Mark Drayson

Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group

Summary. The monoclonal gammopathies are a group of disorders associated with monoclonal proliferation of plasma cells. The characterization of specific entities is an area of difficulty in clinical practice. The International Myeloma Working Group has reviewed the criteria for diagnosis and classification with the aim of producing simple, easily used definitions based on routinely available investigations. In monoclonal gammopathy of undetermined significance (MGUS) or monoclonal gammopathy, unattributed/unassociated (MG[u]), the monoclonal protein is < 30 g/l and the bone marrow clonal cells < 10% with no evidence of multiple myeloma, other B‐cell proliferative disorders or amyloidosis. In asymptomatic (smouldering) myeloma the M‐protein is ≥ 30 g/l and/or bone marrow clonal cells ≥ 10% but no related organ or tissue impairment (ROTI)(end‐organ damage), which is typically manifested by increased calcium, renal insufficiency, anaemia, or bone lesions (CRAB) attributed to the plasma cell proliferative process. Symptomatic myeloma requires evidence of ROTI. Non‐secretory myeloma is characterized by the absence of an M‐protein in the serum and urine, bone marrow plasmacytosis and ROTI. Solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas (± recurrent) are also defined as distinct entities. The use of these criteria will facilitate comparison of therapeutic trial data. Evaluation of currently available prognostic factors may allow better definition of prognosis in multiple myeloma.

Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset

CD4+ CD25+ T regulatory cells (TReg), suppress antigen‐specific immune responses and are important for allograft tolerance. During pregnancy the mother tolerates an allograft expressing paternal antigens (the fetus) requiring substantial changes in immune regulation over a programmed period of time. We analysed whether immune‐suppressive TReg cells were altered during pregnancy and therefore might play a part in this tolerant state. The presence of TReg cells was assessed in the blood of 25 non‐pregnant, 63 pregnant and seven postnatal healthy women by flow cytometry. We observed an increase in circulating TReg cells during early pregnancy, peaking during the second trimester and then a decline postpartum. Isolated CD25+ CD4+ cells expressed FoxP3 messenger RNA, a marker of TReg cells, and suppressed proliferative responses of autologous CD4+ CD25– T cells to allogeneic dendritic cells. These data support the concept that normal pregnancy is associated with an elevation in the number of TReg cells which may be important in maintaining materno‐fetal tolerance.

Serum free light chains for monitoring multiple myeloma.

Monoclonal immunoglobulin free light chains (FLC) are found in the serum and urine of patients with a number of B-cell proliferative disorders, including multiple myeloma. Automated immunoassays, which can measure FLC in serum, are useful for the diagnosis and monitoring of light chain (AL) amyloidosis, Bence Jones myeloma and non-secretory myeloma patients. We report the results of a study investigating the utility of serum FLC measurements in myeloma patients producing monoclonal intact immunoglobulin proteins. FLC concentrations were measured in presentation sera from 493 multiple myeloma patients with monoclonal, intact immunoglobulin proteins. Serial samples were assayed from 17 of these patients and the FLC measurements were compared with other disease markers. Serum FLC concentrations were abnormal in 96% of patients at presentation. FLC concentrations fell more rapidly in response to treatment than intact immunoglobulin G (IgG) and showed greater concordance with serum beta2 microglobulin concentrations and bone marrow plasma cell assessments. It was concluded that serum FLC assays could be used to follow the disease course in nearly all multiple myeloma patients. In addition, because of their short serum half-life, changes in serum FLC concentrations provide a rapid indication of the response to treatment.Prior studies have demonstrated the utility of serum free light chains (FLC) in the diagnosis and monitoring of non-secretory (Drayson et al, 2001) and light chain myeloma (LCMM) (Bradwell et al, 2003). Mead et al (2004) have also suggested a role in myelomas that produce an intact immunoglobulin paraprotein (IIMM), where 96% of patients had an abnormal FLC ratio and/or monoclonal FLC concentration at diagnosis and it was concluded that serum FLC assays could be used to follow the disease course in nearly all multiple myeloma patients. We have reservations, however, regarding the broader application of FLC monitoring to patients with IIMM, in particular to the use of the FLC assay in monitoring for disease relapse post-autologous stem cell transplantation. We assessed whether the serum kappa to lambda (K/L) FLC ratio might be an early predictor of disease progression in patients with IIMM following autologous stem cell transplantation. Sera of patients with IIMM or LCMM who underwent autologous transplantation and were in complete remission or plateau phase were analysed. The FLC concentration was measured using a kit assay (The Binding Site Ltd, Birmingham, UK) and the Immage (Beckman Coulter, Brea, CA, USA) protein system. Monoclonal paraprotein was detected by serum protein electrophoresis (Beckman Coulter) and/or immunofixation (IFE). Myeloma response and relapse were defined according to international criteria (Bladé et al, 1998). Thirty-four patients were monitored post-transplant, on an average bimonthly, for a median of 16 months (range, 3–36 months). K/L FLC ratios were within the manufacturer’s reference interval for IIMM and LCMM patients in complete remission (0Æ41–1Æ59; n 1⁄4 15) except for one LCMM patient (K/L ratio 0Æ15) with no Bence Jones protein detected on IFE and 2% polyclonal plasma cells on bone marrow biopsy. Seventy-two per cent (13/18) of IIMM and LCMM patients in plateau phase (i.e. residual serum paraprotein ranging from <1 to 19 g/l or trace Bence Jones proteinuria) had a normalised FLC ratio (0Æ39–1Æ49) with four patients having abnormal ratios (0Æ16, 0Æ23, 0Æ24, 3Æ4, 5Æ5). Eleven patients with IIMM have relapsed. Whereas the FLC ratio and monoclonal FLC concentration have been reported to reflect changes in disease progression in LCMM (Bradwell et al, 2003), we did not observe the same correlation in IIMM (Table I). Of 11 relapsed IIMM patients, four had persisting normal FLC concentrations and ratios, despite rising paraprotein concentrations of 10–36 g/l and abnormal bone marrow biopsy (plasma cells 9–100%). In two other patients, increasing paraprotein concentration (IgA lambda 1Æ7–23 g/l; IgG kappa 11–27 g/l) preceded increasing monoclonal lambda FLC concentration (14–35 mg/l, ratio 0Æ96–0Æ29) and kappa FLC concentration (60–75 mg/l, ratio 5Æ5–11Æ9) by 8 and 4 months respectively. In another, increasing lambda FLC (40–179 mg/l; ratio 0Æ49–0Æ05) preceded an increase in paraprotein (19–31 g/l) by 11 months, and in four others, serum paraprotein and monoclonal FLC concentration increased simultaneously. Thus, 55% (6/11) of our transplanted group failed to give an abnormal ratio or elevated FLC concentration at or prior to disease relapse. Our data suggest that serum FLC measurement may not be useful as an early predictor of disease reoccurrence compared with the serum paraprotein in patients with IIMM posttransplantation. Systematic study of the role of FLC monitoring needs to occur in the context of larger prospective studies before it is routinely applied to the monitoring of patients with IIMM.

Secretory immunoglobulin A and cardiovascular reactions to mental arithmetic, cold pressor, and exercise: Effects of beta‐adrenergic blockade

We investigated the influence of sympathetic nervous system processes on mucosal immunity by comparing the effects of beta-adrenoceptor blockade with 40 mg propranolol and placebo on secretory immunoglobulin A (sIgA) at rest and during paced serial arithmetic, cold pressor, and submaximal cycling. These tasks produced patterns of cardiovascular activity indicative of combined alpha- and beta-adrenergic, alpha-adrenergic, and beta-adrenergic activation, respectively. The effectiveness of the beta blockade was confirmed by the attenuation under propranolol of the shortening of the cardiac preejection period and the tachycardia elicited by mental arithmetic and exercise. The cold pressor test did not affect sIgA under either the placebo or the propranolol. Mental arithmetic increased sIgA concentration, and this increase was not blocked by propranolol. Exercise elicited increases in both sIgA concentration and sIgA secretion rate, which were not diminished by beta blockade. These data suggest that sIgA is not regulated by beta-adrenergic mechanisms.

The impact of attaining a minimal disease state after high-dose melphalan and autologous transplantation for multiple myeloma

Initial studies with high‐dose therapy (HDT) in myeloma suggest some beneficial effects of attaining a complete response (CR); however, the effect on survival is difficult to assess owing to inconsistencies in the definition of response between studies. We have analysed 96 newly diagnosed patients aged less than 65 years who received HDT and assessed the effect of response on survival using electrophoresis, immunofixation and fluorescent IgH polymerase chain reaction (PCR) to define CR. Patients received induction chemotherapy with C‐VAMP (adriamycin, vincristine, methylprednisolone, cyclophosphamide) followed by melphalan 200 mg/m2 and reinfusion of peripheral blood stem cells. There was a high response to C‐VAMP [CR = 24%, partial response (PR) = 64%], with all but one patient improving the depth of response after HDT (CR = 69%, PR = 31%). The progression‐free survival (PFS) and overall survival (OS) were excellent at a median of 46·4 months and 72+ months. There was a trend towards an improved PFS in patients with an immunofixation‐negative CR compared with patients with a PR (49·4 months, 41·14 months; P = 0·26). This was not evident when electrophoresis was used to define CR. The method used to define CR did not impact on the overall survival and fluorescent IgH PCR failed to add any additional prognostic information. This study supports the widespread use of the European Bone Marrow Transplantation group (EBMT) response criteria and suggests that immunofixation should be performed on all patients who become electrophoresis negative.

Cellular and mucosal immune reactions to mental and cold stress: Associations with gender and cardiovascular reactivity

To examine gender differences in immune reactions to stress and relationships between immune and cardiovascular reactivity, measures of cellular and mucosal immunity and cardiovascular activity were recorded in 77 men and 78 women at rest and in response to active (mental arithmetic) and passive (cold pressor) stress tasks. Both tasks reduced CD4+ T cells and the CD4/8 ratio. Total lymphocytes, NK cells, CD8+ T cells, and secretory immunoglobulin A (sIgA) increased with active stress. Passive stress decreased sIgA. At rest, men had more NK cells, less CD4+ T cells, and fewer neutrophils than women. Mental stress increased sIgA in men but not women. Cardiovascular reactivity to active stress was associated with increases in NK cells. The data support the hypothesis that stress-related increases in lymphocytes are beta-adrenergically mediated, and suggest that the fall in CD4+ T cells may be alpha-adrenergically driven. Mechanisms underlying sIgA reactions are more difficult to determine. Men and women differed in some cell counts, but not in reactivity, although gender influenced sIgA reactions to arithmetic.

Antibody response to vaccination and psychosocial stress in humans:relationships and mechanisms.

The purpose of this review is to determine the effects of psychosocial stress on antibody response to vaccination in humans, consider possible mechanisms, and identify agenda for future research. Studies of the association between stress and vaccination response in humans were reviewed. There is evidence of a negative association between stress and antibody response to vaccination, which is most apparent with thymus-dependent vaccines and when measured at extended times after vaccination. Preliminary findings implicate the hypothalamic-pituitary-adrenal axis and sympathetic nervous system as potential mechanisms, although a role for unhealthy behaviours cannot be discounted at this stage. Results to date are sufficiently indicative to direct future research to untangling their theoretical ramifications, as well as realising their clinical implications.

Secretory immunoglobulin A and cardiovascular activity during mental arithmetic and paced breathing.

The role of the autonomic nervous system in secretory immunoglobulin A (sIgA) responses to laboratory challenge was explored in a study in which sIgA and cardiovascular activity were recorded at rest and during mental arithmetic and paced breathing. These tasks were selected to preferentially engage the sympathetic and parasympathetic nervous systems, respectively. Mental arithmetic elicited a mixed pattern of increased alpha- and beta-adrenergic activity and a reduction in parasympathetic activity; diastolic blood pressure, total peripheral resistance, and systolic blood pressure increased, preejection period shortened, and heart rate variability decreased. In contrast, paced breathing primarily elicited an increase in parasympathetic activity; heart rate variability increased. Mental arithmetic also provoked an increase in sIgA concentration but no change in saliva volume, whereas paced breathing affected neither sIgA concentration nor saliva volume. These data suggest that sIgA responses to laboratory challenges are mediated by sympathetic rather than parasympathetic processes.

Stress, coping, and hepatitis B antibody status

Objective The present study investigated the association between exposure to stressful life events, coping style, and antibody status after hepatitis B vaccination. Methods Two hundred sixty medical school undergraduates, who had received the three-dose hepatitis B vaccine before recruitment to this study, completed questionnaires measuring exposure to stressful life events during the past year, customary coping strategies, and health behaviors. Antibodies against hepatitis B surface antigen were determined; levels <100 mIU/ml were deemed inadequate. Results Two participant cohorts were identified: those vaccinated within the last year and those vaccinated earlier. In the early vaccination cohort, participants with greater-than-average stress exposures had a more than two-fold increased risk of having an inadequate antibody titer. Coping by accepting the reality of stressful situations proved protective, whereas coping by substance use increased the risk of having an inadequate antibody count in this cohort. These associations remained significant after adjustment for possible mediators. Furthermore, the effects of stress and coping were largely independent of one another. Neither stress nor coping was significantly associated with antibody status in the recently vaccinated cohort. Conclusions The present study confirms that the immune system is sensitive to variations in psychological factors. Stressful life events and coping strategy seem to have a continuing impact on hepatitis B antibody status.

Life events, perceived stress and antibody response to influenza vaccination in young, healthy adults.

OBJECTIVES Chronic stress has been associated with impaired response to influenza vaccination in the elderly. This study investigated whether mild, intermittent stress experienced by young, healthy adults has a similar effect. METHODS Antibody and psychological status were determined prevaccination and 5 weeks and 5 months later; a fourfold increase in antibody to at least one viral strain was considered protective. RESULTS At 5 months, unprotected participants reported significantly more life events and tended to report more perceived stress than those who were protected. CONCLUSIONS Psychological stress is detrimental to long-term maintenance of antibody levels following vaccination in young, healthy adults.