Benign Monoclonal Gammopathy Research Articles

The Acquired Deficiency of C1-Inhibitor: Lymphoproliferation and Angioedema

Acquired deficiency of C1 inhibitor (C1-INH) with angioedema symptoms (acquired angioedema, AAE) is characterized by local increase in vascular permeability (angioedema) of the skin and the gastrointestinal and oro-pharyngo-laryngeal mucosa. The mediator of symptoms is bradykinin, a potent vasoactive peptide, released from high molecular weight kininogen when it is cleaved by plasma kallikrein a serine protease controlled by C1-INH. Autoantibodies inactivating C1-INH are detected in the majority of patients and account for the deficiency. Irrespectively to the presence of anti-C1-INH autoantibodies lymphoproliferative diseases, ranging from benign monoclonal gammopathies to malignant lymphoma, are frequently associated with AAE. Demonstration that monoclonal components correspond to anti-C1-INH autoantibodies and correlation between course of lymphoma and course of AAE provide strong support to consider the two diseases expression of the same pathologic process.

Amyloid neuropathy

Amyloidosis is the name given to a group of diseases characterized by the extracellular deposition of insoluble amyloid fibrils in different tissues and organs like kidneys, heart, liver, skin, nerves etc. Clinical manifestations of amyloidosis are determined by the amyloid precursor protein type, by the tissue containing amyloid deposits, and by the quantity of stored amyloid. We present here the data of a patient with sensory polyneuropathy, orthostatic hypotension, nephritic syndrome and benign IgG monoclonal gammopathy, in which we diagnosed amyloid neuropathy.

Neuromuscular diseases associated with benign monoclonal gammopathy

In over 1200 cases examined by isoelectric focusing of CSF and serum proteins, 4 patients had benign monoclonal gammopathy. These patients were affected by amyotrophic lateral sclerosis of bulbar onset, sensitive neuropathy of Thevenard type, myasthenia gravis, and limb-girdle muscular dystrophy, respectively. The difficulty to relate the differences in the clinical features of these cases to a common physiopathological mechanism and the incidence of this finding (0.4% in 873 cases ranging from 21-60 years of age) do not seem to suggest any pathogenetic relationship between benign monoclonal gammopathy and the different neurological disorders encountered in these patients.

Subcorneal pustular dermatosis: 50 years on

We review the key developments in our understanding of subcorneal pustular dermatosis (SCPD, also known as Sneddon-Wilkinson disease) over the past 50 years. SCPD is a rare, chronic, sterile pustular eruption that was first described by Sneddon and Wilkinson in 1956. The primary lesions are pea-sized pustules classically described as half-pustular, half-clear flaccid fluid blisters. Histologically the salient feature is a subcorneal accumulation of neutrophils, suggesting the presence of chemoattractants such as tumour necrosis factor (TNF)alpha in the uppermost epidermis. However, to date its exact pathophysiology is unknown. Cases in association with pyoderma gangrenosum, benign monoclonal IgA gammopathy and multiple myeloma are well documented. There are anecdotal reports of SCPD associated with other internal malignancies such as chronic lymphocytic leukaemia, thymoma, apudoma and epidermoid carcinoma of the lung. The treatment of choice is dapsone. Therapeutic alternatives include retinoids, phototreatment with psoralen ultraviolet (UV) A, broadband or narrow band UVB and corticosteroids. Anecdotal uses of tacalcitol, ketoconazole, azithromycin, tetracycline, minocycline, vitamin E, ciclosporin, colchicine, mizoribine, mebhydrolin, infliximab and adalimumab with mycophenolate mofetil have all been reported.

AID-Dependent Activation of a MYC Transgene Induces Multiple Myeloma in a Conditional Mouse Model of Post-Germinal Center Malignancies

By misdirecting the activity of Activation-Induced Deaminase (AID) to a conditional MYC transgene, we have achieved sporadic, AID-dependent MYC activation in germinal center B cells of Vk*MYC mice. Whereas control C57BL/6 mice develop benign monoclonal gammopathy with age, all Vk*MYC mice progress to an indolent multiple myeloma associated with the biological and clinical features highly characteristic of the human disease. Furthermore, antigen-dependent myeloma could be induced by immunization with a T-dependent antigen. Consistent with these findings in mice, more frequent MYC rearrangements, elevated levels of MYC mRNA, and MYC target genes distinguish human patients with multiple myeloma from individuals with monoclonal gammopathy, implicating a causal role for MYC in the progression of monoclonal gammopathy to multiple myeloma.

Phenotypic Analysis of Plasma Cells in Monoclonal Gammopathy and Multiple Myeloma Subjects.

Introduction: Multiple myeloma (MM) is a B-cell neoplasia caused by the proliferation of clonal plasma cells (PCs). MM and benign monoclonal gammopathy of unknown significance (MGUS) are routinely distinguished on the basis of paraprotein concentration, level of PCs infiltration and the presence or absence of other clinical features. Flowcytometric detection of PCs according to the expression of CD38 and CD138 has limitation in discrimination between normal and abnormal PCs, but this is possible in multicolor phenotypic analysis. The aim of this study is to compare the numbers of normal and abnormal PCs in MGUS and MM subjects and to find some parameter useful for evaluation PCs distribution.Materials and methods: 51 newly diagnosed untreated MM patients (63,9±10,0 years old) and 31 non-treated MGUS subjects (64,2±13,8 years old) were analysed. Lysed whole bone marrows were analysed by flowcytometric immunophenotyping and PCs were indentified by expression of CD38, CD138, CD45 and also CD56 and CD19.Results: Discrimination between normal CD19+ PCs and abnormal CD56+ PCs was done on CD38+CD138+ population. Ratio of normal PCs count and abnormal PCs counts (normal/abnormal=N/A) was used to describe a distribution of PCs. Subjects with MGUS had 0,97±1,65% (average±SD) of CD38+CD138+ cells (median 0,45; range 0,03–7,47%) with average N/A ratio 2,91±3,94 (median 1,36; range 0,01–18,44). Newly diagnosed MM patients had 4,96±9,94% of CD38+CD138+ cells (median 0,85; range 0,02–41,80%) with average N/A ratio 1,70±3,03 (median 0,13; range 0–11,5). In 9,7% MGUS subjects evaluation of distibution of PCs showed transformation of MGUS into MM. In some newly diagnosed MM patients (31,4%) CD38+CD138+ plasma cells were positive for CD19 although they were aberrant and these PCs were mostly CD45+. In some patients (9,7% of MGUS; 17,6% of MM) PC did express neither CD19 nor CD56 and this fact may complicate further evaluation of PCs.Conclusions: Results confirmed that in MGUS subjects we can find lower numbers of PCs which are mostly CD45+CD19+. A majority of plasma cells in newly diagnosed MM patients are abnormal CD56+ PCs and these plasma cells are usually CD45−. Further follow-up of patients can confirm the N/A ratio as a predictive factor for transformation of MGUS into MM and its value for evidence of relapse or progression to active myeloma.

Antibodies against the CUB1-2 domains of ADAMTS13 in a patient with benign monoclonal gammopathy: no causal relationship

We present a patient with a history of benign monoclonal gammopathy, who developed thrombotic thrombocytopenic purpura (TTP), initially presenting as bilateral serous retinal detachment. Plasma of the patient contained high titers of anti ADAMTS13 antibodies that were directed towards the disintegrin/TSR1/cysteine-rich/spacer and CUB1-2 domains. ADAMTS13 activity was undetectable. Total IgG purified from plasma of the patient partially inhibited ADAMTS13 activity. In contrast, the isolated M-protein did neither bind to, nor inhibit activity of ADAMTS13. We conclude that in this patient the monoclonal gammopathy and TTP co-existed as distinct pathological entities.

Interphase fluorescence in situ hybridization in multiple myeloma and monoclonal gammopathy of undetermined significance without and with positive plasma cell identification: analysis of 192 cases from the Region of Southern Denmark

Interphase fluorescence in-situ hybridization (i-FISH) was used to investigate 192 patients with multiple myeloma (MM; n = 182) and benign monoclonal gammopathy of undetermined significance (MGUS; n = 10). Of the 182 MM cases, 132 were investigated without and 50 with positive plasma cell identification (PC-ID+); 134 were investigated at diagnosis, 32 at time of progression, 7 at time of relapse, and 9 were investigated with partial remission or no response. The FISH analysis detected 11q23 ( n = 61), 13q13∼q14 ( n = 181), 14q32 ( n = 121), 17p13.1 ( n = 181), t(4;14) ( n = 76), and t(11;14) ( n = 73). Of the 132 patients investigated without PC-ID+, 61 (46%) showed chromosomal abnormalities, compared with 45 of 49 of evaluable cases (92%) with PC-ID+. The increase in abnormal cases identified was due mainly to the detection of more cases with 13q−, 17p−, and der(14)(q32). G-banding cytogenetics was performed in 72 patients; abnormalities were revealed in 19 cases (26%). Concordance between G-banding and i-FISH for one or more aberrations was found in 14 patients. Translocation (11;14) was detected by both methods in four of five cases. In four out of seven cases with either near-tetraploidy/triploidy or hypoploidy in the G-banded karyotypes, the modal number in the G-banded karyotypes could not be elucidated with certainty with i-FISH. Three of the 10 MGUS patients showed abnormalities. In conclusion, PC-ID+ is important for the detection of structural aberrations and disclosing translocations involving 14q32. Of these, translocations t(4;14) constituted 9% and t(11;14), 20%. Finally, based on the small number of cytogenetically abnormal cases, it is recommended to include cytogenetics (and, for example, the DNA index) in the prognostic armamentarium.

Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis

AbstractMonoclonal gammopathy of undetermined significance (MGUS) can progress to multiple myeloma (MM). Although these diseases share many of the same genetic features, it is still unclear whether global gene-expression profiling might identify prior genomic signatures that distinguish them. Through significance analysis of microarrays, 52 genes involved in important pathways related to cancer were differentially expressed in the plasma cells of healthy subjects (normal plasma-cell [NPC]; n = 22) and patients with stringently defined MGUS/smoldering MM (n = 24) and symptomatic MM (n = 351) (P < .001). Unsupervised hierarchical clustering of 351 patients with MM, 44 with MGUS (24 + 20), and 16 with MM from MGUS created 2 major cluster branches, one containing 82% of the MGUS patients and the other containing 28% of the MM patients, termed MGUS-like MM (MGUS-L MM). Using the same clustering approach on an independent cohort of 214 patients with MM, 27% were found to be MGUS-L. This molecular signature, despite its association with a lower incidence of complete remission (P = .006), was associated with low-risk clinical and molecular features and superior survival (P < .01). The MGUS-L signature was also seen in plasma cells from 15 of 20 patients surviving more than 10 years after autotransplantation. These data provide insight into the molecular mechanisms of plasma-cell dyscrasias.

CKS1B, Mapping to an Amplicon on Chromosome 1q21 and over Expressed in Aggressive Disease, Regulates Multiple Myeloma Growth and Survival through p27Kip1-Dependent and Independent Mechanisms.

While deregulated expression of a D-type cyclin is thought to represent an initiating event in myelomagenesis, the molecular mechanisms of disease progression are not understood. We recently reported that disease progression and high-risk disease are strongly correlated with increased copy number and expression of genes mapping to chromosome 1q. Here we report that elevated expression of CKS1B, a regulatory subunit of the SCF-Skp2 ubiquitin ligase that regulates p27Kip1 protein stability, mapping to an amplicon at 1q21 and over expressed in high-risk myeloma, is required for myeloma cell survival both in vitro and in-vivo. CKS1B expression, absent in plasma cells from healthy individuals and the benign plasma cell dyscrasia monoclonal gammopathy of undetermined significance, is inversely correlated with p27Kip1 protein levels in primary MM. Silencing of CKS1B in MM cell lines JJN3 and OCI-MY5 using shRNAs delivered by constitutive and inducible lentivirus vectors induced stabilization of p27Kip1, cell cycle arrest and apoptosis. Over expression of a non-degradable form of p27Kip1 in JJN3 and OCI-MY5 cells inhibited cell cycle progression, but did not induce apoptosis. We propose that CKS1B may play in important role in myeloma progression through p27Kip1-related and unrelated mechanisms.

Interphase FISH in Multiple Myeloma.

192 patients with multiple myeloma (MM) and benign monoclonal gammopathy of undetermined significance (MGUS, n=10) were investigated by interphase fluorescence in-situ hybridisation (iFISH) without (n= 132) and with positive plasma cell identification (PC-ID+) (n= 50).134 were investigated at diagnosis 32 at time of progression, 7 at time of relapse and 9 were investigated with partial remission or no response. 10 of the MM cases were investigated twice. The patients were investigated with FISH probes detecting 11q23 (n=61), 13q13-14 (n=181), 14q32 ((n=121), 17p13.1 (n=181), t(4;14) (n=76) and t(11;14) (n=73). 61/132 (46%) of patients investigated without PC-ID+ showed abnormalities as opposed to 45/49 of evaluable cases (92%) with PC-ID+. The increase in abnormal cases was mainly due to the detection of more cases with loss of 13q and 17p and der(14)(q32): For patients investigated at diagnosis without and with PC-ID+, respectively: 13q-: 17% and 28%, 17p-: 3% and 15%, and 14q split signals (excluding the specific translocations): 8% and 24%. Based on the relatively small number investigated, the t(4;14) and the t(11;14) were not detected more frequently. G-band cytogenetics was carried out in 72 patients (25 without PC-ID+ and 47 with PC-ID+). 19 cases were abnormal (26%). Concordance for 1 or more aberration was found in 14 patients. t(11;14) was detected by both methods in 4 of 5 patients. Out of 7 cases with either near-tetraploidy/triploidy or hypoploidy in the G-band karyotypes, the modal number in the G-banded karyotypes could not be elucidated with certainty in 4 by iFISH with the applied probes. 7/10 patients investigated twice by iFISH showed new abnormalities on reinvestigation, 5 of these had a normal 1st analysis. 3 of 10 MGUS patients showed abnormalities.In conclusion, PC-ID+ is important for the detection of numerical aberrations and disclosing translocations involving 14q32, as translocations involving the IgH locus are frequent occurring in 64 % (n = 32) at diagnosis. Of these the t(4;14) and the t(11;14) constituted 8% and 20%, respectively. Re-examination of patients with a normal analysis should be considered in non-responders and progressing patients. Lastly, by applying the set of probes we chose in accordance with the proposed recommendations from the European Myeloma Network FISH Workshop, Royal Marsden Hospital, London UK, March 2005, failure to accurately the exsistence of detect near-tetraploid/near-triploid-, and hypoploid clones, is not insignificant (26%) and, based on the small number of cytogenetically abnormal cases it is recommended to include extra probes to classify the patients according to modal number by iFISH.

Immune-Mediated Etiology of Acquired von Willebrand Syndrome in Systemic Lupus Erythematosus and in Benign Monoclonal Gammopathy: Therapeutic Implications

The most common nonimmune etiology of acquired von Willebrand syndrome (AvWS) includes hypothyroidism, Wilms' tumor, thrombocythemia, or congenital heart defects, and the use of various drugs. AvWS type 1 in patients with hypothyroidism is due to decreased Willebrand factor (vWF) synthesis and is reversible by treatment with thyroxin. AvWS type 1 or 3 in children with Wilms' tumor disappears after successful chemotherapy or tumor resection but the mechanism of the vWF deficiency is unknown. The AvWS type 2 in patients with thrombocythemia of various myeloproliferative disorders is caused by increased proteolysis of large vWF multimers at increasing platelet counts to above 1000 x 10 (9)/L. Reduction of platelet counts to normal results in correction of the vWF parameters together with disappearance of the bleeding tendency. Type 2-like AvWS in children with congenital heart valve defects is caused by shear stress-induced proteolysis of large vWF multimers and is reversible after surgical correction. AvWS associated with the use of drugs disappears after discontinuation of the causative agent. Immune-mediated AvWS is associated with either systemic lupus erythematosus (SLE) or immunoglobulin G (IgG) benign monoclonal gammopathy (BMG), and usually shows a type 2 vWF deficiency. Using a simple enzyme-linked immunosorbent assay, an IgG antibody against vWF is detectable in AvWS associated with SLE and IgG BMG. The IgG-autoantibody-factor (F) vWF/VIII complex is rapidly cleared from the circulation, which explains the combined FVIII:coagulant activity (C) and vWF deficiency and the poor responses of FVIII:C and vWF parameters to intravenous desmopressin acetate and vWF/FVIII concentrates. A transient correction of both FVIII:C and vWF parameters to normal for a few weeks after high-dose intravenous immunoglobulin is seen in AvWS associated with SLE and IgG BMG. AvWS associated with SLE uniformly shows a curative response to corticosteroids. AvWS associated with IgG BMG does not respond to corticosteroids, immune suppression, or chemotherapy. AvWS associated with IgM BMG is rare and does not respond to any conventional treatment.

Xanthogranulome nécrobiotique sans gammapathie monoclonale d’évolution rapidement fatale

Necrobiotic xanthogranuloma is an extremely rare form of histiocytosis that presents clinically as yellowish infiltrated plaques or nodules. Ocular involvement is seen in over 80% of cases. Histopathology reveals numerous xanthomous histiocytes and collagen necrobiosis. Benign monoclonal gammopathy associated with myeloma is found in 80% of patients, but the course is normally long, with 100% survival at 10 years. A 76-year-old man presented skin lesions that subsequently became ulcerated. The clinical appearance and histopathological examination resulted in diagnosis of necrobiotic xanthogranuloma. No monoclonal gammopathy or myeloma was seen. The disease was marked by sensitivity to corticosteroids with failure of other therapies (cyclophosphamide, alpha interferon), onset ofcorticosteroid dependency, iatrogenic Cushing's syndrome and diabetes, which were in part responsible for the infectious complications and subsequent death of the patient. Necrobiotic xanthogranuloma is difficult to treat, even in the absence of myeloma or monoclonal gammopathy. Corticosteroids are probably the most efficacious treatment, but can give rise to multiple complications, resulting in this particular case in death of the patient.

The risk of venous thromboembolic disease in patients with monoclonal gammopathy of undetermined significance

Recent evidence indicates that patients with multiple myeloma receiving combination chemotherapy containing thalidomide are at a significantly high risk for venous thromboembolic disease (VTD). However, information on the occurrence of VTD in a related disorder, benign monoclonal gammopathy of undetermined significance (MGUS), is limited. We prospectively investigated patients with MGUS for the occurrence of VTD. The diagnosis of MGUS was based on well known criteria for the disorder. The variables examined were sex, age, race, presence of underlying conditions, level and type of immunoglobulin [serum monoclonal (M)-protein] platelet counts and level of fibrinogen. Of a total of 310 patients with MGUS, 19 (6.1%) developed VTD after a median follow-up of 44 months (range 12-67 months). In a univariate analysis, age >/=65 years (P=0.01), M-protein >/=16 g/l (P=0.001) and progression to plasma cell or lymphoproliferative disorders (28 of 310 patients; P=0.001) were significant risk factors for VTD. In multivariate analysis, M-spike >/=16 g/l [risk ratio (RR)=6.3; 95% confidence interval (CI) 2.25-17.6; P=0.001] and future development of plasma cell or lymphoproliferative disorder (RR = 4.2; 95% CI 1.64-10.7; P=0.003) were variables strongly associated with the occurrence of VTD. A total of 46 patients (14.8%) died during the follow-up period of the study. This study demonstrates that patients with MGUS are at increased risk for VTD. Although a clear reason for the pre-thrombotic state in these patients is not currently evident, few risk factors were identified in the group of patients examined.

Characterization of amyloidogenic immunoglobulin light chains directly from serum by on‐line immunoaffinity isolation

Primary systemic amyloidosis (AL) is characterized by the overproduction of immunoglobulin light chain proteins by a monoclonal, terminally differentiated B-lymphocyte or plasma cell clone. The free immunoglobulin light chains are deposited in an abnormal conformation as amyloid in a variety of organs in the body. The mechanism of amyloid formation is not well understood, but appears to be associated with some form of cleavage of the immunoglobulin light chain with subsequent aggregate formation. In an attempt to characterize the structure of amyloid-forming light chain proteins we developed an on-line immunoaffinity purification and subsequent characterization of free kappa and free lambda immunoglobulin light chains by electrospray ionization mass spectrometry. The methodology is totally automated and requires 20 micro L of serum. Mass spectral analysis of Bence Jones proteins under non-denaturing conditions was also utilized to examine the tertiary and quaternary structure of light chain proteins and clearly shows covalent dimer formation of lambda type light chain. This type of on-line assay may prove helpful in elucidating distinguishing features capable of discriminating AL from benign monoclonal gammopathies of undetermined significance as well as diagnosing AL.

Subcorneal Pustular Dermatosis in Association with Chronic Lymphocytic Leukaemia

Sir,Subcorneal pustular dermatosis (SPD) is a chronic,relapsing, pustular eruption, the aetiology and patho-genesis of which are unknown. It has previously beenreported in association with rheumatoid arthritis (1),Crohn’s disease (2), pyoderma gangrenosum, Sweet’ssyndrome and other neutrophilic dermatoses, benignmonoclonal gammopathies (3) and IgA myeloma (4).Here we describe a patient with SPD in association withchronic lymphocytic leukaemia (CLL) and discuss thepossibility of a pathogenetic link. No cases havepreviously been reported of SPD and CLL.CASE REPORTA 78-year-old woman was referred to the DermatologyDepartment in August 1996 with a pruritic rash affect-ing her scalp, axillae, inguinal and infra-mammaryflexures. She had no personal or family history ofpsoriasis. Examination showed erythema, papules andpustules. A biopsy was inconclusive, showing in someareas hyperkeratotic, parakeratotic and mildly acan-thotic epidermis with spongiosis and focal neutrophilexocytosis, while in other areas there were well-formedsubcorneal pustules. Special stains were negative forbacteria and fungi. The patient was treated with topicalsteroids, emollients, tar preparations and calcipotriol,each with little benefit. She then received oral acitretin(10–25 mg daily for a total of 29 months), bath PUVA(twice weekly for 3 months) and oral methotrexate (upto 20 mg once weekly for 6 months); each produced atbest a short-lived partial improvement in the rash.In September 1999 the patient had a widespreaderythematous pustular eruption affecting the trunk andlimbs with a flexural distribution. She was systemicallywell and denied any joint or gastrointestinal symptoms.On this occasion, a mild lymphocytosis (white cellcount 11.8610

Global gene expression profiling in the study of multiple myeloma.

Multiple myeloma (MM) is a rare but uniformly fatal malignancy of antibody-secreting plasma cells. Although several key molecular events in disease initiation or progression have been confirmed (eg, FGFR3/MMSET activation) or implicated (eg, chromosome 13 deletion), the mechanisms of MM development remain enigmatic. Although it is generally indistinguishable morphologically, MM importantly exhibits a tremendous degree of variability in its clinical course, with some patients surviving only months and others for many years. However, measures of current laboratory parameters can account for no more than 20% of this outcome variability. Furthermore, the means by which current drugs impart their anti-MM effect are mostly unknown. The development of serious comorbidities, such as osteopenia and/or focal lytic lesions of bone, is also poorly understood. Finally, very little knowledge exists concerning the molecular triggers for the conversion of benign monoclonal gammopathy of undetermined significance (MGUS) to overt MM. Given that abnormal gene expression lies at the heart of most if not all cancers, high-throughput global gene expression profiling has become a powerful tool for investigating the molecular biology and clinical behaviors Here I discuss recent progress made in addressing many of these issues through the molecular dissection of the transcriptome of normal plasma cells, MGUS, and MM.

Inherited Bisalbuminemia with Benign Monoclonal Gammopathy Detected by Capillary but not Agarose Gel Electrophoresis

Bisalbuminemia (or alloalbuminemia) is characterized by the presence of two albumin components (in equal or unequal amounts) on serum protein electrophoresis (1). Bisalbuminemia may be inherited (genetic) or acquired. The cumulative frequency of inherited bisalbuminemia is typically 1:10 000 to 1:1000 (2)(3)(4), with inheritance showing an autosomal codominant pattern (5). Inherited bisalbuminemia has no pathologic or therapeutic consequences, but it is of interest for investigations of the evolution of functional differences in the protein, including altered affinity for steroid hormones, thyroxine, and several dyes (6). An acquired or transient form has been described that usually has a faster mobility (1)(7)(8). The faster form may be seen in patients who receive large amounts of β-lactam antibiotics or have pancreatic diseases, usually complicated by a ruptured false cyst (9). Acquired bisalbuminemia has been reported as a rare occurrence in patients with myeloma (10) or in nephrotic syndrome (1). We recently …

Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma.

To evaluate the natural history of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), identify early predictors of evolution, and assess whether associated conditions correlate with disease progression. A total of 1,231 consecutive patients with either MGUS (n = 1,104) or SMM (n = 127) diagnosed from July 1975 to March 1998 were included in the study. Cumulative survival probability and cumulative probability of transformation into lymphoproliferative disease were calculated by means of the Kaplan-Meier estimator. Univariate and multivariate Cox models were used to identify possible predictors of malignant evolution. Cumulative transformation probability at 10 and 15 years was 14% and 30%, respectively. At a median follow-up of 65 months (range, 12 to 239 months), 64 MGUS cases (5.8%) evolved to multiple myeloma (MM) (n = 43), extramedullary plasmacytoma (n = 1), primary amyloidosis (n = 1), Waldenström's macroglobulinemia (n = 12), non-Hodgkin's lymphoma (n = 6), and B-chronic lymphocytic leukemia (n = 1). At a median follow-up of 72 months (range, 12 to 247 months), 25 SMMs (19.7%) evolved to overt MM. A lower evolution risk was observed in MGUS than in SMM (P <.0001). Greater than 5% marrow plasmacytosis, detectable Bence Jones proteinuria, polyclonal serum immunoglobulin reduction, and high erythrocyte sedimentation rate (ESR) were independent factors influencing MGUS transformation. SMM progression correlated with greater than 10% marrow plasma cells, detectable Bence Jones proteinuria, and immunoglobulin (Ig) A isotype. Neither concomitant diseases nor immunosuppression correlated with progression. Careful evaluation of marrow plasmacytosis, urinary paraprotein, background immunoglobulins, ESR, and paraprotein isotype might help identify at presentation patients with benign monoclonal gammopathies requiring stricter monitoring.

Prognostic Factors for Malignant Transformation in Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma

PURPOSE: To evaluate the natural history of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), identify early predictors of evolution, and assess whether associated conditions correlate with disease progression. PATIENTS AND METHODS: A total of 1,231 consecutive patients with either MGUS (n = 1,104) or SMM (n = 127) diagnosed from July 1975 to March 1998 were included in the study. Cumulative survival probability and cumulative probability of transformation into lymphoproliferative disease were calculated by means of the Kaplan-Meier estimator. Univariate and multivariate Cox models were used to identify possible predictors of malignant evolution. RESULTS: Cumulative transformation probability at 10 and 15 years was 14% and 30%, respectively. At a median follow-up of 65 months (range, 12 to 239 months), 64 MGUS cases (5.8%) evolved to multiple myeloma (MM) (n = 43), extramedullary plasmacytoma (n = 1), primary amyloidosis (n = 1), Waldenström’s macroglobulinemia (n = 12), non-Hodgkin’s lymphoma (n = 6), and B-chronic lymphocytic leukemia (n = 1). At a median follow-up of 72 months (range, 12 to 247 months), 25 SMMs (19.7%) evolved to overt MM. A lower evolution risk was observed in MGUS than in SMM (P < .0001). Greater than 5% marrow plasmacytosis, detectable Bence Jones proteinuria, polyclonal serum immunoglobulin reduction, and high erythrocyte sedimentation rate (ESR) were independent factors influencing MGUS transformation. SMM progression correlated with greater than 10% marrow plasma cells, detectable Bence Jones proteinuria, and immunoglobulin (Ig) A isotype. Neither concomitant diseases nor immunosuppression correlated with progression. CONCLUSION: Careful evaluation of marrow plasmacytosis, urinary paraprotein, background immunoglobulins, ESR, and paraprotein isotype might help identify at presentation patients with benign monoclonal gammopathies requiring stricter monitoring.