Synthesis of abnormal immunoglobulins in lymphoplasmacytic disorders with visceral light chain deposition

Three patients presented with renal or more diffuse tissue deposits of a nonamyloid material reactive with anti-κ antibody by immunofluorescence. All patients had progressive renal failure with the nephrotic syndrome and extensive tubular basement membrane deposits. Glomerular lesions were conspicuous but heterogeneous. One patient also had hepatic deposits with peliosis at histopathologic examination. An underlying lymphoplasmacytic disorder was found in all patients: multiple myeloma in one, pleomorphic lymphoplasmacytic malignancy analogous to Waldenström's macroglobulinemia in one and bone marrow monoclonal plasmacytosis without overt myeloma in one. Biosynthesis experiments in two cases showed production of abnormal κ chains which were not detected in appreciable amounts in serum and urine. These light chains had an aberrant size (abnormally short or large), their apparent molecular weight was larger in secretion than in cytoplasmic extracts (suggesting their glycosylation) and they were secreted as polymers. These results suggest a causal relationship between production of abnormal light chains and tissue deposition.     

Plasma cell acid phosphatase score in multiple myeloma and related disorders

A detailed classification of plasma cells stained for acid phosphatase activity is introduced. With this method, patients with multiple myeloma, non-myeloma gammopathies, reactive plasmacytosis and other diseases in which plasma cells are involved, were investigated. The results show that our method can discriminate between multiple myeloma and reactive plasmacytosis. The overlap between multiple myeloma and other monoclonal gammopathies is much smaller than observed in other studies. Surprisingly low levels of acid phosphatase activity were found in the cells from patients with lymphoplasmacytoid immunocytoma. It is concluded that the acid phosphatase score can be of value for studying disorders in which plasma cells are involved.     

The bone marrow in multiple myeloma: correlation of plasma cell ultrastructure and clinical state.

The bone marrow plasma cells of 52 patients with various kinds of monoclonal gammopathies were studied by electron microscopy, and compared to the bone marrow plasma cells of 22 patients with reactive plasmacytosis. Virtually every marrow from patients with myeloma and macroglobulinemia contained plasma cells with disparity between the nuclear maturation and cytoplasmic differentiation. This asynchronous development was not present in plasma cells of reactive marrows nor in plasma cells from patients with megaloblastic anemias. The degree of asynchrony observed in myeloma and macroglobulinemia was proportional to the extent of disease as judged by clinical criteria. For the most part plasma cells of patients with non-myelomatous monoclonal gammopathy failed to exhibit significant asynchrony. These observations are consistent with the view that multiple myeloma is a neoplastic disorder with a definably malignant-appearing cellular proliferation.     

Presence of a bone marrow stromal cell line with myoid differentiation in reactive plasmacytosis and plasma cell myeloma

The presence of myoid cells (MCs) - stromal cells with myogenic differentiation - in human bone marrow (BM) has been observed during hematopoiesis in embryonic life, whereas during adult life, it is strictly related to various pathologic conditions. The aim of this study was to examine the presence, distribution and quantitation of cells in the stroma of the BM expressing alpha-smooth muscle actin (alpha-SMA) in reactive BM plasmacytosis and plasma cell myeloma. For this reason, a series of 10 trephine BM biopsies from patients with plasma cell myeloma and 10 specimens from healthy controls with reactive plasmacytosis were examined for the presence of stromal cells with myoid differentiation, using a monoclonal antibody recognizing alpha-SMA. Our results suggest that the incidence of MCs and subsequent fibrosis rises in plasma cell myeloma and in a lesser degree in the BM stroma of individuals with reactive plasmacytosis.     

Perivascular plasmacytosis: a light-microscopic and immunohistochemical study of 93 bone marrow biopsies.

In bone marrow biopsies from 13 hematologically normal persons and from 80 patients with a variety of disorders, we found perivascular plasmacytosis. In all instances except the one case of multiple myeloma, plasma cells were polyclonal and normal in morphology. This was especially pronounced in patients with HIV infection, and in individuals following chemotherapy. In the same patients, sinusoids were also prominent, and appeared dilated. In biopsy sections, small endothelial-lined vessels appeared to arise from attenuation of the sinusoidal lumen. After a short segment of only endothelial-lined vessels, perivascular plasmacytosis appeared. When smooth muscle cells began to line the endothelium, plasma cells virtually disappeared. The biological significance of this finding is unknown. Possibly, the close proximity of plasma cells to endothelial cells early in the development of blood vessels could facilitate entry of immunoglobulins into the blood.     

Efficacy of recombinant interferon-alpha (rIFN-α) in polycythaemia vera: a study of 17 patients and an analysis of published data

Summary. In this paper we describe a new, rapid and sensitive method to determine plasma cell isotype and clonality in bone marrow using flowcytometry. With the use of a new fixation and permeabilization reagent (Permeafix®), which preserves cell structure and morphology, and a monoclonal antibody (Mab) specific for plasma cells (B-B4), it has become possible to specifically select plasma cells and to determine the cytoplasmatic immunoglobulins by flowcytometry.
Thirty successive bone marrow aspirates from multiple myeloma patients and patients with MGUS were studied as well as 10 bone marrow samples from patients with reactive plasmacytosis. Each sample was analysed both by immunofluorescence on cytospin smears and FACS analysis. There were no discrepancies between plasma cell isotype as determined by FACS and cytospin. Moreover, FACS analysis was shown to allow detection of very low numbers of plasma cells and to determine whether these plasma cells are mono-or polyclonal. Possible applications are discussed.     

Computed tomography in diagnosis and management of multiple myeloma and its variants

The use of computed tomography (CT) was evaluated in 25 patients with multiple myeloma, six with extramedullary plasmacytoma, and two with undiagnosed lesions. We found that CT was useful for (1) patients with multiple myeloma who had bone pain but normal roentgenograms, (2) patients with an M-protein, bone marrow plasmacytosis, and back pain from osteoporosis and compression fractures but an inconclusive diagnosis of multiple myeloma, (3) the determination of extent of tumor, and (4) guidance in needle biopsy.     

High dose cyclophosphamide, BCNU and VP-16 with autologous blood stem cell support for refractory multiple myeloma

Eleven patients with advanced multiple myeloma refractory to standard doses of alkylating agents and salvage therapy with vincristine, adriamycin and dexamethasone (VAD) were treated with high dose cyclophosphamide, BCNU and VP-16 (CBV) with autologous blood stem cell support. Seven patients had marked marrow plasmacytosis (greater than 30%) and four had extensive pelvic bone disease precluding autologous marrow harvest. Four patients responded with a median remission duration of 7 months. Recovery of granulocytes and platelets occurred promptly in 10 evaluable patients with complete hematologic recovery. Autologous blood stem cells can provide safe and effective support for high dose CBV treatment of myeloma patients with extensive marrow plasmacytosis. The short remissions call for better cytoreductive regimens with consideration for earlier use when the myeloma may be more responsive to therapy.     

Prognostic relevance of morphological classification in multiple myeloma.

One hundred and twenty-two patients with multiple myeloma were classified as mature, intermediate, immature, or plasmablastic subtype according to Greipp's criteria. Contrary to Greipp's report, the survival time of plasmablastic myeloma was not significantly shorter than other subtypes, nor was the plasmablastic subtype identified as a poor prognostic factor. The survival time of mature plus intermediate myeloma was significantly longer than that of immature plus plasmablastic myeloma. Between the former and latter, significant differences were found for sex, clinical stage, thrombocytopenia, bone marrow plasmacytosis, renal insufficiency, bone destruction, and response rate to treatment. Therefore, it was suspected that the immature and plasmablastic subtypes were unfavorable prognostic factors in patients with multiple myeloma.     

Prognostic value of angiogenesis in solitary bone plasmacytoma

Angiogenesis plays an important role in the biology of multiple myeloma (MM) and has prognostic importance in this disease. Solitary plasmacytoma is a localized plasma cell malignancy that progresses to MM in a significant number of patients. We examined if angiogenesis is increased in solitary plasmacytoma and if it can help identify patients likely to progress to myeloma. We studied angiogenesis in plasmacytoma biopsy samples and bone marrow biopsies from 25 patients. High-grade angiogenesis was present in 64% of plasmacytomas. In contrast, bone marrow angiogenesis was low in all patients. Patients with high-grade angiogenesis in the plasmacytoma sample were more likely to progress to myeloma and had a shorter progression-free survival compared with patients with low-grade angiogenesis (P =.02). Angiogenesis is increased in solitary plasmacytoma and is a significant predictor of progression to myeloma and provides further evidence of its importance in the pathogenesis of myeloma.     

Multiple myeloma: 2018 update on diagnosis,risk‐stratification,and management

Multiple myeloma accounts for approximately 10% of hematologic malignancies. The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events: CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging. Patients with del(17p), t(14;16), and t(14;20) have high‐risk multiple myeloma. Patients with t(4;14) translocation and gain(1q) have intermediate‐risk. All others are considered standard‐risk. Initial treatment consists of bortezomib, lenalidomide, dexamethasone (VRd). In high‐risk patients, carfilzomib, lenalidomide, dexamethasone (KRd) is an alternative to VRd. In eligible patients, initial therapy is given for approximately 3‐4 cycles followed by autologous stem cell transplantation (ASCT). Standard risk patients can opt for delayed ASCT at first relapse. Patients not candidates for transplant are treated with VRd for approximately 8‐12 cycles followed by lenalidomide or lenalidomide plus dexamethasone. After ASCT, lenalidomide maintenance is recommended for standard risk patients, while maintenance with a bortezomib‐based regimen is needed for patients with intermediate or high‐risk disease. Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse. Aggressive relapse with extramedullary plasmacytomas or plasma cell leukemia may require anthracycline containing combination chemotherapy regimens.     

Anti-myeloma activity of pamidronate in vivo

Two patients with progressive myeloma were treated with pamidronate disodium every 2-4 weeks. Pamidronate therapy resulted in a significant reduction of marrow plasmacytosis and plasma cell labelling index (PCLI), together with durable (20 months) stabilization of immunoglobulin (Ig) levels and an increase in bone mineral density in the first patient and >50% reduction in Ig levels and bone marrow plasmacytosis in the second. This, to our knowledge, is the first report of an anti-myeloma effect of bisphosphonates in humans and provides evidence that a therapeutic intervention largely directed at the myeloma microenvironment may alter the natural history of the disease.     

Increased expression of vascular endothelial growth factor in bone marrow of multiple myeloma patients

Background: Angiogenesis (neovascularization) is a multistep process in which new blood vessels grow from existing vessels. Angiogenesis is associated with the growth, dissemination, and metastasis of solid tumors. There is increasing evidence that neovascularization may be important in hematological malignancies. Several studies suggest that vascular endothelial growth factor (VEGF) is one of the most important cytokines responsible for the development, maintenance, and progression of multiple myeloma (MM) by promoting bone marrow angiogenesis. A high serum concentration of VEGF has been reported in MM patients. The aim of this study was to evaluate the expression of VEGF in the bone marrow of MM patients. Methods: Eighteen paraffin-embedded bone marrow core biopsy specimens from newly diagnosed patients with MM were evaluated. In addition, 10 bone marrow core biopsy specimens from adult patients without evidence of malignancy were used as controls. Bone marrow sections were stained immunohistochemically for VEGF. Results: Our data show that multiple myeloma is associated with an increased expression of VEGF in the bone marrow. Conclusions: Our observation supports previous studies suggesting that angiogenesis may play a role in the pathophysiology of hematopoietic malignancies. The clinical significance of this phenomenon needs further investigation. However, this study provides rationale for the use of angiogenesis inhibitors in MM therapy.     

Light-heavy chain deposition disease progressing to multiple myeloma

Light chain deposition disease (LCDD) and light and heavy chain deposition disease (LHCDD) are rare clinical entities that have been associated with multiple myeloma, with monoclonal gammopathy of unknown significance (MGUS), or without any detectable protein abnormality. Renal failure is common, the diagnosis is difficult and prolonged survival is rare. The first patient with LHCDD and MGUS who progressed to multiple myeloma after 11 years is presented. A rising level of monoclonal IgA immunoglobulin, bone marrow plasmacytosis, and the presence of multiple bone marrow lesions on magnetic resonance imaging provided the first evidence of disease evolution. When management of serious complications permits a long survival, some patients with LCDD or LHCDD will develop multiple myeloma.     

An Increase in MPC-1- and MPC-1-CD45+ Immature Myeloma Cells in the Progressive States of Bone Marrow Plasmacytosis: The Revised Phenotypic Classification of Monoclonal Marrow Plasmacytosis (MOMP-2005)

The heterogeneity of bone marrow plasmacytosis is clearly analyzed by multicolor staining with anti-CD38 antibody. To date, at least 5 subpopulations of plasma cells have been identified in the bone marrow of multiple myeloma (MM) patients with regard to the expression of MPC-1, CD49e (VLA-5), and CD45: MPC-1(-)CD49e(-)CD45(+) proliferative immature cells, MPC-1(-)CD49e(-)CD45(-) immature myeloma cells, MPC-1(+)CD49e(-)CD45(-) and MPC-1(+)CD49e(-)CD45(+) intermediate myeloma cells, and MPC-1(+)CD49e(+)CD45(+) mature myeloma cells. We performed phenotypic analyses in 75 cases of monoclonal bone marrow plasmacytosis, including 46 cases of MM and 29 cases of monoclonal gammopathy of undetermined significance (MGUS). In 31 cases of progressive MM disease, MPC-1(-) immature and MPC-1(-)CD45(+) proliferative immature myeloma cells were significantly increased up to >25% and >10%, respectively, of the plasma cell fractions (CD38(++) cells), whereas there were no increases in MPC-1(-) or MPC-1(-)CD45(+) proliferative immature myeloma cells in 15 cases of stable disease. Interestingly, the proportions of MPC-1(-) and MPC-1(-)CD45(+) immature monoclonal plasma cells also increased in the 7 progressive cases of MGUS. Finally, we present the revised (2005) phenotypic classification of monoclonal marrow plasmacytosis (MOMP-2005).     

Magnetic resonance imaging patterns in patients with multiple myeloma

Sixty-one consecutive patients with multiple myeloma were studied with magnetic resonance (MR) imaging of the spine. Sagittal T1-weighted and short inversion time (TI) inversion recovery (STIR) images were obtained. The MR patterns of the bone marrow were classified as diffuse (D) ( n  = 26), nodular (N) ( n  = 11), D + N ( n  = 13) or normal (n) ( n  = 11). Abnormal patterns were seen in 50 (82%) of the 61 patients. Correlations were found between the MR imaging patterns and some laboratory findings (WBC, haematocrit, platelet count, serum albumin, and percentage of marrow plasmacytosis). The survival of the patients with abnormal MRI patterns was significantly poorer than that of the patients with normal patterns. However, the survival of patients with a nodular pattern did not differ from those with a normal pattern. The MR imaging pattern of the bone marrow in patients with multiple myeloma is a useful factor in the assessment of prognosis.     

Nonsecretory multiple myeloma

The clinical features and disease course of 29 consecutive multiple myeloma patients without monoclonal globulins are described. This variant accounted for 4.7% of all patients with this disease referred over a 17 year time span. Despite bone marrow plasmacytosis and multiple bone lesions in all, hemoglobin levels were less frequently depressed and immunoglobulin values more frequently preserved in comparison with typical myeloma patients. A low tumor mass was defined in 69%, in comparison with 24% of those with evidence of myeloma protein production. Such earlier disease contributed to the long median survival of 39 months in these patients, a duration about 1 year longer than that of typical patients.     

Plasmacytic lesions of the bone marrow

Although the first cases of the plasma cell lesions were described in the 19^th century, it was Wright who in 1900 suggested that the neoplastic myeloma cells morphologically resembled variants of plasma cells. Later it was discovered that these malignant cells produced monoclonal immunoglobulins, an important marker for the diagnosis and follow-up of patients afflicted with the disease. The usefulness of bone marrow examination was recognized in the late 1930s and is today regarded as the most important factor in the definitive diagnosis of myeloma and related disorders, namely macroglobulinemia, monoclonal gammopathy of undetermined significance, and reactive plasmacytosis of the bone marrow. Differential diagnosis of the above mentioned disorders proven to be the B cell diseases will be the main focus of this presentation and their morphological variations will be emphasized. The usefulness of immunostaining of bone marrow aspirate sections as well as biopsy will also be highlighted.     

Multiple myeloma: 2016 update on diagnosis,risk‐stratification,and management

Multiple myeloma accounts for approximately 10% of hematologic malignancies.The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hyperc alcemia, r enal failure, a nemia, or lytic b one lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging. Patients with del(17p), t(14;16), and t(14;20) have high‐risk multiple myeloma. Patients with t(4;14) translocation and gain(1q) have intermediate‐risk. All others are considered standard‐risk. Initial treatment consists of bortezomib, lenalidomide, dexamethasone (VRD). In high‐risk patients, carfilzomib, lenalidomide, dexamethasone (KRD) is an alternative to VRD. In eligible patients, initial therapy is given for approximately 3–4 months followed by autologous stem cell transplantation (ASCT). Standard risk patients can opt for delayed ASCT at first relapse. Patients not candidates for transplant are treated with Rd until progression, or alternatively, a triplet regimen such as VRD for approximately 12–18 months. After ASCT, lenalidomide maintenance is considered for standard risk patients especially in those who are not in very good partial response or better, while maintenance with a bortezomib‐based regimen is needed for patients with intermediate or high‐risk disease. Patients with indolent relapse can be treated with 2‐drug or 3‐drug combinations. Patients with more aggressive relapse require a triplet regimen or a combination of multiple active agents. Am. J. Hematol. 91:720–734, 2016. © 2016 Wiley Periodicals, Inc.