Soluble B-cell maturation antigen in lacrimal fluid as a potential biomarker and mediator of keratopathy in multiple myeloma.

Belantamab mafodotin (belantamab) is a first-in-class anti-BCMA antibody-drug conjugate approved for the treatment of triple-class refractory multiple myeloma. It provides a unique therapeutic option for patients ineligible for CAR-T and bispecific antibody therapy, and/or patients progressing on anti-CD38 treatment where CAR-T and bispecifics might be kept in reserve. Wider use of the drug can be challenged by its distinct ocular side effect profile, including corneal microcysts and keratopathy. While dose reduction has been the most effective way to reduce these toxicities, the underlying mechanism of this BCMA off-target effect remains to be characterized. In this study, we provide the first evidence for soluble BCMA (sBCMA) in lacrimal fluid and report on its correlation with tumor burden in myeloma patients. We confirm that corneal cells do not express BCMA, and show that sBCMA-belantamab complexes may rather be internalized by corneal epithelial cells through receptor-ligand independent pinocytosis. Using an hTcEpi corneal cell-line model, we show that the pinocytosis inhibitor EIPA significantly reduces belantamab-specific cell killing. As a proof of concept, we provide detailed patient profiles demonstrating that, after belantamab-induced cell killing, sBCMA is released into circulation, followed by a delayed increase of sBCMA in the tear fluid and subsequent onset of keratopathy. Based on the proposed mechanism, pinocytosis-induced keratopathy can be prevented by lowering the entry of sBCMA into the lacrimal fluid. Future therapeutic concepts may therefore consist of belantamab-free debulking therapy prior to belantamab consolidation and/or concomitant use of gamma-secretase inhibition as currently evaluated for belantamab and nirogacestat in ongoing studies.

Safety and Tolerability of SGLT2 Inhibitors in Cardiac Amyloidosis-A Clinical Feasibility Study.

Sodium-glucose transport protein 2 inhibitors (SGLT2i) slow the progression of renal dysfunction and improve the prognosis of patients with heart failure. Amyloidosis constitutes an important subgroup for which evidence is lacking. Amyloidotic fibrils originating from misfolded transthyretin and light chains are the causal agents in ATTR and AL amyloidosis. In these most frequent subtypes, cardiac involvement is the most common organ manifestation. Because cardiac and renal function frequently deteriorate over time, even under best available treatment, SGLT2i emerge as a promising treatment option due to their reno- and cardioprotective properties. We retrospectively analyzed patients with cardiac amyloidosis, who received either dapagliflozin or empagliflozin. Out of 79 patients, 5.1% had urinary tract infections; 2 stopped SGLT2i therapy; and 2.5% died unrelated to the intake of SGLT2i. No genital mycotic infections were observed. As expected, a slight drop in the glomerular filtration rate was noted, while the NYHA functional status, cardiac and hepatic function, as well as the 6 min walk distance remained stable over time. These data provide a rationale for the use of SGLT2i in patients with amyloidosis and concomitant cardiac or renal dysfunction. Prospective randomized data are desired to confirm safety and to prove efficacy in this increasingly important group of patients.

Impaired FADD/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma.

The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM.

Bortezomib induced peripheral neuropathy and single nucleotide polymorphisms in PKNOX1.

We analyzed single nucleotide polymorphisms (SNPs) in PKNOX1 (rs2839629) and in the intergenic region between PKNOX1 and CBS (rs915854) by Sanger sequencing in 88 patients with multiple myeloma treated with bortezomib. All patients (n = 13) harboring a homozygous mutation in PKNOX1 (rs2839629) also had a homozygous mutated rs915854 genotype. Homozygous mutated genotypes of rs2839629 and rs915854 were significantly enriched in patients with painful peripheral neuropathy (PNP) (P < 0.0001), and homozygous mutated rs2839629 genotype was significantly enriched in patients with pain compared to patients with no pain (P = 0.04). In summary, both SNPs rs2839629 and/or rs915854 may be potential biomarkers predicting an increased risk to develop painful PNP under bortezomib.

Minimal residual disease and imaging-guided consolidation strategies in newly diagnosed and relapsed refractory multiple myeloma.

Measurement of minimal residual disease (MRD) by next-generation flow cytometry (NGF) is an important tool to define deep responses in multiple myeloma (MM). However, little is known about the value of combining NGF with functional imaging and its role for MRD-based consolidation strategies in clinical routine. In the present study, we report our experience investigating these issues with 102 patients with newly diagnosed (n = 57) and relapsed/refractory MM (n = 45). Imaging was performed using either positron emission tomography or diffusion-weighted magnetic resonance imaging. In all, 45% of patients achieved MRD-negativity on both NGF and imaging (double-negativity), and 8% and 40% of patients were negative on either NGF or imaging respectively. Thus, in a minority of patients imaging was the only technique to detect residual disease. Imaging-positivity despite negativity on NGF was more common in heavily pretreated disease (four or more previous lines) compared to newly diagnosed MM (p < 0.01). Among the 29 patients undergoing MRD-triggered consolidation, 51% responded with MRD conversion and 21% with improved serological response. MRD-triggered consolidation led to superior progression-free survival (PFS) when compared to standard treatment (p = 0.04). In conclusion, we show that combining NGF with imaging is helpful particularly in patients with heavily pretreated MM, and that MRD-based consolidation could lead to improved PFS.

R-CHOP intensification with mid-cycle methotrexate and consolidating AraC/TT with BCNU/aHSCT in primary aggressive lymphoma with CNS involvement.

PURPOSE: Patients suffering from aggressive systemic peripheral lymphoma with primary central nervous system involvement (PCL) are a rare and sparsely investigated population. Recommended treatment regimens include a combination of intrathecal and systemic chemotherapy as well as whole brain radiotherapy while offering relatively poor survival. METHODS: We conducted a single-center retrospective study that analyzed safety and outcome of 4 + 4 cycles Rituximab (R)-CHOP and R-high-dose Methotrexate (HD-MTX) for newly diagnosed, transplant-eligible patients ("Ping-Pong"), followed by Cytarabine (AraC)/Thiotepa (TT), BCNU/TT, and autologous hematologic stem cell transplantation (aHSCT). We retrospectively analyzed a set of 16 patients with high-intermediate or high-risk IPI status. RESULTS: Overall response rate to Ping-Pong was 100% measured by CT/MRI, including 93.75% complete remissions after BCNU/TT followed by PBSCT. One patient failed to qualify for high-dose chemotherapy due to progression when receiving Cytarabine/TT. All patients experienced grade III adverse events, 3 of them a grade IV adverse event. Estimated progression-free survival is 93.75% after a 4.8-year follow-up currently. CONCLUSION: Our study suggests high effectivity of R-CHOP with mid-cycle MTX with aHSCT consolidation towards acceptable OS results in this challenging patient population.

Multiagent therapy with pomalidomide, bortezomib, doxorubicin, dexamethasone, and daratumumab ("Pom-PAD-Dara") in relapsed/refractory multiple myeloma.

BACKGROUND: Even in the era of novel immunotherapies for multiple myeloma (MM), treatment of late-stage relapsed/refractory (RR) patients remains challenging. The aim of our study was to analyze the efficacy and safety of the five-drug combination pomalidomide, bortezomib, doxorubicin, dexamethasone, and daratumumab ("Pom-PAD-Dara") in RRMM. METHODS: We retrospectively analyzed data of 56 patients with RRMM who received Pom-PAD-Dara between September 2016 and May 2019. RESULTS: Patients were heavily pretreated with a median of four prior lines of therapy, including autologous and allogenic stem cell transplant in 50 (89%) and six (11%) patients, respectively. The overall response rate (ORR) was 78% and we observed partial remission, very good partial remission, and complete remission in 27 (48%), 13 (23%) and four (7%) patients, respectively. Median progression-free survival was 7 months (95% CI, 3.3-10.7) and the median overall survival was not reached at 24 months. Adverse events grade ≥ 3 were observed 41 (73%) patients and included neutropenia (n = 28, 50%), anemia (n = 22, 39%), thrombocytopenia (n = 21, 38%), and pneumonia (n = 6, 11%). CONCLUSION: Pom-PAD-Dara represents a promising multiagent regimen in heavily pretreated RRMM patients with high ORR and an acceptable safety profile.

Fibroblast KATP currents modulate myocyte electrophysiology in infarcted hearts.

Cardiac metabolism remains altered for an extended period of time after myocardial infarction. Studies have shown fibroblasts from normal hearts express KATP channels in culture. It is unknown whether fibroblasts from infarcted hearts express KATP channels and whether these channels contribute to scar and border zone electrophysiology. KATP channel subunit expression levels were determined in fibroblasts isolated from normal hearts (Fb), and scar (sMI-Fb) and remote (rMI-Fb) regions of left anterior descending coronary artery (LAD) ligated rat hearts. Whole cell KATP current density was determined with patch clamp. Action potential duration (APD) was measured with optical mapping in myocyte-only cultures and heterocellular cultures with fibroblasts with and without 100 µmol/l pinacidil. Whole heart optical mapping was used to assess KATP channel activity following LAD ligation. Pinacidil activated a potassium current (35.4 ± 7.5 pA/pF at 50 mV) in sMI-Fb that was inhibited with 10 µmol/l glibenclamide. Kir6.2 and SUR2 transcript levels were elevated in sMI-Fb. Treatment with Kir6.2 short interfering RNA decreased KATP currents (87%) in sMI-Fb. Treatment with pinacidil decreased APD (26%) in co-cultures with sMI-Fb. APD values were prolonged in LAD ligated hearts after perfusion with glibenclamide. KATP channels are present in fibroblasts from the scar and border zones of infarcted hearts. Activation of fibroblast KATP channels could modulate the electrophysiological substrate beyond the acute ischemic event. Targeting fibroblast KATP channels could represent a novel therapeutic approach to modify border zone electrophysiology after cardiac injury.