Light Chain Deposition Disease Research Articles

#2557 Clinical and histological findings in cancer patients—a single center study

Abstract Background and Aims During the last years, there has been an outstanding improvement in cancer treatment. As patients’ survival has been elongated, the prevalence of kidney injury is increasing. However, clinicopathological data are limited in these patients. We aimed to assess the spectrum of kidney biopsy findings in cancer patients and their relation to treatment. Method Single center retrospective study of all patients with solid and hematologic malignancies, who underwent kidney biopsy due to renal impairment, from September 2015 to July 2023. Clinical, laboratory, histopathological and therapeutic data were evaluated Results Fifty-four patients were biopsied, 35 men and 21 women, of median age 66 (42-84) years and follow up 15 (3-84) months. Median serum creatinine was 3 (0.5-22) mg/dl and proteinuria 3 (0.1-23) gr per day at the time of biopsy. Among the solid malignancies (38/54), lung cancer was the commonest (11), followed by gastrointestinal (5), breast (4), sarcoma (5) and melanoma (3); the rest 10 included other solid malignant tumors. Hematologic malignancies (16/54) were mainly multiple myeloma (6) and lymphomas (5), followed by lymphoblastic leukemia (3) and AL amyloidosis (2). The most frequent indication of biopsy was acute kidney injury (AKI) (29/54), followed by both AKI and proteinuria (15/54) and proteinuria with preserved kidney function (9/54); out of 24 patients with proteinuria, 12 exhibited nephrotic range proteinuria (median 10, 3.5-23 gr/day). At the time of biopsy, more than half of patients (30/54) were on cancer treatment; 5 on immunotherapy, 11 on immunotherapy combined to chemotherapy, 10 on chemotherapy solely and four of them received other kind of treatment. Glomerulonephritis (GN) was shown on 24/54 patients. Among GN, focal segmental glomerulosclerosis (FSGS) was the most common lesion (7), followed by light chain deposit disease (LCDD, 3) and membranous nephropathy (MN, 2); among the last, a rare case of MN with a full-house immunoflorescence pattern was reported. Notably, four patients showed amyloidosis (three AL-amyloidosis linked to multiple myeloma and one AA-amyloidosis possibly related to immunotherapy). A rare case of bevacizumab-induced hyaline occlusive glomerular microangiopathy is also reported. The rest 7/24 cases included glomerulosclerosis (1), minimal change disease (MCD, 1), IgA nephropathy (1), diabetic nephropathy (2) and membranoproliferative glomerulonephritis (2). Tubulointerstitial lesions were found on 30 patients. Acute interstitial nephritis (AIN), acute tubular necrosis (ATN) and combination of two (AIN+ATN) were found on 7, 4 and 12 patients respectively (23 in total). Of note, four out of five patients receiving ifosfamide for sarcomas, presented karyomegalic tubulointerstitial nephritis. Four patients, (three with B-cell lymphoma and one with urothelial carcinoma) exhibited renal infiltration by tumor cells. In addition, two patients were shown with oxalate nephropathy and one with nephrocalcinosis. Kidney disease was secondary to treatment in 23 patients, predominantly attributed to immunotherapy (13). Based on histological findings, cancer treatment was withheld in all patients (23/23).Sixteen of all patients received specific treatment for kidney injury, including corticosteroids, cyclosporine or colchicine. In most of them (14), kidney injury was evaluated as secondary to treatment; Two patients, who presented FSGS and MCD, exhibited renal damage attributed to cancer itself. All treated patients (16/16) recovered renal injury. A small proportion of patients (6/54) underwent dialysis—two due to oxalate nephropathy, two with ifosfamide toxicity, one with LCDD and the last due to sepsis. Half of patients (27/54), including 5/6 who were on dialysis, died during observation period. Conclusion Diagnosing and managing kidney injury in cancer patients may be a challenging task. In our single center study, kidney biopsy revealed diverse and rare histological findings, which necessitated tailored therapeutic interventions.

#2108 Secondary amyloidosis in a cancer patient on pembrolizumab—an unusual finding

Abstract Background and Aims With the widening horizon of ICPIs in the management of oncological disorders, we require to remain vigilant of the possible iRAEs. We present a case report of secondary amyloidosis in at metastatic non-small cell lung carcinoma (NSCLC) patient treated with Pembrolizumab. We aim to describe the clinic-biological & histopathological characteristics of ICPI-related kidney injury which may be beyond interstitial nephritis & its response to treatment & the role of kidney biopsy to define ICPI-related kidney injury. Treatment is challenging due to a paucity of relevant data, implicating further studies. Treatment with colchicine and steroids, tocilizumab in the setting of elevated interleukin-6 (IL6) levels have been reported in case series; unfortunately no appreciable renal benefit were noted. Method 77 year male, diabetic & hypertensive on regular medication for >15 yr, reformed smoker (≈50 pack-years of cigarette) diagnosed with NSCLC (EGFR–wild type, PDL1–70%), received Pembrolizumab (13 cycles) & Paclitaxel + Carboplatin & was in remission. Follow up PET showed partial response—new lesions in brain. Gemcitabine added to the treatment & had received 2 cycles, till hospitalization with febrile episode, decreased oral intake & progressive edema. Clinical evaluation was non-contributory. Hematology & biochemical evaluation (Table 1) showed raised serum creatinine 1.1 mg/dL (baseline 1 mg/dL), urinalysis—2+ protein, quantification showed 2.9295 g/24 h → 6.38 g/24 h (baseline uPCR-0.19 g/g). Abdominal ultrasound & ECHO finding were not conclusive. Fundoscopy showed no evidence of proliferative diabetic or hypertensive retinopathy. Results Kidney Biopsy (Figure) was done. LM showed, few of 8 gloms with mild segmental mesangial expansion due to amorphous extracellular deposits which was PAS & silver negative but showed congophilia (Fig. A,B,C,D). If negative for albumin, IgG, IgA, C3, C1q & had 1+ granularity in the mesangium on IgM staining & showed no light chain restriction in glomeruli & tubular cast for kappa & lambda. IHC (Fig. E) was positive for serum amyloid associated proteins. EM revealed minimal subendothelial & mesangial expansion due to extracellular material organized into randomly arranged fine fibrils, & no significant foot process effacement, electron dense deposits along the capillary basement membrane or within mesangium, glomerular basement membrane, thereby excluding possibility of light chain deposition disease. Conclusion Secondary amyloidosis with ICPI use has uncommonly & with Pembrolizumab rarely been reported. Treatment is challenging due to paucity of literature. Hassan Izzedine et al. in their case series, on Pembrolizumab treated cancer patient [N = 676], showed 12 patients (7 men) (Incidence 1.77%) developed AKI (n = 10) &/or Proteinuria (n = 2), median duration of use 9 months. All (n = 12) underwent renal biopsy, which showed AIN in 4, ATI in 5, MCD in 2. Recovery happened with withdrawal of drug coupled with corticosteroid. Reintroduction resulted in more severe recurrence of AIN in 1 patient only. Lapman et al. reported 1 case of secondary amyloidosis in cancer patients treated with Pembrolizumab. 42yr male Caucasian, had no reported chronic illness, except Asthma. Similarly developed significant proteinuria (Urine Pro 3+) & AKI (Sr. Creat 1.58 mg/dl; Baseline 1.0 mg/dl) after 90 days of Pembrolizumab therapy. Under went 2 Kidney Biopsy–1st Biopsy revealed AA amyloid. AA amyloidosis was attributed to Pembrolizumab as repeat Bx revealed progressive deposits despite remission of malignancy, but his kidney disease progressed, and had to be initiation on maintenance hemodialysis. Stopping Pembrolizumab & corticosteroids led to resolution of proteinuria in our patient too.

Primary adrenal insufficiency developed 22 years after the diagnosis of light and heavy chain deposition disease: a case report.

Monoclonal immunoglobulin deposition diseases (MIDDs), including light and heavy chain deposition disease (LHCDD), are rare and heterogeneous disorders associated with underlying B-cell clonal disorders. Adrenal involvement is a potential extrarenal manifestation of MIDDs; however, limited data are available regarding its prevalence and clinical presentation. Herein, the present report describes, for the first time, a case of primary adrenal insufficiency that developed twenty-two years after a diagnosis of LHCDD had been made. A 69year-old woman with a 10year history of hemodialysis suddenly became bedridden after falling down stairs in the absence of focal neurological deficits. Subsequently, she experienced appetite loss, nausea, vomiting, a fever of unknown origin, and unexplained hypotension. Several months later, primary adrenal insufficiency and normal pressure hydrocephalus were diagnosed and successfully managed. The long-term clinical prognosis of MIDDs has not been fully elucidated despite recent advances in the management of the disorders. This report may contribute to improving our understanding of the disease course.

Giant retinal pigment epithelium tears with membranous nephropathy: a case report and literature review

BackgroundKidney and eye diseases may be closely linked. Tears of the retinal pigment epithelium (RPE) have been reported to be related to kidney diseases, such as IgA nephropathy and light-chain deposition disease. However, pigment epithelium tears associated with membranous nephropathy have not been reported or systematically analysed.Case presentationA 68-year-old man presented with decreased right eye visual acuity. Optical coherence tomography (OCT) revealed cystic macular edema, localized serous detachment of the retina and loss of the outer retinal structure in the right eye and retinal pigment epithelium detachment (PED) combined with serous detachment of the retina in the left eye. Fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) revealed giant RPE tears in the right eye and exudative age-related macular degeneration in the left eye. The patient also suffered from severe membranous nephropathy-autoimmune glomerulonephritis. Renal biopsy immunofluorescence revealed a roughly granular pattern, with immunoglobulin G (IgA), immunoglobulin G (IgG), IgM, complement C3(Components 3), λ light chain and κ light chain subepithelial staining.ConclusionsIt is hypothesized that severe membranous nephropathy caused immune complex deposition on the surface of Bruch membrane, resulting in weakened adhesion between the RPE and Bruch membrane and impaired RPE pump function, combined with age-related macular degeneration, leading to giant RPE tears in the right eye. Close attention should be given to the ocular condition of patients with membranous nephropathy to facilitate timely treatment and avoid serious consequences.

Phenotypes and outcome of diffuse pulmonary non-amyloid light chain deposition disease.

Light chain deposition disease (LCDD) is a very rare entity. Clinical manifestations of LCDD vary according to the organs involved. Data on pulmonary LCDD are scarce and limited to small series or case reports. This study aimed to describe the characteristics and outcome of diffuse pulmonary non-amyloid LCDD localized to the lungs. A multicenter retrospective cohort study was conducted. Clinical characteristics were collected, and chest CTs were centrally reviewed. The diagnosis of pulmonary non-amyloid LCDD was confirmed by immunohistochemistry. Thirty-one cases were identified (68% female), with a median age at diagnosis of 50 years (IQR 20). Baseline FEV1/FVC was < 0.70 in 45% of patients. Mean (± SD) FEV1 and DLCO were 86% ± 26.2 and 52% ± 23.9, respectively. CT revealed peculiar patterns of thin-walled cysts (58%) and thin-walled cystic bronchiectases (27%). Increased serum kappa light chain was found in 87% of patients. Histological analysis showed kappa light chain deposits in all patients, except one with lambda chain deposits. Median annual FEV1 decline was 127 ml (IQR 178) and median DLCO decline was 4.3% (IQR 4.3). Sixteen patients received immunomodulatory treatment or chemotherapy; serum light chain levels decreased in 9 cases (75%), without significant improvement in FEV1 (p = 0.173). Overall, 48% of patients underwent bilateral lung transplantation. Transplant-free survival at 5 and 10 years were 70% and 30%, respectively. An annual FEV1 decline greater than 127 ml/year was associated with increased risk of death or transplantation (p = 0.005). Diffuse pulmonary LCDD is characterised by female predominance, a peculiar imaging pattern with bronchiectasis and/or cysts, progressive airway obstruction and severe DLCO impairment, and poor outcome. Lung transplantation is a treatment of choice.

199 Double Trouble: Successful Treatment of CLL-Associated TMA and Light Chain Deposition Disease with Clone-Directed and Anti-Complement Therapies

199 Double Trouble: Successful Treatment of CLL-Associated TMA and Light Chain Deposition Disease with Clone-Directed and Anti-Complement Therapies

UNVEILING A RARITY: LIGHT CHAIN DISEASE COINCIDING WITH PURE RED CELL APLASIA

This paper presents a unique case report of concurrent Light Chain Disease (LCD) and Pure Red Cell Aplasia (PRCA), two rare hematological disorders seldom observed together. Light Chain Disease is a plasma cell disorder characterized by the overproduction of abnormal immunoglobulin light chains, while Pure Red Cell Aplasia is a rare bone marrow failure syndrome resulting in the selective reduction or absence of red blood cell precursors. The co-occurrence of these conditions poses diagnostic and therapeutic challenges due to their distinct pathophysiologies and clinical presentations. Through a detailed examination of the patient's medical history, diagnostic workup, and treatment outcomes, this case sheds light on the complexities associated with managing rare hematological disorders with overlapping manifestations.

Long-term outcomes and renal responses following autologous hematopoietic stem cell transplantation for light chain deposition disease: a retrospective study on behalf of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

There is little long-term outcome data on the efficacy of autologous hematopoietic stem cell transplantation (ASCT) in light chain deposition disease (LCDD). We identified 51 LCDD patients in the EBMT registry who had undergone upfront ASCT between 1995 and 2021. The median serum creatinine was 280 μmol/L and 45% required renal replacement therapy (RRT) at time of transplant. The melphalan dose was 100mg/m2 in 23%, 140mg/m2 in 55% and 200 mg/m2 in 21%. The rate of very good partial response or better improved from 41% pre-transplant to 66% at Day +100 post-ASCT. In RRT-independent patients, there was a modest improvement in renal function within the first 3 months; the median eGFR increased from 44 to 51 ml/min/1.73 m2. There was no further change between 3 and 12 months post- ASCT. No patient who was RRT-independent at ASCT became RRT dependent by Day + 100 post-ASCT. Median follow-up post-ASCT was 84 months (IQR: 46-122). At 6-years post ASCT, overall survival (OS) was 88% (95% CI: 78-98%) and PFS was 44% (95% CI: 28-60%). The 2-year cumulative incidence of relapse and non-relapse mortality (NRM) was 17% (95% CI: 6-27%) and 2% (95% CI: 0-6%), respectively. The cumulative incidence of renal transplantation at 4 years after ASCT was 27% (95% CI 13-41) with renal transplantation performed between 6.3 and 52.9 months post-ASCT (median 24.7 months). ASCT represents a feasible option for LCDD patients even if RRT dependent at time of transplant. Outcomes are favourable with low NRM and good long-term OS.

Light Chain Deposition Disease - Don't Be Fooled By Congo Red

Light Chain Deposition Disease - Don't Be Fooled By Congo Red

Outcomes Associated with Clone-Directed Therapies for Monoclonal Gammopathy of Renal Significance

Background: Monoclonal Gammopathy of Renal Significance (MGRS) is a category of diseases not meeting criteria for cancer, in which a clonal population of B-lymphoid or plasma cells produces a nephrotoxic protein leading to kidney injury. Informal consensus has arisen that therapy targeting the causal clone is most likely to be efficacious, and the primary goal of therapy is to prolong renal survival. Light chain (AL) amyloidosis has been extensively studied, yet there is a paucity of data describing outcomes associated with clone-directed therapy for the various subtypes of non-AL MGRS. Methods: This was a retrospective analysis of patients treated at two National Cancer Institute (NCI)-designated cancer centers in the United States. Medical records of adult patients seen between January 2010 and March 2023 were screened for MGRS. Patients were eligible if they had renal biopsy-confirmed histopathologic findings compatible with MGRS. AL amyloidosis was excluded. The primary outcome was renal survival, defined as time from diagnosis of MGRS to requiring renal replacement therapy (RRT) or renal transplant, with patients censored at last follow up or death. Baseline characteristics were described, including 24-hour proteinuria, estimated glomerular filtration rate (eGFR), whether a clonal population of B cells or plasma cells could be identified on histopathologic examination of marrow or lymph node biopsy, concentration of monoclonal protein, and involved serum free light chain concentration. Initial therapy was reported, although differences in outcomes across therapeutic strategies were not compared. Baseline clinical characteristics between patients who required RRT and those who did not were compared. Baseline clinical variables and time to RRT were compared across the two most common MGRS subtypes in the cohort: proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and light chain deposition disease (LCDD). Continuous variables were compared across subgroups using Wilcoxon rank-sum test. Time-to-event outcomes were analyzed according to the Kaplan-Meier method. All analyses were conducted using R version 3.6.1. Results: In total, 65 patients were included, 23 (35%) of whom ultimately required RRT or transplant. Four patients died, all after RRT. Median baseline proteinuria was 2802 mg/24h (IQR 972.5 - 4492.0) and median eGFR was 33.0 mL/min (IQR 23 - 53) for the entire cohort. In all cases proteinuria was mostly albumin. Median baseline involved light chain concentration was 8.3 mg/dL (IQR 3.1 - 26.4). A majority of patients (n=33, 51%) had no identifiable serum monoclonal protein. The two most common MGRS subtypes were PGNMID (n = 26) followed by LCDD (n = 21). Clonal populations thought to be causing MGRS were identified in 41/64 patients (64%), including 37 (58%) with plasma cell clones, 1 (2%) with a lymphoplasmacytic lymphoma clone, and 3 (4.7%) with other B-cell clones. Clones were not identified in 23 (36%). The most common chemotherapy agents included bortezomib (n=42, 64%) and rituximab (n=14, 22%). Compared to patients not requiring RRT, patients requiring RRT had higher baseline proteinuria (median 3531 vs. 1980 mg/24h, p&amp;lt;0.001) and lower eGFR (median 16 v. 44 mL/min, p&amp;lt;0.001); differences in serum free light chain concentrations were not significant ( Figure 1). A clonal population thought to be causing MGRS was identified on bone marrow biopsy in a majority of LCDD patients (n = 20, 95%), while clones were infrequently found in PGNMID (n = 6, 23%). The vast majority (n=20, 95%) of patients with LCDD received bortezomib-based therapy. Initial therapy in patients with PGNMID was more evenly divided: 9 (35%) received bortezomib-based therapy, 10 (38%) received rituximab-based therapy, and 6 (23%) received other regimens. Despite differences in therapeutic approach, patients with LCDD and in patients with PGNMID had similar risk of RRT (cumulative risk 35% v. 43%, p=0.54; HR 0.83 (95% CI 0.52-1.33); p =0.44) ( Figure 2). Conclusion: Patients with MGRS remain at high risk of requiring RRT even with clone-directed therapy. Despite differences in pathogenic clones and therapeutic strategies, outcomes of patients with PGNMID and LCDD are similar. Because the severity of baseline renal function across MGRS histologies predicts renal survival, early diagnosis and treatment is likely critical to improving renal outcomes.

Long Term Outcomes and Renal Response Following Autologous Stem Cell Transplantation for Light Chain Deposition Disease:a Retrospective Study on Behalf of the Cmwp of the EBMT

Background: There is a paucity of data concerning long-term outcomes following autologous stem cell transplantation (ASCT) for light chain deposition disease (LCDD). The goal of this retrospective study was to analyze the outcomes following ASCT in LCDD patients in terms of toxicity and efficacy with both hematological and renal responses. Methods: Adult patients who underwent a first ASCT for renal biopsy-proven LCDD (AL amyloidosis excluded) between the years 1995 and 2021 were selected from the EBMT registry. The probability of overall survival (OS) and progression-free survival (PFS) was estimated based on the Kaplan-Meier method and differences analyzed using the log-rank test. Engraftment with death as competing event and relapse and non-relapse mortality (NRM) were modeled using the crude cumulative incidence estimator and compared between groups with Gray's test. eGFR, measured at auto-HCT and 3 6, and 12 months was longitudinally modeled using linear mixed effects models. Results: There were 51 patients in 24 centres. 63% were male. The median year of diagnosis was 2011 (IQR: 2008-2015). The underlying plasma cell disorder was either myeloma (47%) or Monoclonal Gammopathy of Clinical Significance (MGCS, 50%), with 3% missing. The median bone marrow aspirate plasmacytosis was 10% (IQR: 7.8-20) and the immunoglobulin isotypes were as follows: Light Chain only 69% (Kappa 82%, Lambda 18%), IgG 24%, IgA 2%, IgD 2% and non-secretory 2%. Of 17 patients with cytogenetic data, 3 were t(11;14) and one del 17p. All 40 patients with data on disease involvement had renal involvement, and, of these, 3 had cardiac and 2 hepatic involvement. At diagnosis, the median serum creatinine was 233 µmol/L (IQR:159-467), median proteinuria was 1,813 mg/24h (IQR:445-5974) and 16% had bone lesions. 42 of 44 patients with available data had received an induction regimen (93% bortezomib-based) and the hematological responses prior to transplant were as follows: CR 12%, VGPR 29%, PR 31%, MR/SD 16%, and relapse/progression 6% (missing: 6%). A total of 59% were transplanted in or after 2012. The median age at transplant was 55 years (IQR:49-61). The median time from diagnosis to transplant was 7.4 months (IQR:5.5-13.0) and 42% were on dialysis at the time of transplant. The Karnofsky Performance Score (KPS) was &amp;gt;80 in 79%. The Melphalan conditioning dose (mg/m 2) was 100 (23%), 140 (55%) or 200 (21%). The median number of infused CD34+ cells x 10 6/kg was 3.4 (IQR:2.5-4.6) and 33% received G-CSF post-ASCT. A total of 13% received consolidation and 8% maintenance treatment post-ASCT. The median follow-up post-ASCT was 84 months (IQR:46-122). The median time to neutrophil engraftment was 12 days (IQR:11-13) and to platelet engraftment 13 days (11-16). The best hematological response at Day +100 post-ASCT (33% missing) was as follows: CR 44%, VGPR 26% and PR 29%. Mean eGFR at auto-HCT was 48.8 mL/min/1.73m 2 (95% CI 36.8-60.8) in those not on dialysis and 15.2 mL/min/1.73m 2 (95% CI 1.9-28.8) in those on dialysis (difference 33.6 mL/min/1.73m 2, p&amp;lt;0.0001). In both groups there were no significant changes in eGFR after auto-HCT (p=0.99 and p=0.80, respectively). The box-plot figure shows eGFR at auto-HCT, and at 3, 6 and 12 months. At 6 years post-ASCT, OS was 88% (95% CI: 78-98%) and PFS was 44% (95% CI 28-60%). The median OS was not reached. The median PFS was 65 months (95% CI: 45-103). The 2-year cumulative relapse incidence was 17% (95% CI: 6-27%) and the 2-year cumulative incidence of NRM was 2% (95% CI: 0-6%). In univariate analysis, transplant from 2012 onwards was associated with a significantly superior OS (6-year OS 100 vs. 75%; log-rank p=0.05). There was a trend to superior OS in females (6-year OS 100 vs 82%, p=0.05). There was no significant association between KPS, Age, Disease Status at ASCT (VGPR or better vs. Other) or Dialysis Status at ASCT with any outcomes in this small cohort evaluation. Conclusions: ASCT is a feasible option for patients with LCDD even though 42% were on dialysis at the time of transplantation. Overall outcomes are favourable with a low NRM and good long-term OS. There was no improvement in renal function.

Evaluation of Immune Reconstitution in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Cevostamab in Phase I Study GO39775

Background: Immunoparesis (IP), the suppression of one or more uninvolved immunoglobulins (Ig) below the lower limit of normal (LLN), is frequently observed in patients with multiple myeloma (MM). IP is associated with a negative impact on survival in patients with relapsed MM (Chakraborty et al. Br J Haematol 2019) and may increase the risk of infection in patients with MM (Pratt et al. Br J Haematol 2007). Cevostamab is a FcRH5xCD3 T-cell engaging bispecific antibody that facilitates T-cell directed killing of myeloma cells. Cevostamab has demonstrated clinically meaningful activity and a favorable toxicity profile when given once every 3 weeks for up to 17 cycles (approximately 1 year) in an ongoing Phase I trial (GO39775; NCT03275103) involving patients with heavily pre-treated RRMM (Trudel et al. ASH 2021). Hypogammaglobulinemia is a potential side effect due to the targeting of FcRH5 on normal plasma cells (Hammons et al. JAMA Netw Open 2022). The purpose of the current study was to evaluate whether reducing monoclonal Ig burden while on therapy allows for polyclonal Ig recovery, despite the mechanism of action of cevostamab. Specifically, we evaluated whether responders in the GO39775 study demonstrated evidence of immune reconstitution (IR) while on cevostamab therapy. Methods: All patients were aged ≥18 years and had RRMM for which no established therapies were available. Cevostamab was administered via intravenous infusion every 21 days for 17 cycles unless disease progression or unacceptable toxicity occurred. Patients who received concomitant IVIg therapy were excluded from the analysis. Patients were included if they were enrolled for ≥100 days, demonstrated a partial response or better, and had IP at baseline, defined as ≥1 Ig below the LLN. IR was defined as recovery of ≥1 polyclonal Ig within the normal range. Results: At data cut-off (March 1, 2023), a total of 310 patients were enrolled in GO39775. 76 patients met the inclusion criteria and were eligible for analysis. Median age was 65 years (range: 43-82), with a median of 6 previous lines of therapy (range: 2-12). 46 patients (60.5%) had IgG isotype, 10 (13.2%) had IgA isotype, and 20 (26.3%) had light chain disease. Of the 76 patients who met the inclusion criteria, 10 (13.2%) experienced IR (see Table); 5 patients had IgG isotype, 3 had IgA isotype, and 2 had light chain disease. The 10 patients with IR were treated for a median of 323 days (range: 64-364). Of these, 6 patients had IR at a median time of Day 156 (range: 123-260) while on cevostamab, while 4 patients had IR at a median time of Day 242 (range: 133-309) after stopping cevostamab. Of the 6 patients who reconstituted on cevostamab, 1 had IgG isotype, 3 had IgA isotype, and 2 had light chain disease. All 4 patients who reconstituted after stopping cevostamab had IgG isotype. Apart from disease isotype, no other baseline characteristic demonstrated a trend with IR. Discussion: The majority of patients with a response to cevostamab in the GO39775 study had baseline IP, consistent with previous findings in RRMM. Among eligible responders, 10 patients (13.2%) reconstituted ≥1 polyclonal Ig, highlighting that disease control may allow some patients to reverse IP. Of the patients who had IR, 6 had immune recovery while on cevostamab therapy, which indicates that IR is possible on cevostamab once disease control is achieved. Our findings demonstrate that despite normal plasma cell targeting, IR can occur while receiving a FcRH5xCD3 bispecific antibody. Further analysis on a larger patient pool may provide more insight into the characteristics of patients with RRMM who experience IR on cevostamab therapy.

Disease Characteristics and Outcomes of 504 Young Patients Diagnosed with Multiple Myeloma Treated with Modern Therapies in Canada

Background:Multiple myeloma (MM) mostly affects older adults. Although representing around 10% of all cases, patients ≤ 50 years old suffer from the highest number of years lost due to their disease. MM in young patients occurs during their most productive years of life, resulting in a significantly higher personal, familial, professional, and economic burden. Young MM patients are currently underrepresented in clinical trials due to small numbers overshadowed in cohorts of older patients. Their disease characteristics and outcomes following modern treatments remain poorly understood (Tanguay M et al., Current Oncol 2023). The purpose of this study is to report disease characteristics, treatments, and outcomes of young MM patients treated in Canada. Methods:This is a retrospective study using the Canadian Myeloma Research Group Database, which is a repository of real-world patient data reflecting 17 of the major MM academic centers across Canada. All patients 18-50 years old with newly diagnosed MM between January 1, 2010 and July 1, 2022 were included. High-risk (HR) cytogenetics were defined as either del17p, t(4;14) or t(14;16). Survival analyses were performed using the Kaplan-Meier method. Results:Among the 6,604 patients newly diagnosed with MM during the study period, 504 (7.6%) were aged between 18-50 years, and included in this analysis. Within this young group, 87 (17.3%) were 18-40 years old and 417 (82.7%) were between 41-50 years. MM was diagnosed in 301 (59.7%) patients between 2010 to 2015, and in 203 (40.3%) patients between 2016 to 2022. The median age at diagnosis was 45.9 years (range 25.6 to 50). Male patients represented 57.7% of the cohort. IgG was the most common isotype in 251 (49.8%) cases, while 115 (22.8%) patients had light chain disease. In 375 patients with available data, 16% were R-ISS 1, 73.1% R-ISS 2, and 10.9% R-ISS 3. Lytic lesions, elevated creatinine, anemia, hypercalcemia, and high LDH were respectively present in 46.8%, 15.5%, 44%, 18.8%, and 18.7% of patients. HR cytogenetics were present in 23.7% of patients, with del17p in 11.5%, t(4;14) in 14.9%, and t(14;16) in 5.1%; while 1q+ and del1p were detected in 27.9% and 15.3%, respectively. Twelve (2.4%) patients were diagnosed with plasma cell leukemia. First-line treatment was proteasome inhibitor (PI)-based in 462 (91.7 %) and immunomodulatory (IMiD) agent-based in 7 (1.4 %); 18 (3.6%) received both a PI and an IMiD and 17 (3.4%) were treated with other modalities. Among all patients, 453 (89.9%) underwent autologous stem cell transplant (ASCT) during their disease course. Some patients did not receive ASCT for the following reasons: early death before ASCT in 10 (2%) cases, lost to follow-up prior to ASCT in 13 (2.6%) cases, deemed ineligible for ASCT or patient declined in 24 (4.8%) cases, and participation in a clinical trial not involving ASCT in 1 (0.2%) case. Out of the entire cohort, allogeneic-SCT (allo-SCT) was performed in only 11 patients (2.2%), including 3 (0.6%) who received allo-SCT alone without ASCT. Among patients who received maintenance post ASCT, 93.6% were treated with a lenalidomide-based regimen. Median duration of the different maintenance treatments was 21.2 months. With a median follow-up of 51.9 months (range 0.9 to 154), median PFS (progression-free survival) was 55.4 months (95% CI 49.1-70.2), while median OS (overall survival) was not reached. The 5-year OS and PFS were 78% (95% CI 74-82) and 48% (95% CI 43-53), respectively, whereas the 10-year OS and PFS were 64% (95% CI 58-71) and 28% (95% CI 22-35), respectively (Figure 1a). Median PFS for patients with any HR cytogenetics was 37.9 months (95% CI 29.6-62.8) vs 64.5 months (95% CI 50.6-80.7) for patients with standard-risk cytogenetics (p=0.004) (Figure 1b). We observed no difference in disease characteristics, treatments, and outcomes after comparing cohorts aged 18-40 years old vs 41-50 years old. Conclusions: This is among the largest real-world cohorts of young MM patients ≤ 50 years old treated with modern therapies ever reported. Most patients were R-ISS 2 (73.1%), 23.7% had known HR cytogenetics, and the majority (91.7%) received a PI-based first-line treatment. Outcomes of specific subgroups are under analysis and will be presented. Although the OS was not yet reached in this young population, the median PFS of only 55.4 months highlights the urgent need to develop more effective treatments to induce deeper and more durable responses.

Young and Distinct: Clinical Characteristics and Outcomes of Patients 50 or Younger with Multiple Myeloma

Introduction: Multiple Myeloma (MM) presents at a median age of 69. Patients age 50 or younger represent only 10% of diagnoses and are less well-characterized. Some studies have suggested that younger MM patients are more likely to present with lytic lesions, be IgD subtype, have high-risk cytogenetics, and have relatively improved survival. We aimed to characterize this understudied population in the modern era. Methods: We conducted a retrospective chart review of patients age &amp;lt;50 meeting IMWG criteria for symptomatic MM treated across our institution's cancer center network between 2010 and 2023. Overall survival was defined as time in months from diagnosis to last follow-up or death. Time to relapse after transplant was captured. Results: We identified 97 younger MM patients, with a median age of 44 (range 26-50). Males and females represented 50.5% and 49.5% of cases respectively. Complete demographics are listed in the table. The most common MM subtype was IgG Kappa (40%), and 23% had light chain-only disease. Incidentally found cases, defined as abnormalities on imaging or labs ordered for another reason, represented 11% of cases. 61% of patients presented with a skeletal issue such as bone pain and/or pathologic fracture. Presenting features are described in the table. At time of diagnosis, 77% of patients were found to have lytic lesions. Few patients had previously identified MGUS (3%) or smoldering MM (5%). Regarding cytogenetics, 18% had one or more high-risk features. The most common frontline treatment was VRD. As shown in the table, 66% and 29% received 3 and 4 drug induction regimens respectively. Of note, 91% were referred for autologous stem cell transplant (ASCT), and 72% proceeded. 4 patients were deceased at the time of analysis. Survival for the entire population was 95.9% at a median follow up time of 65.5 months. In the patients who underwent ASCT, 41.2% relapsed with median progression-free survival of 57 (44-71) months. Conclusions: MM patients age &amp;lt;50 were found to be distinct from the known characteristics of the general population in several notable ways. There was equipoise among demographic features, with a nearly equivalent prevalence in males and females, and similar median ages across racial groups. We found a greater enrichment of light chain disease than expected, but less renal dysfunction at presentation. IgD subtype does not appear increased in this population. Younger patients do not appear more likely to have high risk cytogenetics. Lastly, survival for younger patients was higher compared to the reported 5-year survival of MM, which may be explained by the finding that these patients were treated primarily with triplet or quadruplet anti-myeloma regimens and often proceeded to ASCT.

Impact of Revised International Staging System 2 (R2-ISS) Risk Stratification on Outcomes of Patients with Multiple Myeloma Receiving Autologous Hematopoietic Stem Cell Transplantation

Background: The second revision of the International Staging System (R2-ISS) is a new and simple tool to risk stratify newly diagnosed multiple myeloma (NDMM) patients. Our aim in this study was to evaluate the utility of R2-ISS in NDMM patients who received upfront autologous hematopoietic stem cell transplantation (auto-HCT). Methods: We conducted a retrospective analysis of all NDMM patients who underwent upfront auto-HCT between 1988 and 2021 at MD Anderson Cancer Center and had available data for calculation of R2-ISS, including albumin, β-2 microglobulin, LDH, and fluorescence in-situ hybridization (FISH) analysis at diagnosis. High-risk cytogenetic abnormalities (HRCA) were t(4;14), del(17p), and 1q21 gain or amplification, as detected by FISH. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoint was hematological response after auto-HCT. Results: A total of 1291 patients were included, with a median age of 62 years (range 29 - 83) and 60% were male. Four hundred-and-nineteen patients (32%) had HRCA. Most patients received either bortezomib, lenalidomide, and dexamethasone (VRD) (34%) or carfilzomib, lenalidomide, and dexamethasone (KRD) (25%) induction regimens, and most patients (95%) received melphalan based conditioning. The distribution of R2-ISS stages in our cohort was as follows: 123 (10%) stage I, 471 (36%) stage II, 566 (44%) stage III, and 131 (10%) stage IV. A total of 1027 (80%) patients received post auto-HCT maintenance, mostly lenalidomide with or without dexamethasone (n = 785, 61%) (Table 1). With a median follow-up of 42.2 months (range 0.3 - 181.0) for the entire cohort, the median PFS was 73.0, 65.2, 44.0, and 24.8 months ( P &amp;lt; .001) and the median OS was 130.8, 128.5, 94.2, and 61.4 months ( P &amp;lt; .001) for patients with R2-ISS stages I, II, III, and IV, respectively (Figure 1). On multivariable analysis (MVA) for PFS, using R2-ISS stage I as the reference group, there was no significant difference for R2-ISS stage II (hazard ratio [95% CI], 1.11 [0.76-1.63]; P = .59), but there was a significant worsening in PFS for R2-ISS stage III (1.55 [1.05-2.29]; P = .028) and R2-ISS stage IV (2.04 [1.24-3.36]; P = .005). On MVA for OS, again using R2-ISS stage I as the reference group, there was no significant difference for R2-ISS stage II (1.33 [0.74-2.40]; P = .34) or R2-ISS stage III (1.75 [0.97-3.17]; P = .06), but there was a significant worsening in OS for R2-ISS stage IV (2.43 [1.18-5.01]; P = .017). On MVA, other measures significantly associated with worsening PFS were year of auto-HCT &amp;lt; 2010, lambda light chain disease subtype, presence of HRCA, prior MRD/response other than negative/≥CR, and not achieving MRD negative/≥ CR post auto-HCT. For OS, other measures significantly associated with worsening survival on MVA were presence of HRCA, HCT-CI &amp;gt; 3, having at least one bone lesion, not achieving CR at best response, and not receiving post auto-HCT maintenance therapy. Conclusion: Our study demonstrates that R2-ISS is a reliable prognostic tool for NDMM in a large cohort of patients who received standard anti-myeloma treatment, including modern induction regimens, upfront auto-HCT, and post-transplant maintenance.

A Case of Combined Light Chain Deposition Disease and Light Chain Cast Nephropathy

A Case of Combined Light Chain Deposition Disease and Light Chain Cast Nephropathy

Primary Plasma Cell Leukaemia with Lambda Light Chain secretion and Chromosomal abnormalities presenting as hyperleukocytosis - A case report.

Primary plasma cell leukaemia (pPCL) is a rare and lethal form of plasma cell dyscrasia that can occur either de novo (primary) or as a leukemic transformation of refractory or relapsed multiple myeloma. We report a case of pPCL with lambda light chain disease and multiple chromosomal abnormalities in a 75-year-old female who presented with generalized weakness. Her peripheral blood smear showed hyperleukocytosis with 78% circulating plasma cells. Serum protein electrophoresis (SPE) does not reveal the M band and serum immunofixation (SI) light chain analysis in serum showed an elevated lambda light chain. Skeletal radiography and PET-CT (positron emission tomography—computerized tomography) did not reveal any lytic lesions. Immunophenotypic studies reveal a CD38-positive population with negativity for T cells, B cells, myeloid markers, and a negative CD45. Fluorescent in situ hybridization (FISH) analysis results disclosed the deletion of 13q14.3 and t(11; 14). This case highlighted the usefulness of the peripheral smear findings and high fluorescent lymphocyte activity, which directed the pathologist to initiate workup for pPCL, and comprehensive laboratory biochemical and radiological evaluation further helps to confirm and differentiate pPCL from multiple myeloma. Bangladesh Journal of Medical Science Vol. 22 No. 04 October’23 Page : 932-936

Coinciding kappa AL amyloidosis and kappa light chain deposition disease in the lung.

Coinciding kappa AL amyloidosis and kappa light chain deposition disease in the lung.

Treatment and Outcome of Light Chain Deposition Disease in the Era of Novel Agents and Transplant.

Treatment and Outcome of Light Chain Deposition Disease in the Era of Novel Agents and Transplant.

Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe.

The adaptive immune system of jawed vertebrates generates a highly diverse repertoire of antibodies to meet the antigenic challenges of a constantly evolving biological ecosystem. Most of the diversity is generated by two mechanisms: V(D)J gene recombination and somatic hypermutation (SHM). SHM introduces changes in the variable domain of antibodies, mostly in the regions that form the paratope, yielding antibodies with higher antigen binding affinity. However, antigen recognition is only possible if the antibody folds into a stable functional conformation. Therefore, a key force determining the survival of B cell clones undergoing somatic hypermutation is the ability of the mutated heavy and light chains to efficiently fold and assemble into a functional antibody. The antibody is the structural context where the selection of the somatic mutations occurs, and where both the heavy and light chains benefit from protective mechanisms that counteract the potentially deleterious impact of the changes. However, in patients with monoclonal gammopathies, the proliferating plasma cell clone may overproduce the light chain, which is then secreted into the bloodstream. This places the light chain out of the protective context provided by the quaternary structure of the antibody, increasing the risk of misfolding and aggregation due to destabilizing somatic mutations. Light chain-derived (AL) amyloidosis, light chain deposition disease (LCDD), Fanconi syndrome, and myeloma (cast) nephropathy are a diverse group of diseases derived from the pathologic aggregation of light chains, in which somatic mutations are recognized to play a role. In this review, we address the mechanisms by which somatic mutations promote the misfolding and pathological aggregation of the light chains, with an emphasis on AL amyloidosis. We also analyze the contribution of the variable domain (VL) gene segments and somatic mutations on light chain cytotoxicity, organ tropism, and structure of the AL fibrils. Finally, we analyze the most recent advances in the development of computational algorithms to predict the role of somatic mutations in the cardiotoxicity of amyloidogenic light chains and discuss the challenges and perspectives that this approach faces.