Carfilzomib Dose Research Articles

Endothelial cellular response to oxidative stress key to proteasome inhibitor cardiovascular toxicity profile

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Karolinska Institutet Background/Introduction Proteasome inhibitors (PI) have contributed to longer survival in multiple myeloma although PI related cardiovascular adverse events are common. Associated to carfilzomib hypertension, coronary ischemic events and heart failure (both with reduced and preserved left ventricular ejection fraction). Here we explore the effect of PIs on endothelial gene expression. Methods Human aortic endothelial cells (HAEC) were incubated for 24 h with carfilzomib or bortezomib at different concentrations. Gene expression determined using using bcl2fastq (v2.20.0), and read quality was assessed using FastQC (v0.11.8). For each group the 100 genes with highest ratio were used for analysis of gene ontology (GO), biological processes using ClusterProfiler. The carfilzomib / bortezomib >1.5 was determined in the relevant GO groups. Results PIs induce gene expression related to inflammatory response and oxidative stress, more pronounced for carfilzomib. 44 / 31 genes related to "cytokine-mediated signaling pathway" and "response to oxidative stress pathway. NR4A3 was 15.5 fold above control while its increase with bortezomib was modest. Discussion Both carfilzomib and bortezomib induce genes related in inflammation and oxidative stress. Carfilzomib induced more pronounced upregulations in several genes, that stimulates expression of increased cellular respiration. Our result show a differentiated effect on endothelial cell gene expression by carfilzomib and bortezomib -a possible explanation to the differences in cardiovascular toxicity profile. Figure 1. Selected GO, Biological function characteristics calculated on the top 100 fold-change genes in each group. C2 high dose carfilzomib, B1 and B2 low and high dose bortezomib. C1 did not converge to any GO characteristics.

Isatuximab, carfilzomib, lenalidomide, and dexamethasone in patients with newly diagnosed, transplantation-eligible multiple myeloma (SKylaRk): a single-arm, phase 2 trial

Isatuximab is a CD38 monoclonal antibody approved for relapsed or refractory multiple myeloma. We aimed to evaluate the addition of isatuximab to weekly carfilzomib (K), lenalidomide (R), and dexamethasone (d; Isa-KRd) in transplant-eligible patients with newly diagnosed multiple myeloma and stratified maintenance by cytogenetic risk. This single-arm phase 2 trial was done at three cancer centres (two hospitals and a cancer institute) in Boston (MA, USA). Eligible patients were aged at least 18 years and had transplant-eligible newly diagnosed multiple myeloma and an ECOG performance status of 2 or less. Patients received four 28-day cycles of Isa-KRd, including isatuximab 10 mg/kg intravenously weekly for 8 weeks, then every other week for 16 weeks, and every 4 weeks thereafter; carfilzomib 56 mg/m2 intravenously on days 1, 8, and 15 (20 mg/m2 for cycle 1 day 1); lenalidomide 25 mg orally on days 1-21; and dexamethasone 20 mg orally the day of and day after all doses of carfilzomib and isatuximab. Consolidation involved either upfront haematopoietic stem-cell transplantation (HSCT) with two additional cycles or deferred HSCT with four additional cycles of treatment. The primary endpoint was complete response after four cycles of treatment. Analyses were by intention-to-treat. All patients who received one dose of study drug were included in the safety analyses. This study was registered at ClinicalTrials.gov, NCT04430894, and has completed enrolment. Between July 31, 2020 and Jan 31, 2022, 50 patients were enrolled. Median age was 59 years (range 40-70), 54% (27 of 50 patients) were male, and 44 (88%) were White. 46% (23 of 50) of patients had high-risk cytogenetics. Median follow-up was 26 months (IQR 20·7-30·1). 32% (16 of 50 patients) achieved a complete response after four cycles. The overall response rate (ORR) was 90% (45 patients) and 78% (39 patients) achieved a very good partial response (VGPR) or better. After completion of consolidation, 58% (29 patients) achieved a complete response; the ORR was 90% (45 patients) and 86% (43 patients) achieved a VGPR or better. The most common grade 3 or 4 side-effects (≥two patients) included neutropenia (13 [26%] of 50 patients), elevated alanine aminotransferase (six [12%] patients), fatigue (three [6%] patients), thrombocytopenia (three [6%] patients), acute kidney injury (two [4%] patients), anaemia (two [4%] patients), and febrile neutropenia (two [4%] patients). Grade 1-2 infusion-related reactions were seen in 20% (ten patients), with none grade 3. Grade 1-2 hypertension was seen in 14% (seven patients) with one grade 3 (one [2%] patient). There were two deaths assessed as unrelated to treatment. Although the study did not achieve the prespecified complete response threshold, Isa-KRd induced deep and durable responses in transplant-eligible patients with newly diagnosed multiple myeloma. The treatment proved safe and consistent with similar regimens in this setting. Amgen, Sanofi, and Adaptive.

Abstract A126: Characterization of proteasome stress response reporter mammalian cell lines for the discovery of DDI2 inhibitors in multiple myeloma

Abstract Background The goal of this study was to develop and characterize proteasome stress response (PSR) reporter cell lines to aid in the identification of inhibitors of the aspartic protease DDI2. We recently showed that multiple myeloma (MM) is dependent on DDI2 for survival due to its critical role in activating PSR master-regulator NRF1. Cleaved NRF1 induces de novo proteasome subunit transcription in face of proteasome insufficiency, thus maintaining proteostasis and mediating resistance to proteasome inhibitors (PI), a mainstay of MM therapy. We hypothesize that targeting DDI2 represent an unexplored, attractive therapeutic strategy in MM, able to overcome acquired and innate resistant to PI, a major clinical hurdle in the care of MM patients. We further hypothesize that due to intrinsic proteostasis vulnerability in MM, DDI2 inhibitors will have a favorable therapeutic index in the clinics. However, specific DDI2 inhibitors are not available and mammalian reporter cell lines of PSR activation do not exist, limiting our capabilities to successfully screen for new drugs. Methods We generated a reporter construct comprising 8 repeats of NRF1 DNA binding site, antioxidant response elements (ARE), upstream of a minimal promoter followed by destabilized GFP. To monitor for successful transfection, copy number integration and global changes in transcription, we cloned mCherry under an EF1α promotor within the same vector. We used this lentiviral construct to transduce MM cell lines characterized by distinct sensitivity to PIs, including AMO1-VR, as a model of acquired bortezomib resistance, and DDI2 KO AMO1-VR to assess for DDI2-independent PSR suppression. To induce PSR, we pulse treated cells with a sublethal dose of carfilzomib and monitored changes in the ratio of GFP/mCherry intensity over time via flow cytometry and immunofluorescence. Results We found that the reporter cell lines showed a peak of GFP/mCherry intensity 8-12 hours after carfilzomib treatment, consistent with our prior data showing peak of proteasome subunit transcription at 10 hours. Importantly, the GFP/mCherry ratio returned to baseline after approximately 24 hours from treatment, in the absence of significant cell apoptosis. DDI2 KO AMO1-VR showed significantly blunted peak of GFP/mCherry intensity, consistent with reduced capability to induce proteasome subunit transcription. We hypothesize that redundant transcription factors, such as NRF2 are responsible for the blunted PSR observed, consistent with increased expression of NRF2 in DDI2 KO cells. Importantly, treatment with sublethal doses of genetoxic drug doxorubicin did not induce significant activation of reporter construct. Conclusions We have successfully developed the first mammalian reporter cell line of PSR with preliminary data showing adequate delta and kinetics to assist in pharmacological screening of molecules blocking the PSR and inducing apoptosis in MM. This powerful tool will inform screening and subsequent validation of newly found/synthesized DDI2 inhibitors, currently under development. Citation Format: Cameron VanCleave, Tianzeng Chen, Matthew Ho, Maria Moscvin, Peter G Czarnecki, Giada Bianchi. Characterization of proteasome stress response reporter mammalian cell lines for the discovery of DDI2 inhibitors in multiple myeloma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A126.

Carfilzomib-Pomalidomide-Dexamethasone in Anti-CD38 Antibodies and Lenalidomide Relapse/Refractory Multiple Myeloma: A Real Life Monocentric Cohort

Introduction Several powerful agents have been validated in multiple myeloma (MM) in the last decades: proteasome inhibitors (PI), immunomodulators (IMID), monoclonal antibodies against CD38, and immunotherapy targeting T cells cytotoxicity. Despite the improvement of therapy, relapses always occur, leading to relapse/refractory MM (RRMM) associated with dismal outcomes. At each relapse, treatment choice becomes a more and more complex decision. With the recent validation for combination in newly diagnosed MM of Daratumumab/Bortezomib/Lenalidomide and/or Dexamethasone (D) association, Carfilzomib (K), a second-in class PI and Pomalidomide (P), a second-in class IMID seems an exciting association to treat RRMM. Here, we analyzed our real-life experience of KPD in RRMM to evaluate the time to the next treatment (TTNT) in patients at Saint Louis Hospital, Paris. Methods We performed a real-life study of RRMM patients who received KPD triplet (eligible if they received one complete cycle of KPD without other treatments) from 2016 till June 2023. Responses were assessed as per the International Myeloma Working Group. The study was conformed to the Declaration of Helsinki. Results Twenty-seven patients were treated with KPD for RRMM in our center. The median age was 64 years (IQR 55-69 years), with a male ratio of 67% (n=18). The subtype of immunoglobulin was IgG (44%), followed by IgA (40%). Among the 26 (96%) patients with FISH available at relapse and before KPD, del 17p, t(4;14), gain 1q, and del 1p were present in 4 (15%), 7 (27%), 8 (31%) and 4 (15%), respectively. Nine (35%) had high-risk cytogenetics (del 17p or/and t(4;14)). At the first line, 15 (55%) received intensive options with autologous stem cell transplantation (ASCT). The first line was composed of Velcade (70%), anti-CD38 antibodies (19%) or IMID (78%: 48% Lenalidomide and 30% Thalidomide) with Dexamethasone. None had prior exposition to Carfilzomib, but three patients (11%) had exposition to Pomalidomide. Three (11%) patients had extra-medullary disease before KPD. The median number of prior lines of chemotherapy was 2 (IQR 1-3), including 70% of the patients who received KPD at the second or third line. Fifteen (56%) patients were refractory to Bortezomib, 25 (93%) to Lenalidomide, 22 (82%) to anti-CD38 antibodies and one (4%) to Pomalidomide. The median number of KPD cycles was 4 (IQR 2-10). All patients received a weekly dose of Carfilzomib except one who received a bi-weekly dose. Twenty (74%) patients started pomalidomide at 4 mg, one (4%) at 3 mg and 6 (22%) at 2 mg from day 1 into day 21. ORR was 66%: CR (n=1, 4%), VGPR (n=7, 26%) and PR (n=10, 37%). Two (8%) patients had progressive disease at the first evaluation. The median time to treatment response was 3 months (IQR 2-6). The median duration of response was 1 year (95%CI 0.5-NA years). Among the 3 patients with prior exposition to Pomalidomide, two had a response to KPD: one PR and one VGPR. The patient refractory to Pomalidomide had stable disease after 2 cycles and then quickly progressive disease. Concerning the side effects of KPD, cardiac toxicity from carfilzomib was reported, including 2 (8%) ischemic cardiac events, 1 (4%) transient ischemic attack, and 3 (11%) induced hypertension. Also, 2 (8%) patients experimented with acute renal failure and one (4%) with thrombotic microangiopathy (TMA) was observed. Three (11%) patients required hospitalization for infections (one candidemia, one flu linked to the TMA episode and one without documentation). At a median follow-up of 1.6 years (0.7-3 years), the median TTNT and overall survival (OS) was 0.7 years (95%CI 0.4-NA years, figure A) and 2 years (95%CI 0.7-NA years, figure B). The mortality rate was 44% (n=12). Most patients had active myeloma at death (11 of 12 with 10 deaths related to myeloma and one from infection), and one died of infections. Ten (37%) patients continued the KPD combination at the last follow-up including two (8%) patients in a maintenance phase, including 1 for Pomalidomide and Dexamethasone after 15 cycles and one for Pomalidomide alone after 22 cycles of KPD. Conclusion In high-risk RRMM especially refractory to anti-CD38 antibodies and lenalidomide, KPD seems to be a valid option in early relapse. Second and third centers will be included in this real-life cohort of RRMM receiving KPD to increase the power of this analysis.

Carfilzomib, Daratumumab, and Dexamethasone (KdD) Vs Carfilzomib and Dexamethasone (Kd) for Relapsed/Refractory Multiple Myeloma (RRMM) in the Phase 3 Candor Study: Subgroup Analysis According to Renal Functioning

Renal impairment frequently occurs in patients (pts) with multiple myeloma (MM) and is associated with poor survival outcomes. In the phase 3 CANDOR trial, carfilzomib, dexamethasone, and daratumumab (KdD) met its primary endpoint of prolonged progression-free survival (PFS) vs carfilzomib and dexamethasone (Kd) (28.4 vs 15.2 mo; hazard ratio [HR]: 0.64; 95% CI: 0.49-0.83) after 50 months (mo) follow-up (Usmani Blood Adv 2023). The study aim was to perform a prespecified subgroup analysis of efficacy and safety by baseline renal function in pts with relapsed/refractory MM (RRMM) receiving KdD vs Kd in the CANDOR trial. Adult pts with RRMM were randomized 2:1 to KdD or Kd in the open-label, phase 3 CANDOR trial (NCT03158688) (Dimopoulos Lancet 2020). RRMM pts with measurable disease who had received 1-3 prior lines of therapy, with partial response or better to ≥1 line of therapy were eligible. Dialysis was an exclusion criterion. All pts received carfilzomib (K) as a 30-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m 2 on days 1 and 2 during cycle 1 and 56 mg/m 2 thereafter). Daratumumab (8 mg/kg) was administered IV on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 weeks (wks) for 4 cycles (cycles 3 to 6), and every 4 wks thereafter. All pts received 40 mg dexamethasone oral or IV weekly (20 mg for pts >75 years). Pts were grouped according to baseline renal function (creatinine clearance [CrCl] ≥15-<60 mL/min, ≥60-<90 mL/min, and ≥90 mL/min (Dimopoulous J Clin Onc 2016). The Cockcroft-Gault formula was used to calculate baseline and on study renal function. PFS and overall response rates (ORRs) were protocol-derived/investigator-assessed. Median PFS was estimated using the Kaplan-Meier method, with HRs and corresponding 95% CIs estimated using a stratified Cox proportional hazards model. Response rates were summarized descriptively, with odds ratios (ORs) and corresponding 95% CIs estimated by Mantel-Haenszel methods using stratified randomization. Renal response was defined as pt CrCl improvement to ≥60 mL/min in any 2 consecutive study visits in pts with baseline CrCl of <50 mL/min. A total of 466 pts were randomized; renal subgroups were CrCl ≥15-<60 mL/min (renal impairment), n=67 and n=36; ≥60-<90 mL/min, n=112 and n=57; and ≥90 mL/min, n=132 and n=61 for KdD and Kd, respectively. One pt in the KdD arm with missing baseline CrCl was excluded. Baseline characteristics were generally balanced between treatment arms and renal subgroups ( Table 1). After a median follow-up of ~50 mo (data cutoff: April 15, 2022), pts treated with KdD vs Kd had improved median PFS across all renal subgroups; median PFS was 24.9 mo vs 8.4 mo (HR, 0.61; 95% CI, 0.35-1.06), 31.6 mo vs 19.9 mo (0.63; 0.41-0.96), and 27.4 mo vs 15.3 mo (0.64; 0.43-0.95) for pts with CrCl ≥15-<60 mL/min, ≥60-<90 mL/min, and ≥90 mL/min, respectively ( Table 2). Median overall survival (OS) for KdD vs Kd was 44.6 mo vs 25.2 mo (HR, 0.58; 95% CI, 0.32-1.03), 48.0 mo vs 43.7 mo (0.91; 0.58-1.43), and NE vs NE (0.74; 0.46-1.20), respectively. ORRs were 87% vs 50% (OR, 8.02; 95% CI, 2.84-22.65); 85% vs 82% (1.26; 0.49-3.27); and 86% vs 80% (1.59; 0.69-3.68), respectively. Complete response rates were 36% vs 8% (7.43; 1.85-29.74); 44% vs 21% (3.17; 1.47-6.87); and 38% vs 21% (2.20; 1.08-4.49), respectively. Among 38 KdD pts and 27 Kd pts with baseline CrCl <50 mL/min, the renal response rate was 21% vs 11% (OR, 2.65; 95% CI, 0.63-11.11), respectively. In pts with renal impairment, most common grade ≥3 TEAEs were thrombocytopenia (38% [25/66] vs 23% [8/35]), hypertension (24% [16/66] vs 20% [7/35]), anemia (24% [16/66] vs 29% [10/35]), and pneumonia (23% [15/66] vs 9% [3/35]) in the KdD arm vs Kd arm. Most common grade ≥3 TEAEs of interest in pts with renal impairment were respiratory tract infections (32% vs 14%), hypertension (26% vs 20%), and infusion reaction on the same date of any carfilzomib dosing (14% vs 11%), respectively. Grade ≥3 acute renal failure occurred in 6% vs 11%, 4% vs 7%, and 2% vs 3% of pts with baseline CrCl ≥15-<60 mL/min, ≥60-<90 mL/min, and ≥90 mL/min, respectively. Overall, the safety profile in each subgroups was consistent with the established carfilzomib safety profile (Usmani Blood Adv 2023). KdD showed consistent clinical benefit vs Kd in median PFS, ORR and OS irrespective of the baseline renal function. Safety findings were consistent with the overall study population.

Hypertension, smoking, and preexistence of multiple cardiac risk factors correlate with carfilzomib-induced cardiovascular adverse events in a racially diverse population.

Use of the proteasome inhibitor carfilzomib has become a standard of care in patients with relapsed/refractory multiple myeloma. An association between carfilzomib and cardiovascular adverse events has been well documented, but this had not been investigated in a racially diverse population. Black patients in particular are underrepresented in the reported outcomes of treatment with carfilzomib. The purpose of this study was to identify risk factors for carfilzomib-associated cardiovascular events in a diverse, single-center population. We conducted a retrospective review of 161 patients with multiple myeloma treated with carfilzomib between 2011 and 2020 at the University of Maryland Medical Center. Over half (86) were Black patients, with the remainder (75) being White patients. We did a multivariate analysis to determine risk factors for developing cardiovascular events during treatment with carfilzomib. There was no statistically significant association with cardiotoxicity and race, gender, or age at first dose of carfilzomib. In multivariable analysis, patients with history of hypertension had a higher risk of cardiotoxicity [adjusted odds ratio (OR): 2.5; 95% CI: 1.1-5.9; P = 0.03] as did those with a history of smoking [OR: 2.8; 95% CI: 1.3-6.4; P = 0.01]. Here we report the largest cohort of Black patients treated with carfilzomib as yet reported. The results of this single center retrospective study show history of hypertension and smoking are associated with carfilzomib associated cardiotoxicity in a diverse patient population. There is a need for well-designed prospective studies enrolling a diverse population to investigate potential interventions to prevent carfilzomib-associated cardiotoxicity.

Patients with Very High Risk of Cardiovascular Adverse Events during Carfilzomib Therapy: Prevention and Management of Events in a Single Center Experience.

Carfilzomib (CFZ) improves the prognosis of multiple myeloma (MM) patients but has shown cardiovascular toxicity. The risk stratification of cardiovascular adverse events (CVAEs) now seems well established, while little is known about the course and management of patients with a high-cardiovascular-risk profile or experiencing CVAEs during therapy. Therefore, we aimed to describe our experience in decision making to support health professionals in selecting the best management strategies to prevent and treat CVAEs. A total of 194 patients with indication to CFZ underwent baseline evaluation of CVAEs risk and were prospectively followed. We propose a novel approach, which includes advanced cardiac imaging testing for patients at high baseline CV risk to rule out clinical conditions that could contraindicate starting CFZ. After baseline evaluation, 19 (9.8%) patients were found at high risk of CVAEs: 13 (6.7%) patients underwent advanced cardiac testing and 3 (1.5%) could not receive CFZ due to CV contraindications. A total of 178 (91.7%) patients started CFZ: 82 (46%) experienced arterial-hypertension-related events and 37 (20.8%) major CVAEs; 19 (10.7%) patients had to discontinue or modify the CFZ dosing regimen. Along with baseline risk stratification, subsequent cardiovascular clinical events and diagnostic follow-up both provided critical data to help identify conditions that could contraindicate the anticancer therapy.

High-dose carfilzomib achieves superior anti-tumor activity over low-dose and recaptures response in relapsed/refractory multiple myeloma resistant to lowdose carfilzomib by co-inhibiting the β2 and β1 subunits of the proteasome complex.

Optimal carfilzomib dosing is a matter of debate. We analyzed the inhibition profiles of proteolytic proteasome subunits β5, β2 and β1 after low-dose (20/27 mg/m2) versus high-dose (≥36 mg/m2) carfilzomib in 103 pairs of peripheral blood mononuclear cells from patients with relapsed/refractory (RR) multiple myeloma (MM). β5 activity was inhibited (median inhibition >50%) in vivo by 20 mg/m2, whereas β2 and β1 were co-inhibited only by 36 and 56 mg/m2, respectively. Coinhibition of β2 (P=0.0001) and β1 activity (P=0.0005) differed significantly between high-dose and low-dose carfilzomib. Subsequently, high-dose carfilzomib showed significantly more effective proteasome inhibition than low-dose carfilzomib in vivo (P=0.0003). We investigated the clinical data of 114 patients treated with carfilzomib combinations. High-dose carfilzomib demonstrated a higher overall response rate (P=0.03) and longer progression-free survival (PFS) (P=0.007) than low-dose carfilzomib. Therefore, we escalated the carfilzomib dose to ≥36 mg/m2 in 16 patients who progressed during low-dose carfilzomib-containing therapies. High-dose carfilzomib recaptured response (≥ partial remission) in nine (56%) patients with a median PFS of 4.4 months. Altogether, we provide the first in vivo evidence in RRMM patients that the molecular activity of high-dose carfilzomib differs from that of low-dose carfilzomib by coinhibition of β2 and β1 proteasome subunits and, consequently, high-dose carfilzomib achieves a superior anti-MM effect than low-dose carfilzomib and recaptures the response in RRMM resistant to low-dose carfilzomib. The optimal carfilzomib dose should be ≥36 mg/m2 to reach a sufficient anti-tumor activity, while the balance between efficacy and tolerability should be considered in each patient.

Zingerone Attenuates Carfilzomib-Induced Cardiotoxicity in Rats through Oxidative Stress and Inflammatory Cytokine Network

Carfilzomib (CFZ) is an anticancer medication acting as a selective proteasome inhibitor. However, it can cause cardiovascular problems, increasing mortality and morbidity. This study aimed to investigate whether zingerone (ZRN) could help reduce carfilzomib-induced cardiotoxicity in Wistar albino rats. Rats were divided into five groups of six animals each. The first group received normal saline as a control (NC); the second group received multiple doses (six) of CFZ (4 mg/kg) intraperitoneally (IP); the third and fourth groups received zingerone (50 mg/kg and 100 mg/kg oral) along with six doses of CFZ for 16 days; and the fifth group received only 100 mg/kg zingerone orally. Hematological, biochemical, oxidative stress, and histopathological studies confirmed the findings of CFZ-induced cardiotoxicity. We found that ZRN significantly attenuated the effects of CFZ on oxidative stress by enhancing the antioxidant properties of glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Additionally, ZRN reduces inflammatory cytokines and apoptotic markers, such as IL-1β, IL-6, TNFα, and caspase-3. Overall, zingerone prevents carfilzomib-induced cardiotoxicity in rats, as evidenced by histopathological studies.

Carfilzomib Use Among Patients with Relapsed/Refractory Multiple Myeloma in the Asia Pacific Region: Characteristics and Outcomes By Regimen from a Prospective, Real-World Study

Background: Carfilzomib (CFZ) is a next-generation proteasome inhibitor currently approved in combination with lenalidomide and dexamethasone (KRd) or with dexamethasone alone (Kd) for treatment of multiple myeloma (MM) patients with ≥1 prior line of therapy in the Asia-Pacific (APAC) region. Here, we describe utilization of KRd and Kd in routine clinical practice in APAC, including treatment patterns, patient profile, reasons for discontinuation, clinical outcomes, and frequency of adverse events (AEs). Methods: This prospective, single-arm cohort study recruited adults with relapsed/refractory MM who received ≥1 dose of CFZ in routine clinical practice as either a combination or monotherapy regimen and had received ≥1 prior line of MM treatment before CFZ initiation. Between July 2019 and June 2021, approximately 300 patients were planned to be enrolled in this study. Medical history, patient characteristics, and clinical data are collected at baseline and throughout the 2-year observation period or until death, withdrawal of consent, or loss of follow-up. Follow-up data are collected through chart reviews every 3 months. AEs leading to treatment discontinuation are collected; common AEs associated with drugs/disease were excluded from collection by the protocol (all serious AEs were collected). The study is ongoing, and last patient record for the analysis will be collected no later than Q1 2023. Results: As of data cutoff April 1, 2022, 311 patients were enrolled, of whom 38 are excluded from the present analysis (11 died before waiver of informed consent approval and 27 patients had missing data for the first medical chart review or first CFZ administration). The 273 patients included in this ad hoc interim analysis were enrolled from 5 countries/regions: Australia (n=46), Hong Kong (n=17), Korea (n=172), Singapore (n=13), and Taiwan (n=25). To date, the regimens prescribed were KRd (n=160, 59%), Kd (n=103, 38%), and other CFZ-based regimens (n=10, 4%; monotherapy [n=1]; not classified [1]; or with dexamethasone and cyclophosphamide [5], pomalidomide [2], or daratumumab [1]). Table 1 displays detailed patient and disease characteristics, and Table 2 displays CFZ utilization and response. Overall, 33% of patients reported a history of hypertension, 11% of cardiac disorders, 7% of diabetes mellitus, and 3% of pulmonary embolism, prior to CFZ initiation. On average, patients prescribed KRd were slightly younger than those prescribed Kd. The majority of KRd patients (68%) had received 1 prior line of treatment, whereas one-third of Kd patients (36%) had received ≥4 prior lines of treatment. Similar proportions of KRd (33%) and Kd (34%) populations were bortezomib refractory, and 73% of Kd patients were lenalidomide refractory. The planned CFZ dose at first cycle was in accordance with the local product information and was used in 89% of KRd and 69% of Kd patients (27 and 56 mg/m2 twice weekly, respectively). At data cutoff, 43.1% and 30.1% of KRd and Kd patients, respectively, remained on CFZ treatment. The most common reason for CFZ discontinuation was disease progression/refractory disease. With KRd and Kd, respectively, the best overall response rate was 79.0% (n=94/119) and 54.7% (n=29/53) and median overall survival was 60.9 (95% confidence interval [CI], 55.9-not estimable [NE]) and 54.5 (95% CI, 33.3-NE) months. CFZ-treatment-related AEs of interest occurred in 10 (3.7%) total patients (cardiac arrhythmia, n=1 Kd; cardiac failure, 1 KRd; dyspnea, 2 KRd, 2 Kd, 1 other CFZ; hematopoietic thrombocytopenia, 1 KRd and 1 Kd; ischemic heart disease, 1 KRd; no incidence of treatment-related acute renal failure, hypertension, and peripheral neuropathy). Overall, 10 (3.7%) patients discontinued CFZ owing to an AE. Conclusions: This study investigates the real-world use of CFZ for relapsed/refractory MM in a predominantly Asian patient population across the APAC region. Interim results confirm that the standard dosing schedules for KRd and Kd are well tolerated in real-world practice and suggest a very low rate of discontinuation due to CFZ-related AEs, even in heavily pretreated MM. Further prospective data collection of patients in routine practice is ongoing to assess patterns of longer-term patient management, patterns after CFZ treatment failure, CFZ toxicity according to number of previous lines of therapy, response, survival outcome, and AEs, which will inform optimal use of CFZ. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Renal Toxicity with Carfilzomib in Multiple Myeloma: Secondary Analysis of SWOG S1304 Comparing Low-Dose Versus High-Dose Carfilzomib

Introduction: Randomized controlled trials (RCTs) testing carfilzomib-based combination regimens in myeloma have demonstrated a signal of increased renal toxicity, with a relative risk of 2.3 for grade≥3 toxicities with carfilzomib-based versus non-carfilzomib-based regimens (Ball et al. Annals of Hematology. 2020). Nonetheless, there are insufficient data on detailed characterization of carfilzomib-induced renal toxicity, especially in patients treated with carfilzomib alone or with dexamethasone, without the confounding effect of additional classes of anti-myeloma therapy. The objective of our study was to estimate the incidence, timing, nature, and potential risk-factors of carfilzomib-induced renal toxicity using data from S1304 which compared two doses of carfilzomib (56 mg/m2 (K56) vs 27 mg/m2 (K27) twice-weekly), both with dexamethasone, in relapsed/refractory myeloma (Ailawadhi et al. Clinical Cancer Research. 2020). Methods: Individual patient-level data from S1304 trial (NCT01903811) were utilized to estimate the incidence, nature, and timing of renal toxicities. The toxicity of interest was acute kidney injury (AKI), in which, we included the adverse event description of "increased creatinine". Baseline characteristics in patients who developed AKI versus those who didn't were compared using Fisher's exact test. Results: Our analysis on renal toxicity included 123 patients, with 57 patients randomized to K56 and 66 to K27 arms. All-grade AKI/increased creatinine (hereafter, referred to as AKI) was seen in 21 patients overall (17.1%), with grade≥3 toxicity seen in 6 patients (4.9%). By treatment arms, the incidence of all-grade and grade≥3 AKI for K56 was 21.1% and 5.3% respectively, whereas for K27 arm it was 13.6% and 4.5%, respectively. The median time to onset of AKI was 2.5 (range, 2-3) and 2 (range, 1-7) cycles for all-grade and grade≥3 respectively. Kidney toxicities of interest other than AKI were CKD and proteinuria. The overall incidence of all-grade CKD and proteinuria were low at 1.6% and 2.4% respectively, with no grade ≥3 events. The incidence of CKD in K56 and K27 arms was 1.8% and 1.5% respectively, whereas that for proteinuria was 1.8% and 3% respectively. The median time to onset of CKD was 3.5 cycles (range, 3-4) and that of proteinuria was 2 cycles (range, 1-9). Subsequently, we investigated any potential differences in baseline patient-specific, disease-specific, or treatment-specific characteristics between patients who developed AKI versus those who did not (Table 1). The only variable that showed a near-significant difference between the two was percent bone marrow plasma cells (BMPC), with %BMPC in the two groups being 41% vs 18% respectively (p=0.052). There was no significant difference in the proportion of patients receiving K56 between the two groups (56% vs 45% respectively; p=0.45). Next, we performed a 3-month landmark analysis to estimate progression-free survival (PFS) stratified by development of any-grade AKI that was at least possibly attributable to study treatment prior to 3 months following randomization. There was no significant difference in median PFS between patients who developed kidney toxicity versus those who did not. Conclusion: In summary, we showed that ≥grade 3 AKI is observed in ~5% of patients receiving carfilzomib plus dexamethasone, with most events occurring early at a median of about 2 cycles from treatment initiation. Furthermore, high tumor burden at baseline is a potential predictor of AKI with carfilzomib, whereas dose-intensity of carfilzomib was not different between patients who developed AKI versus those who didn't. Our findings are comparable to that of the ARROW trial which tested once weekly (70 mg/m2) versus twice-weekly (27 mg/m2) carfilzomib, and demonstrated grade≥3 AKI in 4% and 6% of patients, respectively. Future studies should investigate additional risk-factors and reversibility of carfilzomib-induced renal toxicity as well as impact on survival in larger patient cohorts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mineralocorticoid Receptor Pathway Is a Key Mediator of Carfilzomib-induced Nephrotoxicity: Preventive Role of Eplerenone.

Carfilzomib is an irreversible proteasome inhibitor indicated for relapsed/refractory multiple myeloma. Carfilzomib toxicity includes renal adverse effects (RAEs) of obscure pathobiology. Therefore, we investigated the mechanisms of nephrotoxicity developed by Carfilzomib. In a first experimental series, we used our previously established in vivo mouse models of Carfilzomib cardiotoxicity, that incorporated 2 and 4 doses of Carfilzomib, to identify whether Carfilzomib affects renal pathways. Hematology and biochemical analyses were performed, while kidneys underwent histological and molecular analyses. In a second and third experimental series, the 4 doses protocol was repeated for 24 hours urine collection and proteomic/metabolomic analyses. To test an experimental intervention, primary murine collecting duct tubular epithelial cells were treated with Carfilzomib and/or Eplerenone and Metformin. Finally, Eplerenone was orally co-administered with Carfilzomib daily (165 mg/kg) in the 4 doses protocol. We additionally used material from 7 patients to validate our findings and patients underwent biochemical analysis and assessment of renal mineralocorticoid receptor (MR) axis activation. In vivo screening showed that Carfilzomib-induced renal histological deficits and increased serum creatinine, urea, NGAL levels, and proteinuria only in the 4 doses protocol. Carfilzomib decreased diuresis, altered renal metabolism, and activated MR axis. This was consistent with the cytotoxicity found in primary murine collecting duct tubular epithelial cells, whereas Carfilzomib + Eplerenone co-administration abrogated Carfilzomib-related nephrotoxic effects in vitro and in vivo. Renal SGK-1, a marker of MR activation, increased in patients with Carfilzomib-related RAEs. Conclusively, Carfilzomib-induced renal MR/SGK-1 activation orchestrates RAEs and water retention both in vivo and in the clinical setting. MR blockade emerges as a potential therapeutic approach against Carfilzomib-related nephrotoxicity.

Abstract 3023: Fatty acid synthase (FASN) inhibitors synergize with carfilzomib (CFZ) in acute myeloid leukemia (AML) and multiple myeloma (MM)

Abstract Background: Fatty acid synthase (FASN) upregulation during conditions of oxidative stress contributes to tumor proliferation and survival, which appears to be a mechanism of proteasome inhibitor resistance. Here we demonstrate that acute myeloid leukemia (AML) cell lines resistant to carfilzomib (CFZ), a second-generation proteasome inhibitor, have higher basal FASN expression and targeting FASN with small molecule inhibitors enhances the cytotoxic effect of CFZ in both AML and multiple myeloma (MM) cell lines. Methods: In a proliferation assay, human AML and MM cell lines were treated with a single dose of CFZ for 7 days. Inhibition of proliferation was defined using an IC50 cutoff for CFZ of 10nM for AML and 5nM for MM as the threshold for sensitivity. Sensitive and resistant cell lines were subjected to apoptosis and cell cycle analyses by flow cytometry after being exposed to CFZ for 72 hours. Proteomic analysis was performed at baseline using reverse phase protein assay (RPPA). For CFZ and FASN inhibitor combination assays, AML and MM cell lines with varying sensitivities to CFZ were exposed to CFZ and FASN inhibitors, orlistat or TVB-3166, simultaneously, and the apoptosis rate were analyzed by flow cytometry. For western blots, selected AML and MM cell lines were incubated with compounds for 24 hours, and the lysates were probed for selected targets. Results: Single-agent CFZ induced apoptosis in sensitive AML and MM cell lines, while apoptotic rates remained low in resistant cell lines. Cell cycle analysis showed increased sub-G1 population in sensitive cell lines compared to resistant cell lines. RPPA revealed that FASN, a key enzyme involved in lipogenesis, correlated with CFZ sensitivity, and CFZ resistant lines trended towards higher basal FASN levels. When CFZ was combined with FASN inhibitors, orlistat or TVB-3166, significant synergy was observed in the apoptosis assays in the AML and MM cell lines. Western blot analyses showed FASN inhibitors enhanced the anti-proliferation and pro-apoptotic effects of CFZ. Conclusion: CFZ demonstrated single agent activity in nanomolar ranges in human AML and MM cell lines. When combined with agents targeting lipid-metabolism, CFZ showed synergistic effect in apoptosis, suggesting this combination could potentially be a new therapeutic strategy for AML and MM. Citation Format: Maoyu Peng, Sanaz Noelle Ghafouri, Martina SJ McDermott, Dennis J. Slamon, Sarah M. Larson. Fatty acid synthase (FASN) inhibitors synergize with carfilzomib (CFZ) in acute myeloid leukemia (AML) and multiple myeloma (MM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3023.

Step-up titration dosing (TD) of carfilzomib (K) is associated with prolonged duration of therapy and improved treatment outcomes compared to standard dosing (SD) in patients with multiple myeloma (MM).

e20016 Background: K is a 2nd-generation proteasome inhibitor (PI) approved for the treatment of multiple myeloma (MM). K-based regimens are associated with higher rates of CV toxicity compared with other PIs. We conducted a retrospective analysis to assess incidence of CV adverse events (AE) and outcomes of MM patients (pts) treated with K using a step-up TD schedule compared to SD protocol. Methods: A retrospective chart review was performed of MM pts treated with K at The Ohio State University Comprehensive Cancer Center (OSUCCC) from 1/1/13 to 9/1/19. Pt demographics, disease and K-related characteristics, CV AE, and follow-up information were collected. Pts were excluded if treated at both local center and at OSUCCC, not K-naïve when receiving treatment at OSUCCC, received a single dose of K while inpatient with no intent to continue treatment outpatient, or had a treatment plan entered but never received it. Results: Of the 166 pt charts analyzed, 36 were treated using a TD method (ex. step-wise C1D1 20mg/m2, C1D8 27mg/m2, C1D15 36mg/m2, for goal C2D1 56mg/m2 onwards) and 130 pts were treated using a standard dosing method (ex. C1D1 20mg/m2 and C1D8 56mg/m2 onwards). Pre-existing CV risk factors were similar between the two groups. There was a slight difference in baseline renal function (TD: median CrCl 94mL/min, SD: 76mL/min; p=0.01) and prior PI use (TD: 86.1%, SD: 95%; p=0.048) between the two groups. In pts treated with TD, hypertension (HTN) developed earlier compared with SD (p=0.02). There was a lower incidence of onset of dyspnea in the TD group compared to SD group (16.7% vs 36.2%, respectively; p=0.03). There were no differences in incidence of HTN, congestive heart failure, ischemic heart disease, arrythmias, or pulmonary HTN. The median number of cycles administered to titrated pts was 7 (range: 2-56) compared to 3 (range: 1-44) for standard pts (p<0.001). There was no statistical difference in CV AE being the cause for treatment discontinuation between the two groups. The overall response rate (ORR) was higher in the TD group compared to the SD group (63.9% vs 42.8%, respectively; p=0.04). Five-year overall survival (OS) was improved in patients treated with TD than with SD (43.8% vs 17.5%, respectively; p<0.001). By multivariable analysis, TD was associated with improved OS compared to SD (HR 0.47; 95% CI 0.29-0.77-3.58; P=0.003). Conclusions: A simple modification of K titration dosing improved the tolerability of MM therapy without compromising efficacy. Although there were no differences in AE being the cause of treatment discontinuation between the two groups, an improvement in duration of therapy, ORR, and OS was observed in the TD group. As a result, TD is the standard-of-care dosing for MM pts treated with K at the OSUCCC. Prospective trials are needed to confirm the safety and efficacy of this dosing regimen.

Real-world effectiveness and safety analysis of carfilzomib-lenalidomide-dexamethasone and carfilzomib-dexamethasone in relapsed/refractory multiple myeloma: a multicenter retrospective analysis.

Background:Little is known about the real-world survival benefits and safety profiles of carfilzomib–lenalidomide–dexamethasone (KRd) and carfilzomib–dexamethasone (Kd).Methods:We performed a retrospective analysis to evaluate their efficacy and safety in 157 patients registered in the Kansai Myeloma Forum database.Results:A total of 107 patients received KRd. Before KRd, 99% of patients had received bortezomib (54% were refractory disease), and 82% had received lenalidomide (57% were refractory disease). The overall response rate (ORR) was 68.2%. The median progression-free survival (PFS) and overall survival (OS) were 8.8 and 29.3 months, respectively. Multivariate analysis showed that reduction of the carfilzomib dose and non-IgG M protein were significantly associated with lower PFS and reduction of the carfilzomib dose and refractoriness to prior bortezomib-based regimens were significantly associated with lower OS. A total of 50 patients received Kd. Before Kd, 96% of patients had received bortezomib (54% were refractory disease). The ORR was 62.0%. The median PFS and OS were 7.1 and 20.9 months, respectively. Based on the multivariate analysis, reduction of the carfilzomib dose and International Staging System Stage III (ISS III) were significantly associated with lower PFS. Grade III or higher adverse events were observed in 48% of KRd cases and 54% of Kd cases. Cardiovascular events, cytopenia, and infections were frequent, and 4 KRd patients died due to heart failure, arrhythmia, cerebral hemorrhage, and pneumonia.Conclusion:Our analysis showed that an adequate dose of carfilzomib is important for achieving the best survival benefits in a real-world setting. Adverse effects after KRd and Kd therapy should also be considered.

High-Dose Carfilzomib Recaptures Response in Relapsed/Refractory Multiple Myeloma Resistant to Low-Dose Carfilzomib By Co-Inhibiting β2 Subunit of Proteasome Complex: The First in Human Evidence

BackgroundProteasome, a complex involved in the intracellular protein degradation, consists of multiple subunits, but only three subunits have enzymatic activity to cleave and degrade proteins, namely β1, β2 and β5. Carfilzomib (CFZ), a second-generation proteasome inhibitor (PI), can induce cell death by selective and irreversible inhibition of β5 subunit of proteasome. Preclinical data suggested that high-dose CFZ could co-inhibit predominantly β2 proteasome activity, followed by β1 inhibition (Besse et al, Cell Chem Biol. 2019). Over the past few years, CFZ has become a corner stone for multiple myeloma (MM) therapy. Currently, CFZ is approved by the FDA in different dosing schedules in combination with lenalidomide or daratumumab and dexamethasone. However, the optimal CFZ dosing is still a matter of debate, with the approved dosage ranging from 20to 70mg/m 2 in different regimens. In addition, if response can be recaptured by escalating CFZ dose in patients progressing from low-dose CFZ has yet to be determined. The aim of our current study was to analyse the profile of proteasome inhibition in the respective dose cohorts and to elucidate if high-dose CFZ could recapture response in patients resistant to low-dose CFZ.MethodsWe prospectively collected clinical data and peripheral blood mononuclear cells (PBMC) of 32 patients with relapsed/refractory (RR) MM before and 1-8 hours after CFZ administration. PBMC were lysed and labelled for the activity of individual proteasome subunits using activity based proteasome probes and the proteasome subunits were separated using SDS-PAGE. The activity of constitutive and immunoproteasome β1, β2 and β5 subunits was evaluated by densitometry analysis and combination of the activity of constitutive and immunoproteasome individual subunit was used for further analysis.ResultsOverall, six, nine, twelve and five patients received CFZ at a dose of 20, 27, 36 and 56 mg/m 2, respectively. As expected, the total activity of proteasome decreased with higher doses of CFZ. Significant inhibition (median inhibition > 50%) of β5 subunit was observed already at 20 mg/m 2 dose, while β2 subunit started to be co-inhibited only at a dose of ≥27 mg/m 2. Significant co-inhibition of β2 activity was seen at 36 mg/m 2 dose, at which also β1 subunit started to be co-inhibited. Finally, at 56 mg/m 2, the activity of all active subunits was inhibited with a median inhibition of > 50%, with the strongest inhibition of the β5 subunit, followed by β2 and then β1. When we compared the patient groups low-dose CFZ (20 or 27 mg/m 2) versus high-dose CFZ (36 or 56 mg/m 2), we observed a significant difference in β2 (P=0.002) and β5 (P=0.02) subunit inhibition between the both groups. In terms of total proteasome activity, high-dose CFZ demonstrated a significantly higher proteasome inhibition in comparison with patients receiving low-dose CFZ (P=0.01). In brief, our results suggested that high-dose CFZ, in contrast to low-dose CFZ, could obtain superior proteasome inhibition by co-inhibiting β2 subunit of proteasome complex.In light of this finding, we successfully treated six RRMM patients who were resistant to low-dose CFZ with CFZ dose escalation. All six patients were heavily pretreated with 3-12 lines of therapy including daratumumab, two PIs, two immunomodulatory drugs and autologous stem cell transplant. Additionally, one and two patients received prior treatment with B-cell maturation antigen targeted bi-specific antibody and chimeric antigen receptor modified T-cell, respectively. In the last line of treatment, these six patients showed progression during CFZ based regimens with low-dose CFZ, namely 20 or 27 mg/m 2. We therefore increased the CFZ dose to 36 or 56 mg/m 2 and the doses of agents other than CFZ in the combination regimens remained the same. High-dose CFZ dose recaptured response in all six patients with four and two patients that achieved partial remission and very good partial remission, respectively, and the progression free survival ranged from 1-13 months.ConclusionIn summary, high-dose CFZ, namely ≥ 36mg/m 2, showed more effective proteasome inhibition via blocking β5 and β2 subunits, while low-dose CFZ could not achieve a sufficient inhibition of β2 subunit. We provided the first in human evidence that high-dose CFZ could recapture response in RRMM patients resistant to low-dose CFZ by co-inhibiting the β2 subunit activity of proteasome complex. [Display omitted] DisclosuresEinsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding.

A Phase II Study of Once Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Isatuximab in Newly Diagnosed, Transplant-Eligible Multiple Myeloma

A Phase II Study of Once Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Isatuximab in Newly Diagnosed, Transplant-Eligible Multiple Myeloma

Phase 1b Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Phase 1b Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Utilizing HealthTree ® Cure Hub's Real-World Data to Assess Treatment Management of Patients with Multiple Myeloma during the COVID-19 Pandemic

Background: Patients with multiple myeloma (MM) are uniquely susceptible to viral and bacterial illnesses, including COVID-19, due to their immunocompromised state, age, treatments, and comorbidities. With the advent of COVID-19, changes to treatment were recommended whenever possible, in order to reduce visits to the clinic. The total effect of these changes on cancer patients with multiple myeloma remains unclear. The aim of this project was to assess treatment management by changes to treatment of patients with MM during the COVID-19 pandemic.Methods: We utilized HealthTree ® Cure Hub for Multiple Myeloma (healthree.org) and invited patients with active MM cancer or precursor conditions to participate in an online survey. We analyzed patient responses to questions regarding their myeloma treatments during the COVID-19 pandemic.Results: 978 MM patients participated in the survey between February to June 2021. Since March 2020, 151 patients (15%) either delayed, postponed, or stopped a myeloma treatment because of COVID-19. The four most common treatments were daratumumab (20%), lenalidomide (15%), stem cell transplant (13%) and zoledronic acid (11%). There were 110 patients that canceled a planned myeloma treatment. Of these patients, 55 (50%) canceled a planned chemotherapy, 15 (14%) canceled a stem cell transplant, 1 (1%) canceled radiation and 39 (35%) indicated other. Eight patients replaced an intravenous or subcutaneous treatment with an oral treatment because of COVID-19. There were 9 patients that started a new myeloma treatment because of COVID-19, the most common being daratumumab (44%), ixazomib (22%), lenalidomide (22%) and carfilzomib (11%). Finally, 15 patients had their lenalidomide (50%), steroid (42%) and carfilzomib (8%) dose changed.Conclusions: Our results show that decision-making regarding treatment changes were made on an individual basis and that patients who required a change in treatment were the minority. Aggregating real-world data can provide evidence that despite the changes, patients with MM still received and efficacious treatment and avoided putting these patients at risk or mortality. DisclosuresAhlstrom: Bristol Myers Squibb: Other: Patient Advisory; Janssen: Other: Patient Advisory; Pfizer: Other: Patient Advisory; Takeda: Other: Patient Advisory.

Mutations in the Alternative Complement Pathway in Multiple Myeloma Patients with Carfilzomib-Induced Thrombotic Microangiopathy

IntroductionVascular endothelial injury related to treatment with proteasome inhibitors (PI) has been previously described. Carfilzomib is an irreversible PI and has been associated with cardiovascular toxicity, suggesting increased risk of endothelial injury. Thrombotic microangiopathy (TMA) has been described in multiple myeloma (MM) patients receiving PIs; more often with carfilzomib. In the pediatric transplant population, increased risk of TMA was related to heterozygous mutation in the alternative complement pathway. The homozygous deletions enable uncontrolled complement activation and was found three times more frequently in TMA population. We hypothesized that MM patients with complement mutation are at increased risk of PI-related TMA.Materials and MethodsWe identified ten cases of renal TMA in MM patients receiving carfilzomib from two medical institutions in Greece and in the United States. TMA was diagnosed based on either renal biopsy or acute kidney injury, new-onset anemia, thrombocytopenia and increased LDH in the absence of disease progression. We performed targeted sequencing of the twelve genes implicated in TMA: CFH, CFI, MCP, CFB, CFHR5, C3, THBD, DGKE, PLG, ADAMTS13, MMACHC and G6PD genes. Multiplex Ligation-Dependent Probe Amplification (MLPA) was performed for the analysis of the CFH-CFHR5 region.ResultsPatient characteristics and laboratory values at TMA diagnosis are presented in Table 1. The median age of patients was 68 years (range, 47-73), with slight male predominance (60%). Median laboratory values at diagnosis included hemoglobin 9.35 g/dL, platelet count 26,500 x 10 6/L, LDH 356,5 U/L and creatinine 2.25 mg/dL. Patients were treated with carfilzomib doses ranging 20-70 mg/m 2. Regimens included carfilzomib-dexamethasone (Kd, 7 patients), carfilzomib-lenalidomide-dexamethasone (KRd, 1 patient), carfilzomib-pomalidomide-dexamethasone (KPd, 1 patient), and carfilzomib-daratumumab-dexamethasone (DaraKd, 1 patient). All patients had previously received at least one line of therapy and seven patients had previously undergone autologous stem cell transplant (ASCT), 1-12 years prior to TMA diagnosis. The median time between carfilzomib initiation and TMA diagnosis was 4.5 months (range, 1-60 months). Diagnosis was confirmed with renal biopsy in four cases. Carfilzomib was discontinued in all patients and five patients were treated with plasma exchange (PLEX) while one patient received eculizumab. Seven patients demonstrated clinical improvement and resolution of TMA at 1 year after discontinuation of carfilzomib. Two patients progressed to end stage renal disease (ESRD) requiring intermittent hemodialysis, and one patient developed multiorgan failure. Results of genetic panel are shown in Table 2. Deletions of the CFHR3-CFHR5 region were present in seven cases (70%): two patients carrying a homozygous deletion of CFHR3-CFHR1, four patients with a heterozygous deletion of CFHR3-CFHR1, and one patient with heterozygous deletion of CFHR1-CFHR4. Direct gene sequencing revealed identifiable mutations in CD46 (MCP) and CFHR5 in two distinct patients. The functional correlation and clinical significance are yet to be investigated.ConclusionsIn our cohort of ten patients of carfilzomib-induced TMA, deletions of CFHR3-CFHR5 occurred frequently (70%). In the setting of carfilzomib use, heterozygous CFHR3-CFHR1 deletion may represent a risk factor for the development of TMA. Our data set the bases for larger studies assessing complement mutation as a predisposing factor for PI-induced TMA. [Display omitted] DisclosuresKastritis: Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding. Dimopoulos: Janssen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Amgen: Honoraria. Richardson: AbbVie: Consultancy; Secura Bio: Consultancy; Sanofi: Consultancy; GlaxoSmithKline: Consultancy; Karyopharm: Consultancy, Research Funding; Regeneron: Consultancy; AstraZeneca: Consultancy; Oncopeptides: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Bianchi: Jacob D. Fuchsberg Law Firm: Consultancy; MJH: Honoraria; Karyopharm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.