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Objective: Cast nephropathy (CN) is the leading cause of acute kidney injury (AKI) in multiple myeloma (MM). Since it is sparsely documented why some patients with CN do achieve a renal response while others do not, we describe a single-center cohort of patients with multiple myeloma and biopsy-confirmed CN to evaluate potential markers of renal response., Methods: The data was collected as a retrospective, single-center analysis of CN-patients treated at the Medical University Vienna between 01/01/2004 and 01/01/2022. Baseline parameters and clinical outcome was compared between renal responders and non-responders., Results: Among 28 patients with CN, n  = 23 were assessed for renal response (14 responders; 9 non-responders). Renal responders were younger (median age: 61 years; 77 years, p  = 0.039), showed higher overall survival (153months; 58months, p  = 0.044) and achieved hematologic response (≥PR) to first-line therapy ( p  = 0.029), and complete hematologic response (CR) at any time ( p  = 0.025) significantly more often. Further, we could show that rapid initiation of anti-myeloma therapy after initial presentation correlated significantly with renal response (median 9 days; 27 days, p  = 0.016). Analyses of kidney biopsy specimens revealed that patients with a high IF/TA score showed end stage renal disease (dialysis ≥ 3 months) significantly more often ( p  = <0.001)., Discussion: In summary, our data suggests, that a rapid start with systemic hematologic treatment in patients with MM and CN is crucial and achieving an early hematologic response is important for renal recovery. Moreover, achieving a deep hematologic response and subsequent renal recovery improves clinical outcome as reflected by an overall survival benefit.

Methods to estimate bone marrow plasma cells (BMPC) basically include histopathology, cytomorphology, and flow cytometry. The present study compares the outcomes of these methods with special focus on the impact of BMPC-specific characteristics on their recovery by either method. Laboratory reports of diagnostic samples from 238 consecutive patients with suspected or known plasma cell disease were retrospectively analyzed. The median (IQR) proportion of BMPC was 30.0% (15.0-70.0%) by histological review (hBMPC), 7.0% (2.0-16.0%) by smear review (sBMPC), and 3.0% (0.8-10.0%) by flow cytometry (fBMPC). The disparity of results between core biopsy and aspirate smear was enhanced in case of poor quality of the smear, increased BM fiber content, higher grade cell atypia, expression of CD56 (all P < 0.0001), the number of cytogenetic aberrations (P = 0.0002), and abnormalities of the MYC gene (P = 0.0002). Conversely, expression of CD19 and a non-clonal plasma cell phenotype were associated with a lower difference between hBMPC and sBMPC (both P < 0.0001). The disparity between the percentages of sBMPC and fBMPC was associated with the quality of the smear (P = 0.0007) and expression of CD56 (P < 0.0001). Our results suggest that the recovery of BMPC in aspirate specimens not only is a matter of sampling quality but also depends on biological cell properties. Aspiration failure due to malignant type features of BMPC may lead to misclassification of plasma cell disorders and represent a bias for the detection of minimal residual disease after therapy.

Background: Treatment of multiple myeloma is not curative, but targeting CD38 improves patient survival. To further explore this therapeutic approach, we investigated the safety and activity of MOR202, a novel monoclonal antibody targeting CD38, in patients with multiple myeloma., Methods: This is a multicentre, open-label, phase 1-2a trial done at ten hospitals in Germany and Austria. Enrolled patients were aged 18 years or older with relapsed or refractory multiple myeloma and Karnofsky performance status of 60% or higher. Patients were assigned to the different treatment regimens with MOR202 ranging between 0·01 mg/kg and 16 mg/kg in a 3 + 3 design. Dose-escalation and expansion was done either with MOR202 intravenous infusions alone (MOR202 q2w [twice a week] and q1w [weekly] groups) or in combination with dexamethasone (MOR202 with dexamethasone group), with dexamethasone plus pomalidomide (MOR202 with dexamethasone plus pomalidomide group) or plus lenalidomide (MOR202 with dexamethasone plus lenalidomide group). Primary endpoints were safety, MOR202 maximum tolerated dose (or recommended dose) and regimen, and immunogenicity. The primary analysis was assessed in the safety population, which included patients who received at least one dose of any study drug. This trial is registered with ClinicalTrials.gov, NCT01421186., Findings: Between Aug 24, 2011, and Aug 1, 2017, 91 patients were treated, 35 with MOR202 monotherapy, and 56 with MOR202 combination regimens (18 in the MOR202 with dexamethasone group, 21 in the MOR202 with dexamethasone plus pomalidomide group, and 17 in the MOR202 with dexamethasone plus lenalidomide group). MOR202 intravenous infusions were safely administered within 30 min. Infusion-related reactions occurred in 14 (40%) of 35 patients receiving MOR202 monotherapy without steroids, and in four (7%) of 56 patients receiving MOR202 combination treatment. MOR202 maximum tolerated dose was not reached and the recommended regimens were MOR202 administered as an intravenous infusion for 30 min at doses up to 16 mg/kg with dexamethasone (40 mg), or in combination with dexamethasone plus lenalidomide (25 mg) or pomalidomide (4 mg). 35 (38%) of 91 patients developed lymphopenia, 30 (33%) developed neutropenia, and 27 (30%) developed leukopenia; these were the most common grade 3 or higher treatment-emergent adverse events. Serious adverse events were reported in 51 (56%) of 91 patients. None of the deaths were associated with MOR202. One pomalidomide-associated death occurred in the MOR202 with dexamethasone plus pomalidomide group. No anti-MOR202 antibodies were detected in patients., Interpretation: MOR202 is safe and its clinical activity in patients with relapsed or refractory multiple myeloma is promising. Further clinical investigations of combinations with an immunomodulatory drug and dexamethasone are recommended., Funding: MorphoSys AG., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Multiple Myeloma (MM) is an incurable plasma cell malignancy primarily localized within the bone marrow (BM). It develops from a premalignant stage, monoclonal gammopathy of undetermined significance (MGUS), often via an intermediate stage, smoldering MM (SMM). The mechanisms of MM progression have not yet been fully understood, all the more because patients with MGUS and SMM already carry similar initial mutations as found in MM cells. Over the last years, increased importance has been attributed to the tumor microenvironment and its role in the pathophysiology of the disease. Adaptations of MM cells to hypoxic conditions in the BM have been shown to contribute significantly to MM progression, independently from the genetic predispositions of the tumor cells. Searching for consequences of hypoxia-induced adaptations in primary human MM cells, CD138-positive plasma cells freshly isolated from BM of patients with different disease stages, comprising MGUS, SMM, and MM, were analyzed by proteome profiling, which resulted in the identification of 6218 proteins. Results have been made fully accessible via ProteomeXchange with identifier PXD010600. Data previously obtained from normal primary B cells were included for comparative purposes. A principle component analysis revealed three clusters, differentiating B cells as well as MM cells corresponding to less and more advanced disease stages. Comparing these three clusters pointed to the alteration of pathways indicating adaptations to hypoxic stress in MM cells on disease progression. Protein regulations indicating immune evasion strategies of MM cells were determined, supported by immunohistochemical staining, as well as transcription factors involved in MM development and progression. Protein regulatory networks related to metabolic adaptations of the cells became apparent. Results were strengthened by targeted analyses of a selected panel of metabolites in MM cells and MM-associated fibroblasts. Based on our data, new opportunities may arise for developing therapeutic strategies targeting myeloma disease progression., (© 2019 Janker et al.)

Background: The objective of this study was to characterize tumor activity and mineralization status in newly-detected multiple myeloma (MM) bone lesions using 2- 18 F-fluoro-2-deoxy-D-glucose ( 18 F-FDG)-PET/CT and 18 F-sodium fluoride ( 18 F-NaF)-PET/CT before and after antitumor treatment., Materials and Methods: In this retrospective study, seven patients with histologically-verified MM were included (four women, three men; median age=57 years, standard deviation=11.23 years). PET/CT was performed with 18 F-FDG and with 18 F-NaF, both at baseline and after treatment. All patients had positive scans. Volumes of interest (VOIs) were drawn over all 18 F-FDG-PET/CT-positive bone lesions, as well as the corresponding regions in 18 F-NaF-PET/CT. For characterization of bone lesions, semi-quantitative standard uptake value (SUV) parameters were measured., Results: 18 F-FDG-PET/CT in the seven patients detected 39 metabolically active lesions that were correlated with the corresponding sites in 18 F-fluoride-PET/CT. Overall, the lesions showed a response to therapy, with a significant decrease in SUV max on PET/CT using 18 F-FDG (p<0.001) and with 18 F-NaF (p<0.001). In four patients with a second follow-up scan (at a median of 17 months after baseline scan), there was no significant change in lesion uptake., Conclusion: Based on our data, antitumor therapy in MM reduces not only tumor activity, but also the mineralization status of bone lesions. A second follow-up scan in a subset of the cohort yielded no change in mineralization status., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Renal impairment (RI) is a negative prognostic factor in Multiple Myeloma (MM) and affected patients are often excluded from autologous stem cell transplantation (ASCT). However, it remains unclear whether historically inferior outcome data still hold true., Methods: From a total of 475 eligible MM patients who had undergone ASCT between 1998 and 2016, 374 were included in this multi-centric retrospective cohort study. Renal function was determined both at the time of MM diagnosis and ASCT by estimated glomerular filtration rate (eGFR according to the MDRD formula, RI defined as eGFR < 60 ml/min/1.73m 2 ). Patients were categorized into 3 groups: A) no RI diagnosis and ASCT, B) RI at diagnosis with normalization before ASCT and C) RI both at the time of diagnosis and ASCT. Log-rank testing was used for overall and progression-free survival (OS, PFS) analysis., Conclusion: While severe RI at MM diagnosis confers a risk of shorter OS, MM progression after ASCT is not affected by any stage of renal failure. It can be concluded that ASCT can be safely carried out in MM patients with mild to moderate RI and should be pro-actively considered in those with severe RI., Results: When comparing all groups, no difference in OS and PFS was found (p = 0.319 and p = 0.904). After further stratification according to the degree of RI at the time of diagnosis, an OS disadvantage was detected for patients with an eGFR < 45 ml/min/m 2 . PFS was not affected by any RI stage.

Background: Elevated levels of cardiovascular markers including N-terminal B-type natriuretic peptide (NT-proBNP) have been shown to be associated with disease severity and mortality in an unselected population of cancer patients without cardiac disease. The aim of this study was to investigate whether NT-proBNP levels are related to disease severity in multiple myeloma (MM) and to assess the natural course of NT-proBNP levels throughout disease progression., Materials and Methods: We retrospectively analysed a total of 118 patients with MM, who were followed up routinely. NT-proBNP, beta-2-microglobulin (B2M) and levels of plasma cell-derived light chains were measured at baseline and follow-up (FUP) visits. All-cause mortality was defined as primary study endpoint, and the correlation between NT-proBNP and disease severity reflected by B2M and the International Staging System (ISS) was assessed., Results: During a median FUP of 845 (IQR:683-978) days, 31 patients (26%) died. NT-proBNP showed a highly significant positive correlation with B2M at first presentation [r = .65, P < .001] and increased significantly with progressing MM disease stage [133.3 pg/mL (IQR:51.5-282.0) for ISS stage 1, 487.4 pg/mL (IQR:123.8-738.3) for ISS stage 2 and 969.1 pg/mL (IQR:472.8-3748.0) for ISS stage 3, P < .001 between all groups]. During FUP, NT-proBNP levels rose significantly alongside other MM disease severity markers for patients experiencing the primary outcome [356.6 pg/mL (IQR:142.9-782.3) vs 862.9 pg/mL (IQR:338.8-4215.0), P < .001], whereas no significant changes in laboratory parameters could be detected for survivors., Conclusions: Elevated levels of the cardiovascular marker NT-proBNP are associated with disease severity in patients with MM., (© 2018 Stichting European Society for Clinical Investigation Journal Foundation.)

Autologous hematopoietic stem cell transplantation (ASCT) is the standard of care for selected patients with multiple myeloma (MM). Many data exist on ASCT in the era of novel agents. We retrospectively analyzed 189 patients (108 males and 81 females) with biopsy-proven MM, who had received ASCT after induction therapy with either conventional chemotherapy alone or in combination with novel agents at our department. The outcomes of both groups and the risk factors for shorter survival were investigated. The most commonly used induction chemotherapy prior to ASCT was VAD (vincristine, doxorubicin and dexamethasone, 42%), followed by PAD (bortezomib, doxorubicin and dexamethasone, 21%). One-hundred and twenty-nine patients (68%) received cyclophosphamide-recombinant human granulocyte colony-stimulating factor for stem cell mobilization. No differences were observed for progression-free survival in terms of the number of transplanted CD34+ cells (p = 0.261). A trend in improved overall survival (OS) was seen for the use of novel agents when compared to conventional chemotherapy (164.3 vs. 82.0 months; p = 0.046). The International Staging System stages had a significant (p = 0.036) impact on OS. The novel agents improved OS in our patients with MM undergoing ASCT when compared to conventional chemotherapy regimens. The number of transplanted CD34+ cells had no significant impact on hematopoietic reconstitution., (© 2015 S. Karger AG, Basel.)

We report 13 multiple myeloma (MM) or lymphoma patients who were failing PBSC mobilization after disease-specific chemotherapy and granulocyte-CSF (G-CSF), and received plerixafor to successfully collect PBSCs. Patients were considered poor mobilizers when the concentration of PB CD34(+) cells was always lower than 10 cells/μL, during the recovery phase after chemotherapy and/or were predicted to have inadequate PBSC collection to proceed to autologous transplantation. Plerixafor (0.24 mg/kg) was administered subcutaneously for up to three consecutive days, while continuing G-CSF, 10-11 h before the planned leukapheresis. Plerixafor administration was safe and no significant adverse events were recorded. We observed a 4.7 median fold-increase in the number of circulating CD34(+) cells after plerixafor as compared with baseline CD34(+) cell concentration (from a median of 6.2 (range 1-12) to 21.5 (range 9-88) cells/μL). All patients collected >2 × 10(6) CD34(+) cells/kg in 1-3 leukaphereses. In all, 5/13 patients have already undergone autograft with plerixafor-mobilized PBSCs, showing a rapid and durable hematological recovery. Our results suggest that the pre-emptive addition of plerixafor to G-CSF after chemotherapy is safe and may allow the rescue of lymphoma and MM patients, who need autologous transplantation but are failing PBSC mobilization.