the S-IL-6 level correlated with serum CRP level (P<0.05). serum lactate dehydrogenase (P< 0.05) and serum ferritin (P < 0.01). We conclude that the S-IL-6 level is a marker of high tumour burden in multiple myeloma. However, S-IL-6 level can be increased in patients with MGUS in relation to inflammatory parameters. Therefore the S-IL-6 level does not demonstrate high predictive value for the diagnosis of MM in patients with newly identified monoclonal gammopathy.