Benign Gammopathy Research Articles

Characterization of Monoclonal Gammopathy of Undetermined Significance Progression to Multiple Myeloma through Meta-Analysis of GEO Data

Background: Monoclonal gammopathy of undetermined significance (MGUS) is characterized by plasma cell production of abnormal monoclonal protein, or M protein. While MGUS itself is asymptomatic, it generally carries a 1% per year risk to progression to multiple myeloma (MM). The etiology of MGUS, as well as why it progresses to MM in some cases, remains unclear. Moreover, it is not known why some MGUS patients, such as African Americans, have higher risk to progression to MM. Contrasting MGUS and MM can potentially highlight genes that differentiate benign gammopathies from malignant ones and may be involved in disease progression from MGUS to MM. Methods: We employed our STARGEO platform to tag samples from the NCBI Gene Expression Omnibus and performed two separate meta-analysis to compare MGUS and MM transcriptomes. For the first meta-analysis, we tagged MGUS plasma cells recovered from the bone marrow of 101 patients and tagged plasma cells from 64 healthy subjects as a control. For the second analysis. We tagged CD138+ cells from the bone marrow of 383 MM patients and used the MGUS tagged samples as a control. We then analyzed the signature in Ingenuity Pathway Analysis (IPA). Results: From our first meta-analysis of MGUS, we identified EIF2 signaling, regulation of EIF4 and p70S6K signaling, and JAK/STAT signaling as top canonical pathways. Top upstream regulators included TP53, TGFB1, and the proto-oncogene MYCN and MYC (with predicted activation). The most upregulated genes included pro-oncogenes such as KIT and MLLT3, which is well-studied in acute leukemia but not yet described in MGUS. Another top upregulated gene was NRG3, a myeloma growth factor. Additionally, our analysis highlighted key genes involved in transcription and epigenetic regulation. For example, there was upregulation of RBFOX2, which is involved in alternative splicing during oncogenesis and tumor progression, and of PARP15, a transcriptional repressor with poly(ADP-ribose) polymerase activity and candidate gene for drug targeting. Also, there was upregulation of the DNA damage-inducible gene GADD45A, found to promote global DNA methylation. Lastly, we found upregulation of COMMD3, a gene with a recently identified role in humoral activity and B cell migration. From our second meta-analysis comparing MM and MGUS directly, we identified mitochondrial dysfunction, oxidative phosphorylation, purine nucleotides de novo biosynthesis, and sirtuin signaling as top upstream regulators. Like our first analysis, TP53 (with predicted inhibition), TGFB1, and MYC (with predicted activation) were top upstream regulators. The most upregulated gene was NUP62, a nucleoporin and novel regulator of cell proliferation and inducer of MYC activity. Our analysis also illustrated pro-oncogenic signaling pathways such as the Wnt pathway through upregulation of the ubiquitin ligase RNF14 and serine/threonine kinase through upregulation of SRPK2. Moreover, we found upregulation of the super-enhancer DUSP4, a phosphatase whose over-activity may drive MM severity. Lastly, we found upregulation of lysosomal associated membrane protein LAMP5. LAMP5 was recently identified in single-cell RNA sequencing of MM patients and may play a significant role in disease. Conclusions: Our study illustrates signaling pathways in MGUS that are present in MM such as EIF2, JAK/STAT, and MYC signaling. We also illustrate gene activity in MGUS that may predispose to MM progression such as NRG3, RBFOX2, and PARP15. GADD45RA and COMMD3 may play novel roles in MGUS. Our second analysis highlighted disease activity that persist from MGUS to MM, such as MYC signaling. It is possible that the genes from this analysis that aims to distinguish MM from MGUS may be responsible for tipping the scales from benignity to malignancy. Genes such as DUSP4, RN14, LAMP5, and others could serve as novel biomarkers or targets to MM and risk of progression of MGUS to MM. Disclosures No relevant conflicts of interest to declare.

Intraocular Crystals in HIV-Related Hypergammaglobulinemia

Purpose: To describe the occurrence of bilateral iris and retinal crystals in a patient with benign HIV-related gammopathy. Design: Observational case report. Methods: A 45-year-old HIV-positive male with a known, benign hypergammaglobulinemia was referred for routine ophthalmic assessment because of right ophthalmic zoster. Results: Ophthalmoscopic examination revealed the presence of bilateral, multiple, refractile iris and macular crystals. No other signs of uveitis or stigmata of HIV were found. Conclusion: Intraocular crystals are a rare finding, usually seen in chronic uveitis with or without hypergammaglobulinemia. This finding has not been previously described in non-inflamed eyes, nor as an ocular manifestation of HIV. We hypothesize that HIV-related disruption of the blood-aqueous and blood-retinal barriers allows intraocular immunoglobulin deposition in patients with hypergammaglobulinemia.

Analytical variation in the measurement of serum monoclonal component by capillary electrophoresis

The amount of serum monoclonal components (MC), and moreover, their variation with time are important factors for differentiating malignancy-associated from benign gammopathies. Capillary electrophoresis (CE) of serum proteins allows better quantitative measurement in comparison to conventional gel-supported electrophoresis. We investigated the analytical variation of CE measurement of serum MC of different sizes: the variation due to integration settings and the analytical variation of the CE procedure were assessed in separate experiments. “Small” MC (in the interval 4–14% of total protein) were measured with analytical imprecision (CV%) in the interval 5–25%. The step of setting the integration limits was found to generate an important portion of such an overall variability. The imprecision was negatively, nonlinearly related to MC concentration: at the “critical” MC value of 40% of total protein, the analytical imprecision was CV≈2.5%. The variation computed from sets of subsequent routine MC measurements in “stable” patients with MGUS, over observation intervals from 10 to 30 months, behaved similarly to the “pure” analytical variation measured experimentally. This suggested very low, if any, biological variation of MC. Differences between subsequent MC measurements in a patient should be interpreted in light of the analytical variation.

Acquired HDL Deficiency Associated With Apolipoprotein A-I Reactive Monoclonal Immunoglobulins

To the Editor: Immunoglobulins (Igs) directed at components of lipoproteins to cause altered lipoprotein metabolism have been described in patients with multiple myeloma,1,2⇓ xanthomatosis,3 benign gammopathies,4 rheumatoid arthritis,5 systemic lupus erythematosus (SLE), and primary antiphospholipid syndrome (APS).6,7⇓ In most cases, hyperlipidemia results from Igs reactive with apolipoprotein (apo) B present on very low–density lipoproteins and LDLs. Less common have been associations of Igs with hypolipidemia or reactive with HDLs. Here we describe two patients who developed low HDL-cholesterol (HDL-C) levels (<5th percentile) associated with benign gammopathy and the presence of serum Igs reactive with apo A-I. Patient 1 (P1) was a morbidly obese (body mass index, 48 kg/m2), 45-year-old woman with mild normocytic, normochromic anemia (hematocrit, 33 g/L; hemoglobin, 11.6 g/L) and low HDL-C (0.22 mmol/L [8 mg/dL]). Serum Ig levels were elevated. Antinuclear antibodies were detected but were nonreactive with dsDNA, Sm, RNP, SSA, SSB, SCL-70, and histone. Anticardiolipin and anti–β2-glycoprotein I antibodies were negative. Immunofixation electrophoresis (IFE) identified monoclonal IgGκ and IgGλ bands. No Igs or light chains were detected in her urine. Serum lipid levels showed that HDL-C was in the low-normal to normal range between 1992 and 1996 (1.0 to 1.4 mmol/L) but at the time of presentation …

A fatal case of scleredema of Buschke

Scleredema of Buschke is a rare disorder characterized by the development of areas of skin induration which usually resolve spontaneously. It is occasionally associated with a benign gammopathy, and rarely with myelomatosis. We describe a 60-year-old woman with extensive skin changes, who developed IgA myeloma. Unusually, her skin disease did not respond to conventional myeloma therapy. Death occurred as a consequence of the progressive skin disease.

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 gammopathies is examined in detail. The point is made that patients must be followed indefinitely because malignancy may develop more than 20 years later. The association of monoclonal gammopathies with other apparently unrelated diseases is discussed.

Immuntherapie des chronischen Guillain-Barré-Syndroms mit Hochdosis-IgG und Ciclosporin A

We report about the three-year treatment of a patient with chronic relapsing Guillain-Barré syndrome (GBS), who, simultaneously, suffered from benign gammopathy. A casual relationship between the two diseases could not be proven, since specific antimyeline antibodies could not be found. Five severe bouts of the disease occurred during the observation period, only the first two relapses, however, showed improvement with cortisone treatment, while the latter did not so. High dosages of 7S-immunoglobuline, by contrast, led to a rapid improvement during each of the subsequent relapses. The additional therapy with ciclosporine A kept the patient free from neurological deficits for more than six months now. The mechanisms of various immunological therapeutic approaches are discussed, particularly as an alternative to plasmapheresis. Our observation, as well as theoretical considerations, suggest the aforementioned immunological treatment being promising in chronic GBS.

J chain disease: A novel form of plasma cell dyscrasia

Immunohistochemical staining of cells from the bone marrow of patients with plasma cell dyscrasias such as multiple myeloma usually reveals a variable proportion of cells that stain with both anti-heavy and anti-light chain reagents of one immunoglobulin isotype and one light chain type (e.g., IgG-K). In approximately 1% of patients, more than one immunoglobulin isotype may be found, usually in different cells. In other cases the bone marrow cells may produce only light or heavy chains (light or heavy chain diseases) or may not stain with either anti-heavy or -light chain reagents despite their plasma cell morphology and clinical manifestations of multiple myeloma. In contrast to cells from normal bone marrow, cells from patients with various gammopathies may contain J chain in addition to heavy and light chains, irrespective of the immunoglobulin isotype or light chain type produced [l-5]. The presence of J chain in immunoglobulin-producing cells from the bone marrow has been considered a useful marker to distinguish multiple myeloma from benign gammopathy; in the latter disorder the immunoglobulin-producing cells express J chain in a lower frequency than cells from patients with multiple myeloma [5]. In normal individuals, bone marrow cells are usually devoid of intracytoplasmic J chain [6]. The presence of J chain has also been revealed by immunohistochemical techniques in various B-cell lymphomas [7-lo] and is considered a possible marker of malignancy [7]. Furthermore, the Jchain-positive but immunoglobulin-negative cells were detected in three of 90 patients with high-grade lymphoma [9] and in Reed-Sternberg and Hodgkin cells in some [lo] but not other patients with Hodgkin’s disease [7,8]. In tissue samples from normal individuals, J chain is easily detectable in cells that produce polymeric IgM or IgA; secretory glands and mucosa-associated tissues such as mammary, salivary, and lacrimal glands, intestines, and nasal mucosa are particularly rich in J chain- and IgA- or IgM-producing cells [6,11,12]. While examining bone marrow specimens from 88 patients suspected of having a plasma cell dyscrasia or other immunoproliferative diseases by immunofluorescence technique, we observed that cells from four patients displayed unusual staining patterns: in one patient, numerous cells stained for IgG-K or J chain, with a few containing both IgG-K and J chain; in two patients, a few of the IgA- or IgG-containing cells stained for J chain, although most of the J chain-containing cells were negative with either heavy or light

Corneal Manifestations of Scleromyxedema

Bilateral superficial corneal deposits and scleromyxedema, an uncommon dermatosis caused by the accumulation of acid mucopolysaccharide in the skin often associated with a benign monoclonal gammopathy developed in a 71-year-old man. A biopsy specimen of the cornea showed that the deposits stained strongly positive for IgG and lambda chains. Ultrastructurally, the deposits consisted of amorphous granular material. Scleromyxedema should be considered in the differential diagnosis of noninflammatory superficial keratopathies associated with benign gammopathies.

Comparison of Inhibitory and Binding Characteristics of an Antibody Causing Acquired von Willebrand Syndrome: An Assay for von Willebrand Factor Binding by Antibody

AbstractAn acquired inhibitor of von Willebrand factor (vWF) activity occurring in a patient with benign gammopathy and von Willebrand syndrome (vWS) has been partially characterized. The inhibitor-induced syndrome resulted in low to undetectable plasma levels of vWF/ristocetin, vWF/botrocetin, FVIIIR:Ag, and FVIII:C with a normal to slightly prolonged bleeding time. Platelet vWF was normal. Intensive and continuous infusion of a heat-treated factor VIII concentrate (Hemofil-T, Hyland, Glendale, Calif) elevated the FVIII:C plasma levels to about 100%, with an increase in FVIIIR:Ag levels to about 340% and vWF/ristocetin levels to about 40%, much lower than expected based on the dose of Hemofil-T and its content of vWF and FVIII:C activities. The inhibitor bound to staphylococcal protein A (SpA) with high affinity, indicating an IgG antibody (Ab). An assay for the vWF-binding capacity was developed on the basis of absorption of the Ab from serially diluted plasma by SpA and removal of vWF and FVIII:C activities from normal plasma by the SpA-Ab complex. The Ab-binding site was on the vWF component of the factor VIII complex. The Ab was unable to bind isolated FVIII:C. The combined use of the new vWF-binding assay and a battery of tests for inhibition of vWF-dependent platelet aggregation with ristocetin (which detects high molecular weight vWF), with botrocetin (which detects high and low molecular weight vWF), and with platelet-aggregating factor (which detects high molecular weight vWF) provided a means of analysis of Ab effect on in vitro vWF function. Using these tests, a comparison was made of the effects of the vWS Ab with those of an Ab inhibitor occurring in homozygous von Willebrand's disease. The Ab of the vWS patient had weak inhibitory action on vWF/ristocetin without having an effect on vWF/botrocetin and platelet-aggregating factor, a high titer vWF-binding capacity, and no anamnestic response following concentrate therapy. These findings contrasted with those of the Ab occurring in inhibitor von Willebrand's disease in which vWF inhibitor and binding values were similar, with a strong anamnestic response. The findings indicate that the vWS Ab binds to an epitope on the molecular vWF in such a way that causes only limited inhibition of vWF/ristocetin function and no inhibition of vWF/botrocetin function, suggesting that these two functional domains are at separate sites.

Comparison of inhibitory and binding characteristics of an antibody causing acquired von Willebrand syndrome: an assay for von Willebrand factor binding by antibody

An acquired inhibitor of von Willebrand factor (vWF) activity occurring in a patient with benign gammopathy and von Willebrand syndrome (vWS) has been partially characterized. The inhibitor-induced syndrome resulted in low to undetectable plasma levels of vWF/ristocetin, vWF/botrocetin, FVIIIR:Ag, and FVIII:C with a normal to slightly prolonged bleeding time. Platelet vWF was normal. Intensive and continuous infusion of a heat-treated factor VIII concentrate (Hemofil- T, Hyland, Glendale, Calif) elevated the FVIII:C plasma levels to about 100%, with an increase in FVIIIR:Ag levels to about 340% and vWF/ristocetin levels to about 40%, much lower than expected based on the dose of Hemofil-T and its content of vWF and FVIII:C activities. The inhibitor bound to staphylococcal protein A (SpA) with high affinity, indicating an IgG antibody (Ab). An assay for the vWF-binding capacity was developed on the basis of absorption of the Ab from serially diluted plasma by SpA and removal of vWF and FVIII:C activities from normal plasma by the SpA-Ab complex. The Ab-binding site was on the vWF component of the factor VIII complex. The Ab was unable to bind isolated FVIII:C. The combined use of the new vWF- binding assay and a battery of tests for inhibition of vWF-dependent platelet aggregation with ristocetin (which detects high molecular weight vWF), with botrocetin (which detects high and low molecular weight vWF), and with platelet-aggregating factor (which detects high molecular weight vWF) provided a means of analysis of Ab effect on in vitro vWF function. Using these tests, a comparison was made of the effects of the vWS Ab with those of an Ab inhibitor occurring in homozygous von Willebrand's disease. The Ab of the vWS patient had weak inhibitory action on vWF/ristocetin without having an effect on vWF/botrocetin and platelet-aggregating factor, a high titer vWF- binding capacity, and no anamnestic response following concentrate therapy. These findings contrasted with those of the Ab occurring in inhibitor von Willebrand's disease in which vWF inhibitor and binding values were similar, with a strong anamnestic response. The findings indicate that the vWS Ab binds to an epitope on the molecular vWF in such a way that causes only limited inhibition of vWF/ristocetin function and no inhibition of vWF/botrocetin function, suggesting that these two functional domains are at separate sites.

Effect of chemotherapy on T-lymphocyte subsets in B-cell proliferative disorders.

The T-cell subset distribution and the activity markers of 41 patients with multiple Myeloma, Waldenström's macroglobulinaemia and benign monoclonal gammopathy were repeatedly analysed using monoclonal antibodies (T3, T4, T8, anti-TAC, anti DR) and rosetting techniques. In myeloma and macroglobulinaemia the relative and absolute numbers of T4+ cells were diminished while the absolute number of T8+ cells was not decreased. No significant difference between stage I and III of the myeloma disease was seen. The diminished number of T4+ cells in myeloma was partly due to the effect of chemotherapy. Chemotherapy-induced lymphopenia resulted in a drop of circulating T4+ cells and an inverted T4/T8 cell ratio. Untreated patients with myeloma were not significantly different from patients with benign gammopathy. Patients with macroglobulinaemia differed from patients with myeloma as they had an increased absolute T8 cell count and a significantly elevated percentage of TAC+ (= IL 2 receptor expressing) cells. In macroglobulinaemia chemotherapy affected also the T8+ cell subset. Thus, patients with macroglobulinaemia, but not with myeloma appear to have activated T8+ cells in their circulation.

Paraproteinemia Associated with Demyelinating Polyneuropathy or Myositis: Treatment with Plasmapheresis and Immunosuppressive Drugs

Four patients with chronic, progressive demyelinating peripheral polyneuropathy were found to have paraproteinemia. Two of the patients had multiple myeloma [both immunoglobulin (Ig)G lambda]. The other two had benign gammopathies: one of IgG kappa type and the other one with marked polyclonal elevation of IgM. Immunofluorescence studies revealed deposits of the abnormal serum immunoglobulin along the myelin sheaths in two of the patients in whom sural nerve biopsies were performed. All four patients were treated with plasmapheresis in combination with immunosuppressive drugs. Favorable responses to the therapy was observed in all four patients, but the degree of response varied from patient to patient. Two patients who presented clinical and electromyographic findings consistent with polymyositis were found to have serum IgG kappa M components. Immunofluorescence studies performed on muscle biopsy material from both patients revealed deposits of the abnormal serum paraprotein along the sarcolemmal basement membrane. A treatment course of plasmapheresis and immunosuppressive drugs resulted in a sustained increase of muscle strength in both patients.

'Benign' Monoclonal Gammopathy

A series of 241 patients with monoclonal protein but no evidence of multiple myeloma, macroglobulinemia, amyloidosis, or lymphoma (benign monoclonal gammopathy) were followed up for more than ten years. The patients were classified as follows: group 1, patients without increase of monoclonal serum protein during follow-up (benign) (37%); group 2, patients with greater than 50% increase of monoclonal protein or development of monoclonal urine protein (5%); group 3, patients who died of unrelated causes (39%); and group 4, patients in whom myeloma, macroglobulinemia, amyloidosis, or related diseases developed (19%). The median interval from recognition of the monoclonal protein to diagnosis of multiple myeloma was 98 months; macroglobulinemia, 115 months; and systemic amyloidosis, 92 months. No laboratory or clinical data initially differentiated patients with benign gammopathy from those in whom serious diseases developed. Consequently, serial measurement of serum monoclonal protein is essential.

Etude des liquides céphalo-rachidiens dans les dysglobulinémies monoclonales bénignes et malignes

The authors compared 9 cases of myeloma and 2 cases of Waldenström's disease with 10 cases of benign monoclonal gammapathies. None of the patients (except one) had neurological involvement; one patient hab diabetes. The study was focused on the immunoglobulins and proteins in the CSF. The following observations were made: - The CSF protein was raised in 8 out of the 11 malignant gammopathies and in 5 out of the 10 benign gammopathies; - An identical monoclonal protein was found in the CSF and serum in all the cases of malignant gammopathies. In the cases considered to be benign, the results were less concordant: one IgM lymphoma had normal CSF; three IgG dysglobulinemias had different immunoglobulins proteins in their CSF: - The mean CSF immunoglobulin level was much higher in the myeloma patients than in the benign gammopathies; - A number of findings suggest intrathecal secretion (at least in the malignant gammopathies). This is also true in a good number of the benign gammopathy cases. Direct tumoural invasion of the CSF may be more common than generally supposed. However, the study of CSF immunoglobulins alone does not establish the diagnosis of malignant dysglobulinemia. Nevertheless, the authors consider that the finding of intrathecal secretion of immunoglobulin, especially in patients with a discordance in FAB and FC fractions, should lead to a closer follow-up of these patients.

Peripheral neuropathy in patients with benign monoclonal gammopathy--a pilot study.

It is well known that peripheral neuropathy occurs in patients with myeloma or macroglobulinaemia, but its pathogenesis is still obscure. In recent years, neuropathy has also been reported in association with benign monoclonal or oligoclonal gammopathy. Modern histo-immunological methods have revealed evidence of antibody production to peripheral nerve tissue, probably the myelin sheath. The present study included 21 unselected, consecutive patients with benign monoclonal gammopathy observed in the Division of Haematology. Clinical and laboratory investigations included electrophysiological examination and analyses of the M components. Of the 21 patients 11 had noticed slight neuropathic symptoms in their extremities; in 5 both clinical and electrophysiological findings were compatible with neuropathy; 6 showed positive clinical signs of neuropathy; 4 had either positive electromyographic or electroneurographic findings. In summary, 15 of 21 patients had some signs of peripheral neuropathy. In spite of the screening design of the study, this strikingly high frequency is comparable with other recent reports. Haematological studies did not reveal any significant differences between the patient groups with positive or negative neurological findings. The findings indicate that even benign gammopathies may be associated with peripheral neuropathy.

Myeloma neuropathy: passive transfer from man to mouse.

Mice were injected daily, for up to 10 weeks, with purified monoclonal immunoglobulin G from patients with myelomatous polyneuropathy or benign gammopathy. The animals developed a demyelinating polyneuropathy with slowed nerve conduction velocities. The putative antinerve factor may be an antibody since injection of Fab fragments from the monoclonal immunoglobulin G produced a similar demyelination. This provides evidence of a circulating factor in the serum of myeloma patients with polyneuropathy that reproduces typical features of the human disease on passive transfer. This disorder is thus distinguished from other neuropathies that occur as remote effects of malignant disease but have no identified pathogenic factors associated with them.

Pretreatment tumor mass, cell kinetics, and prognosis in multiple myeloma

One-hundred fifty patients with multiple (plasma cell) myeloma had pretreatment tumor mass staging, and 79 also had measurement of the pretreatment labeling index (LI%). There were clear differences in survival by pretreatment stage of disease. The pretreatment LI% of bone marrow plasma cells was an independent prognostic factor both in single factor and multivariate regression analyses, including myeloma stage (p less than 0.02). Other important prognostic factors (multivariate) included performance status, serum creatinine, presence of Bence Jones protein, age, and kappa/lambda subtype. A LI% of less than 1% was associated with long survival in each patient group. Patients with benign gammopathy had excellent survival and very low labeling indices. A pretreatment LI% of greater than 3% in high cell mass patients with a high total number of DNA synthesizing cells (S) conferred a very poor prognosis (p = 0.002). This subgroup of patients with high S values also had a high incidence of central nervous system relapse (27%), Bence Jones proteinuria, and elevated serum uric acid levels. We conclude that the pretreatment labeling index provides helpful prognostic information in addition to tumor mass staging.

Pretreatment Tumor Mass, Cell Kinetics, and Prognosis in Multiple Myeloma

One-hundred fifty patients with multiple (plasma cell) myeloma had pretreatment tumor mass staging, and 79 also had measurement of the pretreatment labeling index (LI%). There were clear differences in survival by pretreatment stage of disease. The pretreatment LI% of bone marrow plasma cells was an independent prognostic factor both in single factor and multivariate regression analyses, including myeloma stage (p less than 0.02). Other important prognostic factors (multivariate) included performance status, serum creatinine, presence of Bence Jones protein, age, and kappa/lambda subtype. A LI% of less than 1% was associated with long survival in each patient group. Patients with benign gammopathy had excellent survival and very low labeling indices. A pretreatment LI% of greater than 3% in high cell mass patients with a high total number of DNA synthesizing cells (S) conferred a very poor prognosis (p = 0.002). This subgroup of patients with high S values also had a high incidence of central nervous system relapse (27%), Bence Jones proteinuria, and elevated serum uric acid levels. We conclude that the pretreatment labeling index provides helpful prognostic information in addition to tumor mass staging.

Identification of Crystalline Deposits-Reply

In Reply. —The diagnosis of monoclonal gammopathy was established by urine and serum immunoelectrophoresis, but not on the basis of immunoperoxidase stains of the corneal tissue. The article stated that the corneal deposits stained with antiserum to immunoglobulins IgG, IgA, IgM, and κ light chains (page 126). In addition, λ light chain staining was also positive. It is possible that the deposits could be related to rheumatoid-factor-like activity, although the serum rheumatoid factor determination was negative. The patient has a benign gammopathy at this time, with normal results of bone marrow and roentgenographic studies. However, careful follow-up is indicated.