TEMPI syndrome: difficult to diagnose, "easy" to treat?

TEMPI syndrome is a rare, acquired disorder with multisystemic manifestations. It is classified as a plasma cell disorder and is characterized by telangiectasias, erythrocytosis, monoclonal gammopathy, perinephric fluid collections and intrapulmonary shunt. Even though TEMPI's pathophysiology remains elusive, it responds to anti-myeloma therapy indicating that the monoclonal protein or clone plays a key role. We present a challenging case of a 73-year-old man with erythrocytosis and deteriorating renal function with nephrotic-range proteinuria in whom after extensive work up, the diagnosis of TEMPI syndrome was made. He was received treatment with daratumumab-bortezomib-cyclophosphamide and dexamethasone (Dara-VCD) and achieved a hematological and clinical response. We also report preliminary data on a multiplex assay for cytokines and growth factors for two patients with TEMPI syndrome and note lower levels for non-specific innate immunity related cytokines. A direct link between renal impairment and TEMPI syndrome is not currently established; cytokine deregulation could potentially be involved in the ischemic changes observed in the renal biopsy of our patient.

Examining the immunological responses to COVID-19 vaccination in multiple myeloma patients: a systematic review and meta-analysis.

BACKGROUND: Impaired immune response in multiple myeloma renders the patients vulnerable to infections, such as COVID-19, and may cause worse response to vaccines. Researchers should analyze this issue to enable the planning for special preventive measures, such as increased booster doses. Therefore, this meta-analysis aimed to evaluate the response and efficacy of COVID-19 vaccines in patients with multiple myeloma. METHODS: This meta-analysis followed PRISMA 2020 guidelines, conducting a comprehensive database search using specified keywords. Study selection involved a two-phase title/abstract and full-text screening process. Data extraction was performed by two researchers, and statistical analysis involved meta-analysis, subgroup analysis based on vaccine dosage and study time, random effects meta-regression, and heterogeneity testing using the Q test. RESULTS: The meta-analysis revealed that patients with multiple myeloma (MM) had a lower likelihood of developing detectable antibodies after COVID-19 vaccination compared to healthy controls (Log odds ratio with 95% CI: -3.34 [-4.08, -2.60]). The analysis of antibody response after different doses showed consistent lower seropositivity in MM patients (after first dose: -2.09, [-3.49, -0.69], second: -3.80, 95%CI [-4.71, -3.01], a booster dose: -3.03, [-5.91, -0.15]). However, there was no significant difference in the mean level of anti-S antibodies between MM patients and controls (Cohen's d -0.72, [-1.86, 0.43]). Evaluation of T-cell responses indicated diminished T-cell-mediated immunity in MM patients compared to controls. Seven studies reported clinical response, with breakthrough infections observed in vaccinated MM patients. CONCLUSIONS: These findings highlight the impaired humoral and cellular immune responses in MM patients after COVID-19 vaccination, suggesting the need for further investigation and potential interventions.

The promise and harms of screening for plasma cell dyscrasias.

In this perspective, we highlight both the promise and harms of screening for plasma cell dyscrasias, as well as the implications of the use of mass spectrometry for diagnosing monoclonal gammopathy of undetermined significance in routine practice.

The exploration of B cell maturation antigen expression in plasma cell dyscrasias beyond multiple myeloma.

BACKGROUND: B cell maturation antigen (BCMA) targeted immunotherapies have demonstrated remarkable clinical efficacy in multiple myeloma (MM). Here, we evaluated the BCMA expression in MM and other plasma cell dyscrasias (PCDs), hoping to provide a potential treatment strategy for the relapsed/refractory PCDs besides MM. METHODS: From January 2018 to August 2021, 377 patients with PCDs were enrolled in this study, including 334 MM, 21 systemic light chain amyloidosis (AL), 5 POEMS syndrome, 14 monoclonal gammopathy of undetermined significance (MGUS), and three monoclonal gammopathy of renal significance (MGRS). The membrane-bound BCMA expression measured by multiparameter flow cytometry was defined by BCMA positivity rate and the mean fluorescence intensity (MFI). RESULTS: The patients with MM had a median BCMA positive rate of 88.55% (range, 0.2% - 99.9%) and median BCMA MFI of 1281 (range, 109 - 48586). While the median BCMA positive rate in other PCDs was 55.8% (6.2% -98.9%), and the median BCMA MFI was 553 (182- 5930). BCMA expression level was negatively associated with hemoglobin concentration in multivariate analysis in terms of BCMA positive rate and MFI. CONCLUSIONS: In conclusion, BCMA has the potential to be a therapeutic target for other PCDs besides MM.

Diffusion-weighted imaging (DWI) in diagnosis, staging, and treatment response assessment of multiple myeloma: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the role of diffusion-weighted imaging (DWI) in the initial diagnosis, staging, and assessment of treatment response in patients with multiple myeloma (MM). MATERIALS AND METHODS: A systematic literature review was conducted in PubMed, the Cochrane Library, EMBASE, Scopus, and Web of Science databases. The primary endpoints were defined as the diagnostic performance of DWI for disease detection, staging of MM, and assessing response to treatment in these patients. RESULTS: Of 5881 initially reviewed publications, 33 were included in the final qualitative and quantitative meta-analysis. The diagnostic performance of DWI in the detection of patients with MM revealed pooled sensitivity and specificity of 86% (95% CI: 84-89) and 63% (95% CI: 56-70), respectively, with a diagnostic odds ratio (OR) of 14.98 (95% CI: 4.24-52.91). The pooled risk difference of 0.19 (95% CI: - 0.04-0.42) was reported in favor of upstaging with DWI compared to conventional MRI (P value = 0.1). Treatment response evaluation and ADCmean value changes across different studies showed sensitivity and specificity of approximately 78% (95% CI: 72-83) and 73% (95% CI: 61-83), respectively, with a diagnostic OR of 7.21 in distinguishing responders from non-responders. CONCLUSIONS: DWI is not only a promising tool for the diagnosis of MM, but it is also useful in the initial staging and re-staging of the disease and treatment response assessment. This can aid clinicians with earlier initiation or change in treatment strategy, which could have prognostic significance for patients.

An Analysis of M-protein in Plasma cell Dyscrasia Patients Identifies that IgG Lambda Subtype is More Commonly Associated with Normal Serum Free Light Chain (SFLC) Ratio.

The determination of monoclonal protein (M-protein) by SPE, IFE and SFLC assay is fundamental in the diagnosis of Plasma cell proliferative disorder (PCPD). In the present study, we seek to assess the diagnostic performance and concordance of these three techniques in un-treated PCPD patients. All new patients with dysproteinemia and/or suspected PCPD were included in this retrospective observational study. The baseline parameters were retrieved from electronic medical records. SPE was performed on gel electrophoresis system; monoclonal component was identified by IFE. SFLC assays were performed by nephelometry using a latex-enhanced immunoassay. Total 402 patients of PCPD were included (10.9% of MGUS/SMM and 89.1% of multiple myeloma). The combination of SPE + rSFLC (ratio of kappa/lambda light chain) and SPE + IFE + rSFLC was able to detect M-protein across all subgroups of patients. In 61 patients, rSFLC values were within normal range (54.5% of MGUS/SMM and 10.3% of MM) and was more commonly seen with IgG lambda M-protein (57.4% vs. all-others). The median dFLC value, among these patients, was higher for MM than MGUS/SMM patients (23.8 vs. 14.4 mg/L, respectively). The combination of SPE and rSFLC can be reliably used to detect M-protein in PCPD patients. In a small subgroup of MM patients, despite the presence of an intact immunoglobulin (M-protein), the rSFLC is not abnormal. Historically, these patients should respond better to treatment. However, a further follow-up analysis with more number of such patients would be advantageous for better understanding.

Quantitative and qualitative assessment of plasma cell dyscrasias in dual-layer spectral CT.

OBJECTIVES: Virtual non-calcium (VNCa) images could improve assessment of plasma cell dyscrasias by enhancing visibility of bone marrow. Thus, VNCa images from dual-layer spectral CT (DLCT) were evaluated at different calcium suppression (CaSupp) indices, correlating results with apparent diffusion coefficient (ADC) values from MRI. METHODS: Thirty-two patients with initial clinical diagnosis of a plasma cell dyscrasia before any chemotherapeutic treatment, who had undergone whole-body low-dose DLCT and MRI within 2 months, were retrospectively enrolled. VNCa images with CaSupp indices ranging from 25 to 95 in steps of 10, conventional CT images, and ADC maps were quantitatively analyzed using region-of-interests in the vertebral bodies C7, T12, L1-L5, and the iliac bone. Independent two-sample t-test, Wilcoxon-signed-rank test, Pearson's correlation, and ROC analysis were performed. RESULTS: Eighteen patients had a non-diffuse, 14 a diffuse infiltration in conventional MRI. A significant difference between diffuse and non-diffuse infiltration was shown for VNCa-CT with CaSupp indices from 55 to 95, for conventional CT, and for ADC (each p < 0.0001). Significant quantitative correlation between VNCa-CT and MRI could be found with strongest correlation at CaSupp index 65 for L3 (r = 0.68, p < 0.0001) and averaged L1-L5 (r = 0.66, p < 0.0001). The optimum CT number cut-off point for differentiation between diffuse and non-diffuse infiltration at CaSupp index 65 for averaged L1-L5 was -1.6 HU (sensitivity 78.6%, specificity 75.0%). CONCLUSION: Measurements in VNCa-CT showed the highest correlation with ADC at CaSupp index 65. VNCa technique may prove useful for evaluation of bone marrow infiltration if MRI is not feasible. KEY POINTS: • VNCa-CT images can support the evaluation of bone marrow infiltration in plasma cell dyscrasias. • VNCa measurements of vertebral bodies show significant correlation with ADC in MRI. • Averaging L1-L5 at CaSupp index 65 allowed quantitative detection of infiltration comparable to MRI ADC.

Paraproteinemia and neuropathy.

Paraproteinemia is associated with different peripheral neuropathies. The major causes of neuropathy correlated with paraproteinemia are the deposition of immunoglobulin in the myelin, represented by anti-myelin-associated glycoprotein (MAG) neuropathy; deposition of immunoglobulin or its fragment in the interstitium, represented by immunoglobulin light chain amyloidosis (AL amyloidosis); and paraneoplastic mechanisms that cannot be solely attributed to the deposition of immunoglobulin or its fragment, represented by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS) syndrome. Patients with anti-MAG neuropathy and POEMS syndrome present with slowing of nerve conduction parameters. This characteristic fulfills the electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) defined by the European Academy of Neurology and Peripheral Nerve Society (EAN/PNS). Although direct damage caused by the deposition of amyloid can induce axonal damage in AL amyloidosis, some patients with this condition have features fulfilling the EAN/PNS electrodiagnostic criteria for CIDP. Conventional immunotherapies for CIDP, such as steroids, intravenous immunoglobulin, and plasma exchange, offer no or only minimal-to-modest benefit. Although rituximab can reduce the level of circulating autoantibodies, it may only be effective in some patients with anti-MAG neuropathy. Drugs including melphalan, thalidomide, lenalidomide, and bortezomib for POEMS syndrome and those including melphalan, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, and daratumumab for AL amyloidosis are considered. Since there will be more therapeutic options in the future, thereby enabling appropriate treatments for individual neuropathies, there is an increasing need for early diagnosis.

The Ultrastructure of Tissue Damage by Amyloid Fibrils.

Amyloidosis is a group of diseases that includes Alzheimer's disease, prion diseases, transthyretin (ATTR) amyloidosis, and immunoglobulin light chain (AL) amyloidosis. The mechanism of organ dysfunction resulting from amyloidosis has been a topic of debate. This review focuses on the ultrastructure of tissue damage resulting from amyloid deposition and therapeutic insights based on the pathophysiology of amyloidosis. Studies of nerve biopsy or cardiac autopsy specimens from patients with ATTR and AL amyloidoses show atrophy of cells near amyloid fibril aggregates. In addition to the stress or toxicity attributable to amyloid fibrils themselves, the toxicity of non-fibrillar states of amyloidogenic proteins, particularly oligomers, may also participate in the mechanisms of tissue damage. The obscuration of the basement and cytoplasmic membranes of cells near amyloid fibrils attributable to an affinity of components constituting these membranes to those of amyloid fibrils may also play an important role in tissue damage. Possible major therapeutic strategies based on pathophysiology of amyloidosis consist of the following: (1) reducing or preventing the production of causative proteins; (2) preventing the causative proteins from participating in the process of amyloid fibril formation; and/or (3) eliminating already-deposited amyloid fibrils. As the development of novel disease-modifying therapies such as short interfering RNA, antisense oligonucleotide, and monoclonal antibodies is remarkable, early diagnosis and appropriate selection of treatment is becoming more and more important for patients with amyloidosis.

High-risk cytogenetics in multiple myeloma: Further scrutiny of deletions within the IGH gene region enhances risk stratification.

Multiple myeloma is a clonal malignancy of plasma cells in the bone marrow. Risk stratification is partly based on cytogenetic findings that include abnormalities of the IGH locus as determined by fluorescence in situ hybridization (FISH), such as rearrangements that result in either standard-risk or high-risk gene fusions. IGH deletions have been evaluated as a group in multiple myeloma patients with respect to cumulative outcomes but have provided limited guidance. Whether these deletions have the potential to result in gene fusions and thus further stratify patients is unknown. We identified 229 IGH deletions in patients referred for plasma cell dyscrasia genetic testing over 5.5 years. Follow-up was conducted on 208 of the deletions with dual fusion FISH probes for standard-risk (IGH-CCND1) and high-risk IGH gene fusions (IGH-FGFR3, IGH-MAF, IGH-MAFB). Of all deletions identified with follow-up, 44 (21%) resulted in a gene fusion as detected by FISH, 15 (7%) of which were fusion partners associated with high-risk multiple myeloma. All fusion-positive 3'-IGH deletions (6 fusions) resulted in high-risk IGH-FGFR3 fusions. Of the 15 high-risk fusion-positive cases, eight were without other high-risk cytogenetic findings. This study is the first to evaluate the presence of IGH gene fusions upon identification of IGH deletions and to characterize the deletion locus. Importantly, these findings indicate that follow-up FISH studies with dual fusion probes should be standard of care when IGH deletions are identified in multiple myeloma.

Acral localized acquired cutis laxa as presenting sign of underlying systemic amyloidosis.

Acral localized acquired cutis laxa (ALACL) is a rare variant of acquired cutis laxa, and the clinical appearance is characterized by loose, redundant and wrinkled skin of the distal extremities. By definition, histopathology of affected tissue reveals sparse or fragmented elastic fibers. However, this can be difficult to assess on routine staining, and sometimes requires electron microscopy. The condition has been associated with plasma cell dyscrasias or recurrent inflammatory states. We present a case of a 65-year-old man who presented with enlarged and doughy finger pads. Skin biopsy showed diffuse dermal amyloid deposition displacing dermal stroma and reduction of elastic fibers, although these changes were subtle on routine hematoxylin and eosin staining. Mass spectrometry of laser capture microdissected tissue showed AL kappa-type amyloid and further workup revealed a diagnosis of primary systemic AL-kappa amyloidosis requiring bone marrow transplantation. This case represents an unusual presentation of acquired cutis laxa and highlights the need for a high index of suspicion when reviewing histopathology of this entity. In addition, the case highlights the importance of investigation into possible systemic associations, such as plasma cell dyscrasias.

Crystalglobulinemia manifested as acute renal failure and thrombotic vasculopathy.

Crystalglobulinemia is an extremely rare pathology that is associated in most cases with plasma cell dyscrasia, mainly multiple myeloma. In most cases, it may be the manifestation of incipient gammopathy or it manifests shortly after diagnosis. We report a patient with ischemic lesions of thrombotic origin in lower limbs. Subsequently, renal involvement occurs, in view of this involvement, it is suspected that the patient may have an associated vasculitis. After performing the biopsy and with the subsequent diagnosis of monoclonal gammopathy of uncertain significance, the diagnosis is made. We review the most recent bibliography of patients who have been diagnosed with crystalglobulinemia associated with plasma dyscrasia focusing in those with thrombotic vasculopathy or acute renal failure. In our case, in addition to being associated with monoclonal gammopathy of undetermined significance that is less frequent, the debut of the symptoms is years before the detection of the monoclonal peak. This could speak of patients with a low peak of monoclonal component (not detected by immunoelectrophoresis) who could have kidney and vascular damage.

Venous Thromboembolism in Autologous Blood or Marrow Transplantation Survivors: A Report from the Blood or Marrow Transplant Survivor Study.

Hemostatic complications are commonly encountered in blood or marrow transplantation (BMT) recipients, increasing their morbidity and mortality and are well described in the immediate post-transplantation period. The risk of venous thromboembolism (VTE) in long-term survivors of autologous BMT has not been studied previously. Patients who underwent autologous BMT between January 1, 1974, and December 31, 2010 for a hematologic malignancy, lived 2 years or more after transplantation, and were age ≥18 years were surveyed for long-term outcomes. The median duration of follow-up was 9.8 years (interquartile range, 6.4 to 14.3 years). We analyzed the risk of VTE in 820 autologous BMT recipients who survived for ≥2 years, compared with 644 siblings. BMT survivors were at a 2.6-fold higher risk of VTE compared with siblings (95% confidence interval [CI], 1.6 to 4.4; P =.0004), after adjusting for sociodemographic characteristics. Conditional on surviving for ≥2 years after BMT, the mean cumulative incidence of VTE was 3.9 ± .8% at 5 years and 6.1 ± 1.1% at 10 years. A diagnosis of plasma cell disorder (hazard ratio [HR], 2.37; 95% CI, 1.3 to 4.2; P = .004) and annual household income ≤$50,000 (HR, 2.02; 95% CI, 1.2 to 3.6; P = .015) were associated with increased VTE risk. Our data indicate that autologous BMT survivors are at elevated risk for developing late-occurring VTE. The development of risk prediction models to identify autologous BMT survivors at greatest risk for VTE and thromboprophylaxis may help decrease the morbidity and mortality associated with VTE.

Characteristics of long-term survivors with multiple myeloma: A National Cancer Data Base analysis.

BACKGROUND: There exist insufficient data characterizing patients with multiple myeloma (MM) who experienced prolonged survival. A population-based analysis of long-term survivors was conducted to investigate the roles of sociodemographic factors and upfront stem cell transplantation (SCT). METHODS: The National Cancer Data Base is a US cancer database of approximately 34 million patients from >1500 cancer centers. Patients with MM were identified using the International Classification of Diseases for Oncology (ICD-O) code 9732 from January 2004 to December 2006 and were divided into 4 groups based on overall survival (OS). Sociodemographic characteristics, treatment facility, and use of SCT were recorded. The univariate and multivariate analyses were performed using multiple logistic regression and Pearson chi-square tests. RESULTS: A total of 26,986 patients with MM were identified. The median OS was 2.74 years. The majority of patients were male (54%), white (77%), insured (93%) and otherwise healthy (78%), lived in a metropolitan area (82%), were of high income (66%) and educational (58%) levels, and received treatment at nonacademic facilities (63%). Upfront SCT was used in 10% of patients. One in 6 patients (16%) were long-term survivors (group 4). When comparing group 4 (OS of ≥8.22 years) with the other groups (OS of <8.22 years), young age, female sex, high income and educational levels, residence in a rural area, insured status, no comorbidity, receipt of upfront SCT, and treatment at high-volume facilities were associated with long-term survival. CONCLUSIONS: Key differences in sociodemographic characteristics, patient volume at treatment facilities, and upfront SCT were associated with long-term survival. Improvements in health care access and health literacy, upfront SCT, and treatment at high-volume facilities might prolong patient survival.

Renal crystal-storing histiocytosis involving glomeruli - A comprehensive clinicopathologic analysis.

Crystal-storing histiocytosis (CSH) is a rare manifestation of monoclonal gammopathy in which histiocytes containing monoclonal proteins in their cytoplasm are found in various organs of the body including the kidney. Within the kidney, these monoclonal crystal-laden histiocytes have been described to occur in the interstitium (most commonly) or in the glomerular mesangium. CSH within glomerular capillary loops has rarely been reported. We describe three cases of CSH primarily affecting the glomerular capillaries and review the literature of CSH in general. Twenty cases of CSH involving the kidney are present in the literature; three describe CSH in glomeruli, only one of which showed histiocytes predominantly in glomerular capillary loops, while 15 had predominantly or solely interstitial CSH. Most cases involve IgG kappa crystals with only one case involving lambda light chain. Patients with CSH predominantly involving the glomerular capillaries showed a trend toward lower serum creatinine and proteinuria at presentation, and several patients with CSH lacked a definitive diagnosis of a monoclonal gammopathy at the time of diagnosis, emphasizing the role that kidney biopsy and particularly electron microscopy play in diagnosis of this entity.

51-year old man with tingling, burning and progressive limb weakness.

Peripheral neuropathy is a common reason for referral to neurology. Chronic acquired demyelinating neuropathies are an important and varied group with overlapping presentations, and may have an immune-mediated cause. Their correct diagnosis is important as they respond to different treatments; timely intervention can prevent irreversible axonal degeneration. We present a case that highlights the approach to an adult presenting with a chronic demyelinating neuropathy.

Panobinostat for the management of multiple myeloma.

Multiple myeloma (MM) is the second most common blood cancer following non-Hodgkin's lymphoma. While the treatments for MM have improved over the past decade, for the most part, it remains an incurable disease. For this reason newer therapeutic agents are needed to combat this malignancy. Panobinostat is a pan-deacetylase inhibitor that impedes protein destruction by disturbing the enzymatic activity of deacetylases. It was US FDA approved in February 2015 for the management of relapsed/refractory MM in combination with bortezomib and dexamethasone. Several trials are ongoing, exploring the utility of panobinostat in various other settings for the management of MM. This review will detail the biology, clinical efficacy and potential future applications of panobinostat in the treatment of MM.

Design and development of the Australian and New Zealand (ANZ) myeloma and related diseases registry.

BACKGROUND: Plasma cell dyscrasias (PCD) are a spectrum of disorders resulting from the clonal expansion of plasma cells, ranging from the pre-malignant condition monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). MM generates a significant burden of disease on the community and it is predicted that it will increase in both incidence and prevalence owing to an ageing population and longer survival secondary to new therapeutic options. Robust and comprehensive clinical data are currently lacking but are required to define current diagnostic, investigational and management patterns in Australia and New Zealand (ANZ) for comparison to both local and international guidelines for standards of care. A clinical registry can provide this information and subsequently support development of strategies to address any differences, including providing a platform for clinical trials. The Myeloma and Related Diseases Registry (MRDR) was developed to monitor and explore variations in practices, processes and outcomes in ANZ and provide benchmark outcomes nationally and internationally for PCD. This paper describes the MRDR aims, development and implementation and discusses challenges encountered in the process. METHODS: The MRDR was established in 2012 as an online database for a multi-centre collaboration across ANZ, collecting prospective data on patients with a diagnosis of MGUS, MM, solitary plasmacytoma or plasma cell leukaemia. Development of the MRDR required multi-disciplinary team participation, IT and biostatistical support as well as financial resources. RESULTS: More than 1250 patients have been enrolled at 23 sites to date. Here we describe how database development, data entry and securing ethics approval have been major challenges for participating sites and the coordinating centre, and our approaches to resolving them. Now established, the MRDR will provide clinically relevant and credible monitoring, therapy and 'real world' outcome data, to support the conduction of high quality studies. In addition, the Myeloma 1000 sub-study is establishing a repository of paired peripheral blood specimens from registry patients to study mechanisms underlying disease progression. CONCLUSION: Establishment of the MRDR has been challenging, but it is a valuable investment that will provide a platform for coordinated national and international collaboration for clinical research in PCD in ANZ.

CD4⁺ T cells in chronic autoantigenic stimulation in MGUS, multiple myeloma and Waldenström's macroglobulinemia.

Hyperphosphorylated paratarg-7 (pP-7) carrier state is the strongest and most frequent molecular risk factor for MGUS, multiple myeloma (MM) and Waldenström's macroglobulinemia (WM), inherited autosomal-dominantly and, depending on the ethnic background, found in up to one third of patients with MGUS/MM. Since P-7 is the antigenic target of paraproteins that do not distinguish between wtP-7 and pP-7, we investigated CD4(+) T-cell responses in pP-7(+) patients and controls. Peptides spanning amino acids 1-35 or 4-31 containing phosphorylated or nonphosphorylated serine17 were used for stimulation. CD4(+) cells from 9/14 patients (65%) showed a pP-7 specific HLA-DR restricted response. These results demonstrate that pP-7 specific CD4(+) cells can mediate help for pP-7 specific chronic antigenic stimulation of P-7 specific B cells, which might ultimately result in the clonal evolution of a B cell into MGUS/MM/WM producing a P-7 specific paraprotein. Prerequisites for pP-7 specific stimulation of CD4(+) cells appear to be both a pP-7 carrier state and an HLA-DR subtype able to present and recognize pP-7. Our results serve as an explanation for the exclusive autoimmunogenicity of the hyperphosphorylated variant of P-7 and for the different hazard ratios of pP-7 carriers from different ethnic origins to develop MGUS/MM/WM.