Bianchi, Giada

Introduction: Autosomal-dominant tubulointerstitial kidney disease (ADTKD) is characterized by chronic kidney disease (CKD) with an average age of end-stage renal disease (ESRD) of approximately 45 years, bland urinary sediment, the absence of proteinuria and autosomal dominant inheritance. While several causative genes have been found, there remain families in whom no molecular diagnosis has been identified (ADTKD-NMD). Methods: We identified BICC1 truncating variants in several families with ADTKD-NMD in the Wake Forest Rare Inherited Kidney Disease Registry and then screened families in our database and other referred families for BICC1 truncating variants. We performed segregation analysis and characterized affected individuals for clinical and histopathologic phenotypes. We analyzed oligomer formation of BICC1 mutants with wild-type BICC1-, ANKS3- and ANKS6 proteins through co-immunoprecipitation and Western blotting, and we tested for posttranscriptional regulation of the BICC1 target mRNA, Dand5, in a Luciferase reporter assay. Results: We found 6 heterozygous truncating mutations in BICC1 segregating with the ADTKD phenotype in 8 independent pedigrees worldwide. Affected individuals developed kidney failure in the 6th to 7th decade of life that was characterized pathologically by tubular atrophy and interstitial fibrosis. The truncated gene products localized to cytoplasmic bodies and demonstrated various degrees of self-association or binding to the known interaction partners, ANKS3 and ANKS6. While the wild-type BICC1 gene product acts as a posttranscriptional repressor of target mRNAs, all truncation variants exhibited increased expression of substrate mRNA. Conclusions: Truncating variants in BICC1 are a novel cause of ADTKD, segregating with the disease phenotype and upregulating BICC1 target gene expression through a dominant-negative- or a gain-of-function mode of action.

PURPOSE In immunoglobulin light chain (AL) amyloidosis, amyloid fibrils cause organ dysfunction. Anselamimab, a monoclonal antibody, selectively binds to amyloid fibrils, accelerating their clearance. METHODS Newly diagnosed patients with European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis were randomly assigned to receive anselamimab or placebo with cyclophosphamide, bortezomib, and dexamethasone (with or without daratumumab). The primary end point was a hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVHs), analyzed using the Finkelstein-Schoenfeld test and win ratio estimation. RESULTS Among 406 randomly assigned patients, the primary end point win ratio for anselamimab versus placebo was 1.11 (95% CI, 0.83, 1.50; P = .332) and the hazard ratio (HR) for ACM was 0.80 (95% CI, 0.57, 1.13; P = .290). CVH rates in the anselamimab and placebo groups were 0.59 (95% CI, 0.42, 0.83) and 0.89 (95% CI, 0.55, 1.43), respectively ( P = .145). Among patients with kappa isotype (n = 72), the win ratio was 2.06 (95% CI, 0.98, 4.31; P = .100) and anselamimab reduced ACM by 62% versus placebo (HR, 0.38; 95% CI, 0.17 to 0.86; nominal P = .012), and CVH by 71% (IRR, 0.29; 95% CI, 0.10 to 0.87; nominal P = .028) with improvements in Kansas City Cardiomyopathy Questionnaire-Overall Score. There was no clinical benefit observed in the lambda population. Anselamimab was generally well-tolerated; safety data were comparable between treatment arms overall. CONCLUSION Treatment with anselamimab, an antifibril antibody used alongside antiplasma cell dyscrasia therapy, while not meeting the primary end point in the overall population, significantly improved ACM and CVH in patients with kappa AL, potentially offering a new therapeutic option for this isotype.

7501 Background: AL amyloidosis is a plasma cell dyscrasia (PCD) characterized by κ or λ Ig light chain amyloid fibrils that deposit in vital organs. Anselamimab is an investigational mAb designed to complement anti-PCD therapy through accelerated removal of amyloid fibrils. Cardiac Amyloid Reaching for Extended Survival (CARES) studies (NCT04512235 and NCT04504825) investigated the efficacy and safety of anselamimab compared with placebo, in addition to anti-PCD therapy. Methods: Alongside anti-PCD therapy with CyBorD (daratumumab was permitted) newly diagnosed patients with European modification of Mayo stage IIIa or IIIb AL amyloidosis were randomized 2:1 to receive anselamimab (1000 mg/m 2 ) or placebo (normal saline) IV every 7 days for 4 weeks followed by every 14 days for the remainder of the blinded study (18 months after the last participant enrolled). The primary endpoint was a hierarchical combination of time to all-cause mortality (ACM) and frequency of adjudicated cardiovascular hospitalizations (CVH) using the Finkelstein-Schoenfeld test and win-ratio in the combined study population. Subgroup analysis by involved κ or λ free light chain (iFLC) was prespecified. Results: 271 patients were randomized to receive anselamimab and 135 placebo. Baseline characteristics were similar between treatment arms. The median duration of treatment was 21.4 months and 21.1 in the anselamimab and placebo arms, respectively. Daratumumab was used in 79.3% and 83.7% of the anselamimab and placebo arms, respectively. Results of the primary efficacy analyses are shown in the table. Anselamimab-treated patients with κ iFLC had a 62% reduction in ACM (HR = 0.38; 95% CI, 0.17, 0.86; nominal P = 0.012) and a 71% reduction in risk for CVH (estimated CVH rate ratio = 0.29; 95% CI, 0.10, 0.87; nominal P = 0.028). Patients with λ iFLC had a 10% reduction in risk for CVH; none in ACM. Safety data were comparable between both treatment arms. In anselamimab-treated patients, safety findings were similar between κ subgroup and full population. Conclusions: Anselamimab, a κ light chain–directed anti-fibril monoclonal antibody used alongside standard of care chemotherapy, offers a first-in-class, new therapeutic option for patients with newly diagnosed κ AL amyloidosis. Clinical trial information: NCT04512235 and NCT04504825 . Summary of primary efficacy endpoints. Endpoint Overall κ Isotype λ Isotype Anselamimab (N=271) Placebo (N=135) P -value Anselamimab (N=48) Placebo (N=24) P -value Anselamimab (N=219) Placebo (N=109) P -value ACM and CVH win ratio (95% CI) 1.1 (0.8, 1.5) 0.332 2.06 (0.98, 4.31) 0.100 0.9 (0.6, 1.3) 0.848 ACM n (%) 90 (33.2) 52 (38.5) 15 (31.3) 14 (58.3) 73 (33.3) 37 (33.9) HR (95% CI) 0.8 (0.6, 1.1) 0.290 0.38 (0.2, 0.9) 0.012 1.0 (0.7, 1.5) 0.647 CVH Frequency/year (95% CI) 0.6 (0.4, 0.8) 0.9 (0.6, 1.4) 0.145 0.41 (0.2, 0.8) 1.4 (0.6, 3.4) 0.028 0.7 (0.4, 1.0) 0.8 (0.4, 1.3) 0.664 Incidence risk ratio (95% CI) 0.7 (0.4, 1.2) 0.29 (0.1, 0.9) 0.9 (0.5, 1.7)

Introduction: Light-chain amyloidosis (ALA) is a rare plasma cell disorder characterized by multiorgan involvement. Patients often present with non-specific symptoms, which can lead to a delay in diagnosis. This is associated with progressive organ involvement and shorter survival. Reducing the time from symptom onset to diagnosis is a critical step in improving outcomes. This study was designed to evaluate the clinical prodrome and challenges associated with the diagnosis of ALA from the patient perspective. Methods: This retrospective study surveyed patients with ALA through the online HealthTree® Cure Hub platform, which helps patients navigate their disease in a holistic way. The survey consisted of 32 questions, including 23 multiple-choice, 7 date-entry, and two free-response questions. Data on diagnosis and demographics were extracted from the electronic health record and self-reported data linked to HealthTree® Cure Hub. Results were reported as numbers and percentages, and comparisons were made by age (≥70 vs. <70 years) and sex. The following statistical methods were used: Fisher's exact test for categorical data, two-sample t-test and F-test for normally distributed continuous data, Wilcoxon rank-sum test for skewed data and Spearman correlation coefficient. Results: We surveyed 248 patients. Of those, a total of 87 patients with a self-reported diagnosis of ALA completed the questionnaire between March 12, 2023, and May 8, 2024. The median age was 66 years; 55% were female, and 91% were white. The most common initial symptoms prompting patients to seek medical evaluation were fatigue/weakness (47%), swelling (38%), shortness of breath (28%), chest pain (23%), and foamy urine (22%). Pain in hands/feet, carpal tunnel syndrome, loss of appetite, hoarseness, macroglossia, diarrhea, periorbital puffiness, nail changes, and erectile dysfunction each accounted for <10% of cases. Signs and symptoms were first detected by patients themselves in 58% of cases, by a physician in 33% and by a family member or friend for the rest. The median number of symptoms per individual was 2; 31% reported only one symptom, 37% 2-3, 18% 4-6, and 14% >6; with chest pain being the most common (39%), followed by swelling (22%), shortness of breath (13%), and foamy urine (13%); one patient reported erectile dysfunction and another reported arrhythmias as their only symptom. There was a correlation between hoarseness and nail changes (ρ=0.71), and carpal tunnel syndrome and orthostatic hypotension (ρ=0.63). Only 16% were aware of ALA as a condition prior to symptom onset. Thirty six percent presented to a general practitioner for initial evaluation; about 50% sought a specialist, including a myeloma/amyloid specialist (21%), and 14% were first evaluated in the emergency department. While most patients (45%) were diagnosed by a hematologist/oncologist, patients reported seeing a median of 3 physicians (range: 1-10) before the diagnosis was established. Among responders, 61% reported having myeloma at the time of testing. After diagnosis, about 50% were referred to a center specialized in ALA, and 72% met with a stem cell transplant specialist. Most patients reported receiving multidisciplinary care, with a median of 3 additional specialists participating in ALA care (range: 0-16). More than half of patients (59%) felt the diagnosis was delayed; among those, 42%, 24%, 24%, and 11% reported a delay of 1-6, 7-12, 13-24, and >24 months, respectively. The proportion of patients reporting >12-month delay was higher among older patients (54% vs. 27%, P=0.02). A quarter of responders felt their treatment was delayed. Half of patients felt the diagnostic delay contributed to a decrease in treatment efficacy and 48% did not feel that all medical professionals were knowledgeable about ALA. Only 38% felt the diagnostic process was simple and easy within their healthcare system. Conclusion: Most patients with AL amyloidosis initially present with non-specific symptoms, with fatigue/weakness being the most common. Over a third were evaluated first by a general practitioner, and about a third reported a diagnostic delay of >12 months. The diagnostic process is associated with high healthcare utilization, even among patients with concurrent multiple myeloma. Increasing disease awareness among patients and medical providers may shorten the time to diagnosis and contribute to improved outcomes.

Background: Multiple myeloma (MM) is characterized by somatic mutations involving cancer-associated genes. The MyDRUG trial was initiated to explore the efficacy of specific molecularly-targeted therapies in combination with a standard triplet combination in MM. Methods: MyDRUG (NCT03732703) is a genomically-guided umbrella trial for patients with functional high-risk MM, defined as early relapse following primary therapy (3 years for transplant with maintenance, 18 months without), with specific genetic abnormalities. Patients with no actionable mutation or mutations with allelic burden below 30% were randomly assigned to one of the “non-actionable” arms. Here we present the data for the Y3 arm which combines selinexor (60mg po days 1,8,15), ixazomib (4mg po days 1,8,15), pomalidomide (3mg po days 1-21) and dexamethasone (40mg po weekly) (Seli-IPD), given on a 28-day cycle. The primary objective of the Y3 sub-protocol was to evaluate the overall response rate (ORR) according to the International Myeloma Working Group consensus criteria. Secondary objectives included assessment of adverse events (AEs). Results: 17 patients were enrolled into the Y3 arm. The average age was 62 (51-79), 65% were male with a median of 29 months since initial diagnosis and a median of 2 prior lines of therapy. The ORR (> PR) was 52.9% with a clinical benefit rate (> MR) of 58.8%. The median progression free survival was 10.2 months ( 95% CI: 3.9; 12.9) with a median overall survival which has not yet been reached; with all 17 patients still alive at the current data cutoff. No dose-limiting toxicities were seen. Eight patients (47.1%) experienced a serious AE with 2 patients (11.8%) experiencing an AE leading to treatment discontinuation. Two patients (11.8%) required dose reductions. The most common non-hematologic AEs were fatigue, nausea and constipation; all of which were grade 1 and 2. Conclusions: In this platform study of patients with relapsed, functionally high-risk MM, patients who received Seli-IPd exhibited significant efficacy and a manageable AE profile. Furthermore, this provides an all-oral option for patients wishing to minimize their office visits and parenteral therapy administrations.

The treatment landscape of multiple myeloma (MM) has evolved considerably with the FDA-approval of at least 15 drugs over the past two decades. Together with the use of autologous stem cell transplantation, these novel therapies have resulted in significant survival benefit for patients with MM. In particular, our improved understanding of the BM and immune microenvironment has led to the development of highly effective immunotherapies that have demonstrated unprecedented response rates even in the multiple refractory disease setting. However, MM remains challenging to treat especially in a high-risk setting. A key mediator of therapeutic resistance in MM is the bone marrow (BM) microenvironment; a deeper understanding is necessary to facilitate the development of therapies that target MM in the context of the BM milieu to elicit deeper and more durable responses with the ultimate goal of long-term control or a cure of MM. In this review, we discuss our current understanding of the role the BM microenvironment plays in MM pathogenesis, with a focus on its immunosuppressive nature. We also review FDA-approved immunotherapies currently in clinical use and highlight promising immunotherapeutic approaches on the horizon.

8055 Background: Multiple myeloma (MM) is characterized by somatic mutations involving cancer-associated genes. The most commonly mutated genes are N- and K-Ras, which increase in prevalence as the disease progresses. Case reports and retrospective data suggest efficacy of targeting the MAPK pathway in N/K-Ras mutated MM. The MyDRUG trial was initiated to explore the efficacy of specific molecularly-targeted therapies in combination with standard therapies in MM. Methods: MyDRUG (NCT03732703) is a genomically-guided umbrella trial for patients with functional high-risk MM, defined as early relapse following primary therapy (3 years for transplant with maintenance, 18 months without), with specific genetic abnormalities. Subjects undergo molecular profiling of their MM cells and are assigned to a targeted arm if a variant allele frequency (VAF) over 25% is identified. The targeted mutated genes and respective agents (approved for non-MM indications and with a known phase 2 dose) are: KRAS/NRAS/BRAF (cobimetinib), FGFR3 (enasidenib), IDH (erdafitinib), CDKN2C (abemaciclib), t(11;14) (venetoclax). Patients receive the investigational drug for 2 cycles as a single agent followed by addition of an active MM combination (ixazomib, pomalidomide and dexamethasone, IPd). Limited dose escalation was performed with the single agent followed by dose assessment in combination with IPd. Here we present the results of the dose escalation portion of C1 arm exploring cobimetinib in patients with N/K-RAS or BRAF mutations. Cobimetinib was administered at 40 mg daily in combination with standard doses of IPd. Results: Eleven subjects with BRAF/RAS mutations were screened between August 2019 and October 2020, with 4 screen failures. Seven were enrolled, 5 males, median age 65 years, and median time from diagnosis of 30 months. N-RAS, K-RAS or BRAF mutations were seen in 4, 2, and 1 subject(s), respectively, with VAF ranging from 33-93%. Median number of prior lines of therapy was 1 (1-3), 3 patients had extramedullary disease, and 1 patient had high risk cytogenetics. Median duration of therapy was 12 months. One patient was not evaluable for dose limiting toxicity. All but 1 patient had at least one cycle delayed due to adverse events (AEs), but no dose reductions were required. No dose limiting toxicities were observed across the cycles, either during single agent therapy (Cycles 1-2) or in combination with IPd (Cycles 3 and 4). Six patients responded to therapy (4 PR, 2 VGPR). One patient was not response evaluable. Fatigue was the most common non-hematological AE followed by diarrhea. Conclusions: Here we report on the feasibility of genomically-guided, precision medicine therapy in K/N-RAS/BRAF-mutated MM. The MEK inhibitor cobimetinib in combination with IPd appears safe in functionally high-risk patients. Ongoing study will provide more information regarding the efficacy of this approach. Clinical trial information: NCT03732703.

Abstract Multiple myeloma (MM) cells suffer from baseline proteotoxicity as the result of an imbalance between the load of misfolded proteins awaiting proteolysis and the capacity of the ubiquitin-proteasome system to degrade them. This intrinsic vulnerability is at the base of MM sensitivity to agents that perturb proteostasis, such as proteasome inhibitors (PIs), the mainstay of modern-day myeloma therapy. De novo and acquired PI resistance are important clinical limitations that adversely affect prognosis. The molecular mechanisms underpinning PI resistance are only partially understood, limiting the development of drugs that can overcome it. The transcription factor NRF1 is activated by the aspartic protease DNA damage inducible 1 homolog 2 (DDI2) upon proteasome insufficiency and governs proteasome biogenesis. In this article, we show that MM cells exhibit baseline NRF1 activation and are dependent upon DDI2 for survival. DDI2 knockout (KO) is cytotoxic for MM cells, both in vitro and in vivo. Protein structure-function studies show that DDI2 KO blocks NRF1 cleavage and nuclear translocation, causing impaired proteasome activity recovery upon irreversible proteasome inhibition and, thereby, increasing sensitivity to PIs. Add-back of wild-type, but not of catalytically dead DDI2, fully rescues these phenotypes. We propose that DDI2 is an unexplored promising molecular target in MM by disrupting the proteasome stress response and exacerbating proteotoxicity.