Impact of cytogenetic abnormalities on the risk of disease progression in solitary bone plasmacytomas.

Most patients with solitary bone plasmacytomas (SBP) progress to multiple myeloma (MM) after definitive radiation therapy as their primary treatment. Whether the presence of high-risk (HR) cytogenetic abnormalities by fluorescence in situ hybridization (FISH) in the clonal plasma cells, obtained either directly from the diagnostic SBP tissue or the corresponding bone marrow examination at the time of diagnosis, is associated with a shorter time to progression (TTP) to MM is unknown. This study evaluated all patients diagnosed with SBP at the Mayo Clinic from January 2012 to July 2022. The presence of del(17p), t(14;16), t(4;14), or +1q (gain or amplification) by FISH in clonal plasma cells was defined as HR. A total of 114 patients were included in this cohort, and baseline FISH was available for 55 patients (48%), of which 22 were classified as HR (40%). The median TTP to MM for patients with SBP and HR FISH was 8 months (95% confidence interval [CI], 6.3-26) compared with 42 months (95% CI, 25-not reached [NR]) in patients with SBP without HR FISH (P < .001). In a multivariate analysis, only HR FISH was a significant predictor for shorter TTP to MM, independent of minimal marrow involvement and an abnormal serum free light chain ratio at diagnosis. Deletion (17p) and gain 1q abnormalities were the most common FISH abnormalities responsible for the short TTP to MM. Thus, assessing for HR FISH abnormalities in clonal plasma cells derived from either the diagnostic SBP tissue or the staging bone marrow examination of patients with newly diagnosed SBP is feasible and prognostic for a shorter TTP to MM.

A proteomic atlas of kidney amyloidosis provides insights into disease pathogenesis.

The mechanisms of tissue damage in kidney amyloidosis are not well described. To investigate this further, we used laser microdissection-mass spectrometry to identify proteins deposited in amyloid plaques (expanded proteome) and proteins overexpressed in plaques compared to controls (plaque-specific proteome). This study encompassed 2650 cases of amyloidosis due to light chain (AL), heavy chain (AH), leukocyte chemotactic factor-2-type (ALECT2), secondary (AA), fibrinogen (AFib), apo AIV (AApoAIV), apo CII (AApoCII) and 14 normal/disease controls. We found that AFib, AA, and AApoCII have the most distinct proteomes predominantly driven by increased complement pathway proteins. Clustering of cases based on the expanded proteome identified two ALECT2 and seven AL subtypes. The main differences within the AL and ALECT2 subtypes were driven by complement proteins and, for AL only, 14-3-3 family proteins (a family of structurally similar phospho-binding proteins that regulate major cellular functions) widely implicated in kidney tissue dysfunction. The kidney AL plaque-specific proteome consisted of 24 proteins, including those implicated in kidney damage (α1 antitrypsin and heat shock protein ß1). Hierarchical clustering of AL cases based on their plaque-specific proteome identified four clusters, of which one was associated with improved kidney survival and was characterized by higher overall proteomic content and 14-3-3 proteins but lower levels of light chains and most signature proteins. Thus, our results suggest that there is significant heterogeneity across and within amyloid types, driven predominantly by complement proteins, and that the plaque protein burden does not correlate with amyloid toxicity.

At what COST?: A prospective longitudinal cohort assessment of financial toxicity, quality of life, and associated risk factors in patients with plasma cell disorders.

Financial toxicity is prevalent and harmful to patients with plasma cell disorders.

Clinical specificity of two assays for immunoglobulin kappa and lambda free light chains.

OBJECTIVES: Free light chain (FLC) assays and the ratio of κ/λ are recommended for diagnosis, prognosis and monitoring of plasma cell dyscrasias (PCD). Limited data exists on FLC clinical specificity in patients diagnosed with other conditions. METHODS: We assessed the κ, λ, and κ/λ FLC ratio using the FreeLite assay and the Sebia FLC ELISA assay in 176 patients with clinical presentations of fatigue, anemia, polyclonal hypergammaglobulinemia, joint disorders, kidney disease and non PCD-cancers with no monoclonal protein observed on serum protein electrophoresis or MASS-FIX immunoglobulin isotyping. Manufacturer defined reference intervals (RI) and glomerular filtration rate (GFR) specific RI (renal RI) were utilized. RESULTS: For the κ/λ ratio, 68.7 % (121/176) of specimens on the FreeLite and 87.5 % (154/176) of specimens on the Sebia assay were within RI. For κ, 68.2 % (120/176) and 72.2 % (127/176) of results were outside RI for FreeLite and Sebia respectively. For λ, 37.5 % (66/176) and 84.1 % (148/176) of FreeLite and Sebia results were outside RI. With FreeLite and Sebia, patients with kidney disease (n=25) had the highest κ/λ ratios. 44 patients (25.0 %) had GFR <60 mL/min/BSA. When renal RI were applied, 13.6 % had a FLCr outside the renal RI with FreeLite, and 4.5 % with Sebia. CONCLUSIONS: In a cohort of patients with signs and symptoms suggestive of PCDs, but ultimately diagnosed with other conditions, Sebia FLC had improved clinical specificity relative to FreeLite, if one was using an abnormal κ/λ ratio as a surrogate for monoclonality.

Amino acid sequence homology of monoclonal serum free light chain dimers and tissue deposited light chains in AL amyloidosis: a pilot study.

OBJECTIVES: Diagnosis of light chain amyloidosis (AL) requires demonstration of amyloid deposits in a tissue biopsy followed by appropriate typing. Previous studies demonstrated increased dimerization of monoclonal serum free light chains (FLCs) as a pathological feature of AL. To further examine the pathogenicity of FLC, we aimed at testing amino acid sequence homology between circulating and deposited light chains (LCs). METHODS: Matched tissue biopsy and serum of 10 AL patients were subjected to tissue proteomic amyloid typing and nephelometric FLC assay, respectively. Serum FLC monomers (M) and dimers (D) were analyzed by Western blotting (WB) and mass spectrometry (MS). RESULTS: WB of serum FLCs showed predominance of either κ or λ type, in agreement with the nephelometric assay data. Abnormal FLC M-D patterns typical of AL amyloidosis were demonstrated in 8 AL-λ patients and in one of two AL-κ patients: increased levels of monoclonal FLC dimers, high D/M ratio values of involved FLCs, and high ratios of involved to uninvolved dimeric FLCs. MS of serum FLC dimers showed predominant constant domain sequences, in concordance with the tissue proteomic amyloid typing. Most importantly, variable domain sequence homology between circulating and deposited LC species was demonstrated, mainly in AL-λ cases. CONCLUSIONS: This is the first study to demonstrate homology between circulating FLCs and tissue-deposited LCs in AL-λ amyloidosis. The applied methodology can facilitate studying the pathogenicity of circulating FLC dimers in AL amyloidosis. The study also highlights the potential of FLC monomer and dimer analysis as a non-invasive screening tool for this disease.

Sarcopenia identified by computed tomography imaging using a deep learning-based segmentation approach impacts survival in patients with newly diagnosed multiple myeloma.

BACKGROUND: Sarcopenia increases with age and is associated with poor survival outcomes in patients with cancer. By using a deep learning-based segmentation approach, clinical computed tomography (CT) images of the abdomen of patients with newly diagnosed multiple myeloma (NDMM) were reviewed to determine whether the presence of sarcopenia had any prognostic value. METHODS: Sarcopenia was detected by accurate segmentation and measurement of the skeletal muscle components present at the level of the L3 vertebrae. These skeletal muscle measurements were further normalized by the height of the patient to obtain the skeletal muscle index for each patient to classify them as sarcopenic or not. RESULTS: The study cohort consisted of 322 patients of which 67 (28%) were categorized as having high risk (HR) fluorescence in situ hybridization (FISH) cytogenetics. A total of 171 (53%) patients were sarcopenic based on their peri-diagnosis standard-dose CT scan. The median overall survival (OS) and 2-year mortality rate for sarcopenic patients was 44 months and 40% compared to 90 months and 18% for those not sarcopenic, respectively (p < .0001 for both comparisons). In a multivariable model, the adverse prognostic impact of sarcopenia was independent of International Staging System stage, age, and HR FISH cytogenetics. CONCLUSIONS: Sarcopenia identified by a machine learning-based convolutional neural network algorithm significantly affects OS in patients with NDMM. Future studies using this machine learning-based methodology of assessing sarcopenia in larger prospective clinical trials are required to validate these findings.

Utilizing Mass Spectrometry to Detect and Isotype Monoclonal Proteins in Urine: Comparison to Electrophoretic Methods.

BACKGROUND: Matrix assisted laser desorption ionization time of flight mass spectrometry coupled to immune enrichment (MASS-FIX) as an alternative to serum immunofixation electrophoresis has demonstrated increased sensitivity in monoclonal protein (MP) detection with improved laboratory workflow. This study explored similar replacement of urine immunofixation electrophoresis (u-IFE) with urine MASS-FIX (u-MASS-FIX) by method comparison. METHODS: Residual urine (n = 1008) from Mayo Clinic patients with a known plasma cell disease were assayed neat by u-MASS-FIX analysis. Each sample was paired with the following: u-IFE, urine total protein, urine protein electrophoresis, serum κ/λ free light chain (LC) ratio (rFLC), and serum MASS-FIX (s-MASS-FIX). Analytical sensitivities were measured in pooled urine spiked with daratumumab. RESULTS: u-IFE and u-MASS-FIX had 91% agreement in determining the presence/absence of MPs (Cohen kappa = 0.8200). In discrepant cases, serum rFLC statistically aligned more closely with positive u-MASS-FIX cases than u-IFE. Patients positive by both s-MASS-FIX and u-MASS-FIX had matching MP masses (±20 daltons) in 94% of cases. The u-MASS-FIX spectra further identified κ/λ LC fragments and glycosylated LCs not appreciated on u-IFE. The unconcentrated u-MASS-FIX limit of detection of 0.156 mg/mL was determined equivalent to 100× concentrated u-IFE. CONCLUSION: u-MASS-FIX is a reliable alternative to u-IFE with the added benefits of LC glycosylation detection and MP mass tracking between serum and urine. Furthermore, u-MASS-FIX is performed using neat urine. Eliminating the need to concentrate urine for u-IFE has potential to increase productivity by decreasing labor minutes per test.

The lymph node transcriptome of unicentric and idiopathic multicentric Castleman disease.

Castleman disease is a polyclonal lymphoproliferative disorder characterized by unicentric or multicentric lymphadenopathy with characteristic histomorphological features, in addition to variable inflammatory symptomatology. The molecular mechanisms and etiologies of unicentric Castleman disease (UCD) and idiopathic multicentric Castleman disease (iMCD) are poorly understood, and identification of targetable disease mediators remains an unmet clinical need. We performed whole exome sequencing on lymph node biopsies from patients with UCD and iMCD and compared the transcriptomic profiles to that of benign control lymph nodes. We identified significantly upregulated genes in UCD (n=443), iMCD (n=316) or both disease subtypes (n=51) and downregulated genes in UCD (n=321), iMCD (n=105) or both (n=10). The transcriptomes of UCD and iMCD showed enrichment and upregulation of elements of the complement cascade. By immunohistochemistry, C4d deposits indicative of complement activation were found to be present in UCD and iMCD, mostly within abnormally regressed germinal centers, but also in association with plasma cell clusters, endothelial cells and stroma cell proliferations. Other enriched gene sets included collagen organization, S1P3 pathway and VEGFR pathway in UCD; and humoral response, oxidative phosphorylation and proteosome in iMCD. Analysis of cytokine transcripts showed upregulation of CXCL13 but not IL6 in UCD and iMCD. Among angiogenic mediators, the VEGFR1 ligand placental growth factor (PGF) was upregulated in both disease subtypes. We hereby report for the first time the whole lymph node transcriptomes of UCD and iMCD, underscoring findings that could aid in the discovery of targetable disease mediators.

Clinical perspectives on the optimal use of lenalidomide plus bortezomib and dexamethasone for the treatment of newly diagnosed multiple myeloma.

To improve the outcomes of patients with the otherwise incurable hematologic malignancy of multiple myeloma (MM), a key paradigm includes initial treatment to establish disease control rapidly followed by maintenance therapy to ensure durability of response with manageable toxicity. However, patients' prognosis worsens after relapse, and the disease burden and drug toxicities are generally more challenging with subsequent lines of therapy. It is therefore particularly important that patients with newly diagnosed multiple myeloma (NDMM) receive optimal frontline therapy. The combination of lenalidomide, bortezomib, and dexamethasone (RVd) has consistently demonstrated a tolerable safety profile with significant and clinically relevant benefit, including deep and durable responses with improved survival in patients with NDMM regardless of their transplant eligibility. Furthermore, comparative studies evaluating this triplet regimen against both doublet and other triplet regimens have established RVd as a standard of care in this setting based upon its remarkable and concordant efficacy. Given the breadth of clinical data, physician familiarity, inclusion in treatment guidelines, and the emerging potential of RVd-containing quadruplet regimens, RVd will likely continue as a key cornerstone of the treatment of NDMM, and its role will therefore likely continue to grow as a therapeutic backbone in the initial treatment of MM.

POEMS syndrome: Update on diagnosis, risk-stratification, and management.

DISEASE OVERVIEW: POEMS syndrome is a life-threatening condition due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder, sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. DIAGNOSIS: The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyradiculoneuropathy and clonal plasma cell disorder, and at least one of the minor criteria. RISK STRATIFICATION: Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. Risk factors include low serum albumin, age, pleural effusion, pulmonary hypertension, and reduced estimated glomerular filtration rate. RISK-ADAPTED THERAPY: For those patients with a dominant plasmacytoma, first-line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement should receive systemic therapy. Corticosteroids are temporizing, but alkylators and lenalidomide are the mainstays of treatment, the former either in the form of low-dose conventional therapy or as high-dose conditioning for stem cell transplantation. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Daratumumab combinations also appear promising based on case series. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes.

Thrombosis in multiple myeloma: Risk estimation by induction regimen and association with overall survival.

Lenalidomide-containing (R) triplet and quadruplet regimens are the standard of care for multiple myeloma (MM) and have been shown to increase the risk of thrombosis. The association between thromboembolism (TE) and survival in the novel multidrug era is not yet delineated. In this study, we evaluated the incidence of TE during the first year of MM diagnosis, its association with the type of induction regimen, and its impact on overall survival. We studied 672 newly diagnosed MM (NDMM) patients who received a triplet or quadruplet lenalidomide-based induction at the Mayo Clinic, Rochester. TE was diagnosed in 83 patients (12.4%). Of these, 56 (8.3%) had a deep venous thrombosis (DVT), 23 (3.4%) had a pulmonary embolism (PE) with or without the DVT, and 4 (0.6%) patients had a stroke. Carfilzomib-Rd (KRd) had the highest risk of TE (21.1%, 18/85), followed by quadruplets (11.1%, 5/45), bortezomib-Rd (9.6%, 51/531), and 0/11 (0%), treated with other lenalidomide-containing regimens. The difference in TE risk between KRd and the other regimens was statistically significant (OR = 2.6, p < .01). Nine patients developed a TE before being exposed to any treatment. Survival was significantly lower among patients that developed a TE (66 vs. 133 months, p < .01). The association of TE with reduced survival demonstrated in univariate analysis (HR = 2.2, 95% CI = 1.6-3.3) was maintained in the multivariable analysis adjusted for high-risk interphase fluorescence in situ hybridization (FISH), sex, age, receipt of an upfront transplant, the response at induction, and the International Staging System (ISS) (HR = 2.61, CI = 1.74-3.9). We conclude that TE is an important aspect of MM management, and effective management is especially relevant in the novel treatment era.

A phase 1/2 of carfilzomib and melphalan conditioning for autologous stem cell transplantation for multiple myeloma (CARAMEL).

In this phase 1/2 study, carfilzomib was added to high-dose melphalan conditioning prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma that had been treated with ≤2 prior lines of therapy. Carfilzomib was escalated at doses of 27, 36, 45, and 56 mg/m2 on days -6, -5, -2, and -1 before ASCT in the phase 1 component of the study. In addition, all the patients received melphalan 100 mg/m2 on days -4 and -3. The primary endpoint of the phase 1 component was to identify the maximum tolerated dose, and the primary endpoint of the phase 2 component was the rates of complete response (≥CR) at 1 year after ASCT. The phase 1 dose escalation cohort included 14 patients, and 35 patients were included in the phase 2 cohort. The maximum tested dose was 56 mg/m2 (MTD). The median time from diagnosis to study enrollment was 5.8 (range 3.4-88.4) months, and 16% of patients had obtained a ≥CR prior to ASCT. The best response within 1 year after ASCT was a ≥ CR rate in 22% for the entire cohort, and 22% for patients treated at the MTD. The ≥VGPR rates improved from 41% before ASCT to 77% by 1 year after ASCT. One patient had a grade 3 renal adverse event, and renal function returned to baseline with supportive care. The rate of grade 3-4 cardiovascular toxicity was 16%. The addition of carfilzomib to melphalan conditioning was safe and resulted in deep responses after ASCT.

Quality of life and symptoms among patients with relapsed/refractory AL amyloidosis treated with ixazomib-dexamethasone versus physician's choice.

Patient-reported outcomes in AL amyloidosis have not been well-studied. We analyzed health-related quality of life (HRQOL) and AL amyloidosis symptoms data from the phase 3 TOURMALINE-AL1 trial (NCT01659658) (ixazomib-dexamethasone, n = 85; physician's choice of chemotherapy [PC], n = 83). HRQOL and symptom burden were measured with the SF-36v2, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity subscale (FACT/GOG-Ntx), and an amyloidosis symptom questionnaire (ASQ). Score changes during treatment were analyzed descriptively and using repeated-measures linear mixed models; analyses were not adjusted for multiplicity. Least-squares (LS) mean changes from baseline were significantly higher (better HRQOL) for ixazomib-dexamethasone at several cycles for SF-36v2 Role Physical and Vitality subscales (p < .05); no subscales demonstrated significant differences favoring PC. For FACT/GOG-Ntx, small but significant differences in LS mean changes favored ixazomib-dexamethasone over PC at multiple cycles for seven items and both summary scores; significant differences favored PC for one item (trouble hearing) at multiple cycles. ASQ total score trended downward (lower burden) in both arms; significant LS mean differences favored ixazomib-dexamethasone over PC at some cycles (p < .05). Patients with relapsed/refractory AL amyloidosis treated with ixazomib-dexamethasone experienced HRQOL and symptoms that were similar to or trended better than patients treated with PC despite longer duration of therapy.

Natural history, predictors of development of extramedullary disease, and treatment outcomes for patients with extramedullary multiple myeloma.

Extramedullary multiple myeloma (EMM) can present either at initial diagnosis (de novo) or at disease relapse (secondary) and confers an aggressive clinical course. Limited data exist for choosing the optimal therapy for EMM and this remains an area of unmet clinical need. After excluding paraskeletal multiple myeloma and primary plasma cell leukemia, we identified 204 (68%) patients with secondary EMM and 95 (32%) with de novo EMM between January 01, 2000 and 31 December, 2021. The median overall survival (OS) was 0.7 (95% CI: 0.6-0.9) years for secondary EMM and 3.6 (95%CI: 2.4-5.6) years for de novo EMM. The median progression-free survival (PFS) with initial therapy was 2.9 months (95% CI: 2.4-3.2 months) for secondary EMM and 12.9 months (95% CI: 6.7-18 months) for de novo EMM. Patients with secondary EMM treated with CAR-T therapy (n = 20) achieved a partial response (PR) or better in 75% with a median PFS of 4.9 months (3.1 months-not reached; NR). Patients with EMM treated with bispecific antibodies (n = 12) achieved a ≥ PR in 33%, with a median PFS of 2.9 months (95%CI: 2.2 months-NR). In a matched cohort, multivariate logistic regression analysis demonstrated younger age at diagnosis, 1q duplication, and t(4;14) at diagnosis of MM to be independent predictors of development of secondary EMM. Presence of EMM was independently associated with inferior OS in the matched cohorts for both de novo (HR 2.9 [95% CI: 1.6-5.4], p = .0007) and secondary EMM (HR 1.5 [95% CI: 1.1-2], p = .001).

Risk factors for severe infection and mortality In patients with COVID-19 in patients with multiple myeloma and AL amyloidosis.

Patients with multiple myeloma (MM) have a lower efficacy from COVID-19 vaccination and a high rate of mortality from COVID-19 in hospitalized patients. However, the overall rate and severity of COVID-19 infection in all settings (including non-hospitalized patients) and the independent impact of plasma cell-directed therapies on outcomes needs further study. We reviewed the medical records of 9225 patients with MM or AL amyloidosis (AL) seen at Mayo Clinic Rochester, Arizona, and Florida between 12/01/2019 and 8/31/2021 and identified 187 patients with a COVID-19 infection (n = 174 MM, n = 13 AL). The infection rate in our cohort was relatively low at 2% but one-fourth of the COVID-19 infections were severe. Nineteen (10%) patients required intensive care unit (ICU) admission and 5 (3%) patients required mechanical ventilation. The mortality rate among hospitalized patients with COVID-19 was 22% (16/72 patients). Among patients that were fully vaccinated at the time of infection (n = 12), two (17%) developed severe COVID-19 infection, without any COVID-related death. On multivariable analysis, treatment with CD38 antibody within 6 months of COVID-19 infection [Risk ratio (RR) 3.6 (95% CI: 1.2, 10.5), p = .02], cardiac [RR 4.1 (95% CI: 1.3, 12.4), p = .014] or pulmonary comorbidities [RR 3.6 (95% CI 1.1, 11.6); p = .029] were independent predictors for ICU admission. Cardiac comorbidity [RR 2.6 (95% CI: 1.1, 6.5), p = .038] was an independent predictor of mortality whereas MM/AL in remission was associated with lower mortality [RR 0.4 (95% CI: 0.2-0.8); p = .008].

Imaging of Castleman Disease.

Castleman disease (CD) is a group of rare and complex lymphoproliferative disorders that can manifest in two general forms: unicentric CD (UCD) and multicentric CD (MCD). These two forms differ in clinical manifestation, imaging appearances, treatment options, and prognosis. UCD typically manifests as a solitary enlarging mass that is discovered incidentally or after development of compression-type symptoms. MCD usually manifests acutely with systemic symptoms including fever and weight loss. As a whole, CD involves lymph nodes throughout the chest, neck, abdomen, pelvis, and axilla and can have a wide variety of imaging appearances. Most commonly, lymph nodes or masses in UCD occur in the chest, classically with well-defined borders, hyperenhancement, and possible characteristic patterns of calcification and/or feeding vessels. Lymph nodes affected by MCD, while also hyperenhancing, tend to involve multiple nodal chains and manifest alongside anasarca or hepatosplenomegaly. The polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) subtype of MCD may demonstrate lytic or sclerotic osseous lesions in addition to features typical of MCD. Since a diagnosis of CD based solely on imaging findings is often not possible, pathologic confirmation with core needle biopsy and/or surgical excision is necessary. Nevertheless, imaging plays a crucial role in supporting the diagnosis of CD, guiding appropriate regions for biopsy, and excluding other potential causes or mimics of disease. CT is frequently the initial imaging technique used in evaluating potential CD. MRI and PET play important roles in thoroughly evaluating the disease and determining its extent, especially the MCD form. Complete surgical excision is typically curative for UCD. MCD usually requires systemic therapy. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

The characteristics of patients with kidney light chain deposition disease concurrent with light chain amyloidosis.

The type of monoclonal light chain nephropathy is thought to be largely a function of the structural and physiochemical properties of light chains; hence most affected patients have only one light chain kidney disease type. Here, we report the first series of kidney light chain deposition disease (LCDD) concomitant with light chain amyloidosis (LCDD+AL), with or without light chain cast nephropathy (LCCN). Our LCDD+AL cohort consisted of 37 patients (54% females, median age 70 years (range 40-86)). All cases showed Congo red-positive amyloid deposits staining for one light chain isotype on immunofluorescence (62% lambda), and LCDD with diffuse linear staining of glomerular and tubular basement membranes for one light chain isotype (97% same isotype as the amyloidogenic light chain) and ultrastructural non-fibrillar punctate deposits. Twelve of 37 cases (about 1/3 of patients) had concomitant LCCN of same light chain isotype. Proteomic analysis of amyloid and/or LCDD deposits in eight revealed a single light chain variable domain mutable subgroup in all cases (including three with separate microdissections of LCDD and amyloid light chain deposits). Clinical data on 21 patients showed proteinuria (100%), hematuria (75%), kidney insufficiency and nephrotic syndrome (55%). Extra-kidney involvement was present in 43% of the patients. Multiple myeloma occurred in 68% (about 2/3) of these patients; none had lymphoma. On follow up (median 16 months), 63% developed kidney failure and 56% died. The median kidney and patient survivals were 12 and 32 months, respectively. LCDD+AL mainly affected patients 60 years of age or older. Thus, LCDD+AL could be caused by two pathological light chains produced by subclones stemming from one immunoglobulin light chain lambda or kappa rearrangement, with a distinct mutated complementary determining region.

Impact of belantamab mafodotin-induced ocular toxicity on outcomes of patients with advanced multiple myeloma.

Belantamab mafodotin (BLMF) is a B-cell maturation antigen-directed antibody-drug conjugate, recently approved for advanced multiple myeloma (MM). The impact of BLMF-induced ocular toxicity on patient outcomes is unknown. We studied a cohort of 38 consecutively seen patients treated with BLMF outside of trials. Of those, 75% experienced ocular toxicity, with 69% developing keratopathy. Among patients requiring ocular toxicity-related permanent BLMF discontinuation (14%) or dose reduction (11%), 70% had progression of MM within a median of 3 months (95% confidence interval: 0.2-not reached) following BLMF interruption or dose reduction. Ocular toxicity is a major deterrent to the continuous use of BLMF in routine clinical practice. Measures to successfully prevent and mitigate ocular toxicity should be developed to achieve the full potential of this agent.

Kidney Transplantation in Patients With Monoclonal Gammopathy of Renal Significance (MGRS)-Associated Lesions: A Case Series.

RATIONALE & OBJECTIVE: Data on kidney transplantation outcomes among patients with monoclonal gammopathy of renal significance (MGRS) are lacking. STUDY DESIGN: Case series of patients with MGRS, some of whom received clone-directed therapies before kidney transplantation. SETTING & PARTICIPANTS: 28 patients who underwent kidney transplantation from 1987 through 2016 after diagnosis with MGRS-associated lesions including light-chain deposition disease (LCDD), C3 glomerulopathy with monoclonal gammopathy (C3G-MG), and light-chain proximal tubulopathy (LCPT). FINDINGS: Of the 19 patients with LCDD, 10 were treated before kidney transplantation and 9 were treatment-naive. Among the treated patients with LCDD, 3 (30%) experienced histologic recurrence, 2 (20%) grafts failed, and 2 (20%) died during a median follow-up of 70 (range, 3-162) months after transplant. In the treatment-naive LCDD group, 8 (89%) had histologic recurrence, 6 (67%) grafts failed, and 4 (44%) patients died during a median follow-up of 60 (range, 35-117) months. Of the 5 patients who had a complete response before transplant, none died, and only 1 experienced graft failure, 162 months after transplant. Of 5 patients with C3G-MG, 3 were treatment-naive before transplant. Both patients who were treated before transplant had histologic recurrence, and 1 experienced graft failure and died. Among the 3 patients with treatment-naive C3G-MG, histologic recurrence occurred in all, and graft loss and death were observed in 2 and 1, respectively. In the LCPT group (n=4), histologic recurrence was observed in all 3 patients who did not receive clone-directed therapies before transplant, and 2 of these patients died, 1 with a functioning kidney. The 1 patient with LCPT who received therapy before transplant did not have histologic recurrence or graft loss and survived. LIMITATIONS: Small sample size, nonstandardized clinical management, retrospective design. CONCLUSIONS: Recurrence is very common in all MGRS-associated lesions after kidney transplant. Achieving a complete hematologic response may reduce the risks of recurrence, graft loss, and death. More studies are needed to determine the effects of hematologic response on outcomes for each MGRS-associated lesion.

Overview of Castleman disease.

Castleman disease (CD) describes a group of at least 4 disorders that share a spectrum of characteristic histopathological features but have a wide range of etiologies, presentations, treatments, and outcomes. CD includes unicentric CD (UCD) and multicentric CD (MCD), the latter of which is divided into idiopathic MCD (iMCD), human herpes virus-8 (HHV8)-associated MCD (HHV8-MCD), and polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS)-associated MCD (POEMS-MCD). iMCD can be further subclassified into iMCD-thrombocytopenia, ascites, reticulin fibrosis, renal dysfunction, organomegaly (iMCD-TAFRO) or iMCD-not otherwise specified (iMCD-NOS). Advances in diagnosis, classification, pathogenesis, and therapy are substantial since the original description of UCD by Benjamin Castleman in 1954. The advent of effective retroviral therapy and use of rituximab in HHV8-MCD have improved outcomes in HHV8-MCD. Anti-interleukin-6-directed therapies are highly effective in many iMCD patients, but additional therapies are required for refractory cases. Much of the recent progress has been coordinated by the Castleman Disease Collaborative Network (CDCN), and further progress will be made by continued engagement of physicians, scientists, and patients. Progress can also be facilitated by encouraging patients to self-enroll in the CDCN's ACCELERATE natural history registry (#NCT02817997; www.CDCN.org/ACCELERATE).