Leung, Nelson

Abstract Gastrointestinal (GI) involvement is a clinically relevant but undercharacterized manifestation of systemic light chain amyloidosis (AL). We aimed to define the clinical spectrum, histologic patterns, and outcomes of symptomatic GI involvement in AL. We retrospectively analyzed 4396 patients with AL from 2010 to 2024, of whom 521 (11.9%) had provider-attributed symptomatic GI involvement; 66% had biopsy-proven GI AL. Symptoms most commonly included early satiety (61%), bowel irregularities (58%), nausea (35%), abdominal pain (28%), and dysphagia (23%). Autonomic neuropathy was frequent (43% clinician attributed; 23% via autonomic reflex testing) and contributed to dysmotility-related symptoms, often without GI biopsy positivity. Among 747 GI biopsies, mucosal infiltration predominated (71%) and was associated with bleeding (22% vs 9%), cachexia, and inferior survival, whereas vascular involvement was associated with lower bleeding risk. Combined involvement of mucosa, submucosa, and vessels conferred the worst prognosis (median overall survival [mOS], 2.4 vs 5.1 vs 7.8 years for 3 vs 2 vs 1 layer); mOS was 6.8 years and was primarily driven by cardiac stage and hematologic response (very good partial response [VGPR] or better: hazard ratio, 0.20; 95% CI 0.13-0.32), with more favorable outcomes in patients with isolated GI involvement. Cachexia and persistent diarrhea were the main drivers of morbidity, need for nutritional support, and GI-related mortality (odds ratio, 2.7 for the combined end point). GI bleeding rarely recurred after achieving VGPR or better. Overall, mucosal involvement, cachexia, and dysmotility define clinically meaningful GI AL and support systematic assessment of autonomic dysfunction as well as evaluation of the need for nutritional support as a GI-specific end point for AL trials.

Abstract Systemic light chain amyloidosis (AL) arises from monoclonal immunoglobulin light chains, but determinants of progression from precursor states remain poorly defined. In a cross-sectional cohort comprising 1950 systemic AL patients diagnosed 2010-2024, 258 (13.2%) patients with a previously diagnosed plasma cell disorder (PCD) were compared to patients with no prior PCD diagnosis. Patients with monoclonal gammopathy of undetermined signficance (MGUS) and smoldering multiple myeloma (SMM) in the former group had lower difference between involved and uninvolved FLCs (dFLC), higher M-protein, and lower rates of t(11;14) at AL diagnosis. Patients developing AL from SMM had a shorter time to AL (median 34.2 versus 61.3 months) and higher dFLC (median 28.9 versus 11.0 mg/dl) compared to those from MGUS. Patients developing AL after known multiple myeloma (MM) or lymphoplasmacytic lymphoma (LPL) commonly lacked deep hematologic response before AL (≤ very good partial response in 78% of MM, 100% of LPL patients). We additionally studied longitudinally followed cohorts of 3,966 MGUS and 426 (SMM) patients with longitudinal FLC measurements and matched follow-up, in which 1.8% of MGUS and 7.2% of SMM patients developed AL. Those patients who developed AL showed markedly higher dFLC at MGUS/SMM diagnosis and more frequent λ restriction and rates of t(11;14). Higher dFLC was associated with progressively earlier AL development; a 10% cumulative risk occurred at 20 months for patients with a dFLC >80 mg/dL but was not reached if dFLC <10 mg/dL at an estimated median follow-up of 86 months. In multivariable analysis, dFLC >6.4 mg/dL (HR 11.3) and λ isotype (HR 3.6) independently predicted AL, whereas heavy chain secretion was associated with lower risk (HR 0.2 for IgG). These findings indicate that AL risk is primarily driven by cumulative light chain exposure, refining our knowledge of AL pathophysiology and providing guidance for follow-up of patients with elevated dFLC.

ABSTRACT Background Immune checkpoint inhibitor-associated acute interstitial nephritis (ICI-AIN) requires a kidney biopsy for a definitive diagnosis. A recent study suggested that 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography-computed tomography (F18-FDG PET–CT) may offer a noninvasive alternative, but lack of kidney biopsies in all patients and a proper control group receiving ICI therapy remained important limitations. We conducted the first study addressing these limitations and examined whether PET–CT could differentiate biopsy-proven ICI-AIN from other causes of acute kidney injury (AKI) in patients on ICI therapy. Methods This retrospective cohort study comprises 105 patients on ICI therapy who underwent F18-FDG PET–CT and had a kidney biopsy, along with data from a control group receiving ICIs without AKI. PET–CT scans were performed within 14 days before or 10 days after biopsy, and baseline PET-CTs obtained during ICI therapy before AKI, were reviewed by a blinded nuclear radiologist. Renal cortical standardized uptake values (SUV) were measured in five regions of interest, liver and blood-pool SUVs served as internal references. Results Thirty-two patients were included (5 ICI-AIN, 7 AKI from other causes, 20 controls). Renal SUVs did not differ significantly among groups. In patients with serial PET-CTs, kidney SUVs tended to increase from baseline to AKI in ICI-AIN, but these changes were not statistically significant. Conclusions In this biopsy-validated cohort, PET-CTs did not reliably distinguish ICI-AIN from other causes of AKI in patients receiving ICI therapy. Larger prospective studies are needed to validate these findings.

ABSTRACT Background Although kidney biopsy remains the gold standard for diagnosing immune checkpoint inhibitors–associated acute interstitial nephritis (ICI-AIN), several promising urinary biomarkers have emerged as potential non-invasive diagnostics. Notably, recent studies have highlighted tumor necrosis factor alpha (TNF-α), CXC motif chemokine ligand 9 (CXCL-9) and others as potential biomarkers to help distinguish ICI-AIN from other causes of acute kidney injury (AKI). However, a direct systematic comparison between these two biomarkers in a cohort of patients undergoing immunotherapy has not been performed. Methods We prospectively enrolled a cohort of ICI-treated cancer patients who developed AKI (including both ICI-AIN and ICI-Non-AIN AKI), as well as those without AKI, referred to as the internal validation cohort. Urinary CXCL-9 and TNF-α were measured across all groups using the human Quantikine ELISA Kit. We externally validated our findings in a cohort of biopsy proven ICI-AIN patients from Spain, referred to as the external validation cohort. Results Urinary CXCL-9 levels were significantly higher in ICI-AIN patients from Mayo (n = 40) compared with those with ICI-Non-AIN AKI (n = 36) and ICI-treated patients without AKI (n = 16) (both P ≤ .0001); these findings were confirmed in the validation cohort from Spain (n = 19) with P-values of .0008 and &lt;.0001, respectively. The area under the curve (AUC) for urinary CXCL-9 distinguishing ICI-AIN biopsy proven (combined from both cohorts, n = 45) from ICI-Non-AIN AKI was 0.83 (95% confidence interval 0.74–0.92), while for urinary TNF-α the AUC was 0.63 (0.51–0.75). Conclusions Increased urinary CXCL-9 was superior to TNF-α as a biomarker for the non-invasive diagnosis of ICI-AIN, even after prior corticosteroid exposure, highlighting its promise as clinical diagnostic tool.

Background Light chain (AL) amyloidosis is a rare disease caused by the misfolding of immunoglobulin light chains produced by a plasma cell dyscrasia. Patients can present with involvement of many organs, including the heart, kidneys, liver, nerves, and other sites, resulting in a high symptom burden. Timely and accurate diagnosis is important to prevent organ failure and improve patient survival. Objective These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients and clinicians in the timely and effective diagnosis of AL amyloidosis. Methods ASH formed a multidisciplinary guideline panel that included 22 individuals representing various medical specialties (academic and community hematology, nephrology, neurology, cardiology, internal medicine, and pathology) as well as 1 patient representative. The group was balanced to minimize potential bias from conflicts of interest. The University of Kansas Medical Center supported the guideline development process, including updating or performing systematic evidence reviews (up to 6 March 2023). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results The panel agreed on 12 recommendations. Conclusions The use of serum immunofixation, urine immunofixation, and serum free light chains enhances the clinical suspicion of AL amyloidosis. The diagnosis of AL amyloidosis can be made effectively through surrogate biopsies, which require both a bone marrow biopsy and fat-pad sampling; however, target organ biopsies may be favored in certain clinical situations.

Abstract Castleman disease (CD) is a heterogeneous group of lymphoproliferative disorders anatomically classified by distribution (unicentric CD [UCD], oligocentric CD [oligoCD], or multicentric CD [MCD]). Human herpes virus 8–negative MCD is called idiopathic MCD (iMCD), which includes clinical subtypes with varying phenotypes and responses: TAFRO (thrombocytopenia, anasarca, fever, renal dysfunction and/or reticulin fibrosis, and organomegaly), IPL (idiopathic plasmacytic lymphadenopathy), and not otherwise specified. OligoCD has recently emerged as an intermediate form between UCD and MCD, with unclear clinical behavior, and IPL has not been validated in a Western cohort. We retrospectively analyzed 217 patients with CD evaluated at our institution between January 2004 and August 2024. Survival probabilities were compared using log-rank tests. Overall, 57% had UCD, 20% had oligoCD, and 23% had iMCD. Patients with oligoCD and iMCD more frequently exhibited systemic symptoms than those with UCD. Patients with oligoCD and iMCD had significantly shorter event-free survival (EFS) of 8.9 and 2.3 years, respectively, than those with UCD (not reached; P&lt; .001 and P&lt; .02). Among iMCD subtypes, iMCD-IPL demonstrated a longer EFS than iMCD-TAFRO (P = .02), with no deaths during the follow-up periods. The results validate oligoCD and iMCD-IPL as new subtypes in this Western cohort. The survival outcome in oligoCD was intermediate between UCD and iMCD, with only a subset of patients with oligoCD requiring systemic therapy. iMCD-IPL had a favorable survival outcome in this US cohort, similar to what has been reported in non-Western countries. Tailoring treatment strategies to disease subtypes and vigilant monitoring of oligoCD for progression may improve survival outcomes in CD.

ABSTRACT Monoclonal gammopathy of renal significance (MGRS) is a heterogeneous group of clonal B cell or plasma cell proliferative disorders that cause kidney injury without meeting criteria for overt malignancy. Advances in diagnostic techniques have enhanced the identification and classification of MGRS lesions. Clone-directed therapies such as proteasome inhibitors, anti-CD38 and anti-CD20 monoclonal antibodies are now central to treatment, targeting a deep haematologic response that is strongly associated with improved renal outcomes and reduced risk of recurrence following kidney transplantation. Despite these advances, management remains challenging in patients without detectable clones. This review highlights recent progress in the diagnosis and treatment of MGRS, with an emphasis on therapeutic strategies, transplant considerations and evolving clinical challenges.

PURPOSE The difference in time to serum calcium normalization and rates of subsequent refractory hypocalcemia between bisphosphonates requires further investigation. Our primary objective was to assess the difference in normalization of serum calcium between pamidronate and zoledronic acid during treatment of hypercalcemia of malignancy (HCM) and rates of subsequent, refractory hypocalcemia following therapy. METHODS A retrospective review of patients with cancer who received pamidronate or zoledronic acid inpatient at Mayo Clinic for treatment of HCM between January 2018 and January 2024 was conducted. Logistic regression evaluated the association between treatment groups and outcomes. Multivariable modeling was adjusted for baseline differences, including severity of hypercalcemia. RESULTS We evaluated 856 patients. The median age was 68 (IQR, 59-75) years, and 476 (55.6%) were male. The most common cancer diagnoses were lymphoma (n = 158, 18.5%), followed by multiple myeloma (n = 145, 16.9%) and lung cancer (n = 111, 13%). Overall, 292 (46.8%) patients and 154 (32.8%) patients achieved serum calcium normalization by hospital day 4 and day 7, respectively. The rate of normalization was similar between all bisphosphonates, regardless of pamidronate dose. Significantly higher rates of hypocalcemia were observed on day 4 for patients who received zoledronic acid 4 mg once compared with either dose (60 mg once and 90 mg once) of pamidronate (40.7% v 27.6% v 26.8%, P = .049, respectively). No significant difference in rates of hypocalcemia were observed on day 7 (56.8% v 50% v 42.9%, P = .26, respectively) and day 30 (39.1% v 39.0% v 37.5%, P = .50, respectively). CONCLUSION Bisphosphonates were equally efficacious in normalizing serum calcium in patients with HCM. Pamidronate 90 mg was not more efficacious than 60 mg. Rates of refractory hypocalcemia were similar.

ABSTRACT Acute renal failure due to cast nephropathy (CAN) is a severe complication of multiple myeloma (MM). Here, we aimed to identify parameters associated with renal outcomes and survival in newly diagnosed MM patients with CAN‐related acute renal failure and to validate the IMWG criteria for renal response. CAN diagnosis was based on biopsy or clinical assessment. Of 787 registered patients, 354 met the inclusion criteria, requiring at least two therapy cycles with documented chemotherapy response, renal response, and eGFR. Baseline free light chain (FLC) levels (median 6825.65 mg/L) decreased below 500 mg/L in 67.8% of patients. According to IMWG classification, renal complete response, partial response, and minimal response were achieved in 33.9%, 19.5%, and 28.0% of patients, respectively. The best eGFR values > 60 mL/min/1.73 m 2 were observed in 33.9% of patients, while 33.3%, 22.3%, and 10.5% had best eGFR values of 30–59, 15–29, and < 15 mL/min/1.73 m 2 , respectively. Renal response correlated with baseline FLC levels, IgG kappa, eGFR, and ECOG status in multivariate analysis, as well as with myeloma response and FLC reduction in univariate analysis. Median overall survival was 77.6 months. Survival correlated with age, myeloma response, ECOG status, FLC kappa type, baseline eGFR, standard‐risk cytogenetics, and calcium levels, among other factors. A comparison of IMWG renal response criteria with classification based solely on best eGFR showed similar utility. Of 136 patients requiring dialysis, 80 (58.8%) were able to discontinue dialysis during therapy. Bortezomib containing myeloma therapy, along with significant FLC reduction, was associated with favorable outcome.