Background:Ixazomib is an oral proteasome inhibitor for relapsed/refractory multiple myeloma (RRMM). Our study aimed to analyze the efficacy and tolerability of ixazomib-based combination therapies. Methods:We performed a single-center retrospective analysis of 126 patients with RRMM and other plasma cell neoplasms. Results:The median age was 65 years, with a median of two prior therapy lines, and 16.7% were triple-class refractory. The overall response rate (ORR) was 52.5%; triple-class refractory patients had a significantly lower ORR than non-refractory controls (10.5% vs 60.2%, p < 0.001). After a median follow-up of 27.0 months, the median progression-free survival (PFS) was 7.9 months (95% CI: 6.9-11.0), and the median overall survival (OS) was 84.1 months (95% CI: 68.1-not reached). In multivariate analysis, a glomerular filtration rate of ⩽70 ml/min/1.73 m2 was linked to worse PFS (hazard ratio (HR): 2.11, p = 0.008) and OS (HR: 7.27, p = 0.003). Furthermore, triple-class refractory patients showed a trend toward inferior PFS (HR: 3.76, p = 0.05) and significantly worse OS (HR: 20.46, p = 0.002) compared to non-refractory patients. Grade ⩾3 hematologic adverse events occurred in 15.1% patients, while the most common non-hematologic adverse events were fatigue (5.6%) and peripheral neuropathy (26.2%), with the majority classified as grade 1-2. Conclusion:Altogether, ixazomib regimens are potent in RRMM but are less effective in heavily pretreated patients and those with renal impairment, suggesting earlier use may yield greater benefits.

Belantamab mafodotin (belantamab) is a first-in-class anti-B-cell maturation antigen (BCMA) antibody-drug conjugate approved for the treatment of triple-class refractory multiple myeloma. It provides a unique therapeutic option for patients ineligible for chimeric antigen receptor (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 γ-secretase inhibition as currently evaluated for belantamab and nirogacestat in ongoing studies.

Circulating tumor plasma cells (CTCs) provide valuable prognostic information and are proposed as a strong factor for risk stratification of multiple myeloma (MM) patients. CD31-expressing plasma cells (PCs) have been described in bone marrow (BM), extramedullary sites, and in peripheral blood (PB), but the prognostic significance of CD31-expressing malignant PCs has remained unclear. Recent reports indicate that Junctional Adhesion Molecule A (JAM-A), expressed on BM malignant PCs is a potential therapeutic target and prognostic factor in MM. Therefore, we investigated CD31 expression on circulating PCs and its correlation with JAM-A expressing CTCs throughout disease stages. Peripheral blood samples from 5 monoclonal gammopathy of undetermined significance (MGUS), 15 smoldering multiple myeloma (SMM), 144 newly diagnosed multiple myeloma (NDMM) patients and 20 healthy controls, BM aspirates from 40 matched MM patients and 7 healthy controls were collected. Using adapted Euroflow protocols and flow cytometry analysis, we analyzed normal and malignant PCs. Data were processed with Infinicyt and Metaflow software and statistically analyzed with Metaflow and GraphPad software. In the group of matched samples, CD31 expression on CTCs was significantly higher in NDMM compared to MGUS (p=0.0061), and significantly higher in SMM compared to MGUS (p=0.0073). The expression of CD31 on normal PCs in healthy controls was significantly lower compared to any myeloma disease stage (p<0.0001 for MGUS, p=0.0001 for SMM and p=0.0001 for NDMM). JAM-A values on CTCs from healthy controls were significantly lower compared to JAM-A levels on CTCs from SMM (p=0.0001) and NDMM (p=0.0009). However, no statistically significant differences in CD31 and JAM-A levels were observed in BM across different groups. We also evaluated JAM-A levels on CTCs at diagnosis in high-risk patients, based on cytogenetic abnormalities defined as t(4;14), del(17p13), t(14;16) or 1qamp/gain (24 with 1q gain/amp, 22 with other HR factors and 98 with standard risk). High JAM-A-expressing CTCs correlated with high-risk (HR) cytogenetic abnormalities. Significant differences were observed between the 1q gain/amp group and patients with other HR factors (p<0.0114), or no cytogenetic abnormalities (p<0.0001). However, JAM-A levels in BM counterparts did not correlate with HR cytogenetic abnormalities. Patients with low JAM-A on CTCs at diagnosis had better prognosis compared to those with high JAM-A-expressing CTCs (n = 67). The median progression-free survival in NDMM with higher JAM-A expression was 19 months, significantly shorter than the 23 months in patients with the lower JAM-A (p=0,0013, Log-rank test). Pearson's correlation analysis revealed that the frequency of JAM-A on CTCs correlated with BM JAM-A levels on malignant PCs in the ND group (Pearson´s r=0.71, p=0.002). In the RRMM setting, CD31+ CTCs strongly correlated with JAM-A+ CTCs (Pearson´s r=0,85, p=0.044) and BM malignant PCs (Pearson´s r=0.52, p=0.084). Additionally, CD31 levels on CTCs correlated with BM CD31 levels on malignant PCs (Pearson´s r=0.62, p=0.03247). CD31 and JAM-A expressing CTCs correlated with clinical parameters such as β2 microglobulin and lactate dehydrogenase in the NDMM group. Collectively, these results underscore the potential of CD31 and JAM-A on CTCs as promising biomarkers for risk stratification in myeloma, in a non-invasive fashion. JAM-A-expressing CTCs are notably associated with cytogenetic risk factors and disease outcomes. The expression of CD31 and JAM-A on CTCs provide insights into CTC biology and conceivable mechanisms of malignant PC dissemination. Beyond prognosis, JAM-A levels on CTCs are linked to cytogenetic risk factors and, thus, they may play a key role in MM patient risk stratification and guiding personalized approaches.

ABSTRACTPurposeOffering equal Patient Access to Precision Oncology (PO) is a major challenge of clinical oncologists and cancer center representatives. Here, we provide an easily transferable model adopted from strategic management science to assess the geographic impact of a cancer center – in terms of general cancer care and PO participation.MethodsAs members of the German WERA alliance, the cancer centers Würzburg, Erlangen, Regensburg and Augsburg merged care data regarding their geographical impact. Specifically, we examined the provenance of patients from WERA’s molecular tumor boards (MTBs) between 2020 and 2022 (n = 2243). As second dimension, we added the provenance of patients receiving general cancer care (termed Total Cancer Care, TCC) by WERA. Clustering our outreach along these two dimensions allowed us to set up a four-quadrant matrix consisting of postal code areas with referrals towards WERA. These areas were re-identified on a map of the Federal State of Bavaria and surrounding regions.ResultsIn terms of positive MTB and general cancer care referrals, the WERA Matrix overlooked an active screening area of n = 821 postal code areas – representing about 50% of Bavaria’s spatial expansion and more than six million inhabitants. The WERA Matrix identified regions successfully connected to our outreach structures in terms of subsidiarity – with general cancer care mainly performed locally but PO performed in cooperation with WERA. At the same time, we detected postal code areas with a potential PO backlog – characterized by high levels of cancer care performed by WERA and low levels or no MTB representation.ConclusionsThe WERA Matrix provided a transparent portfolio of postal code areas, which helped assessing the geographical impact of our PO program. We believe that its intuitive principle can easily be transferred to other cancer centers.

In addition to randomized clinical trials, consideration of Real-World Evidence is necessary for mirroring clinical reality. However, processing such evidence for large numbers of patients often requires considerable time and effort. This is particularly true for rare tumor diseases such as multiple myeloma (MM) or for adverse effects that occur even more rarely. In such cases, artificial intelligence is able to efficiently detect patients with rare conditions. One of these rare adverse events, and the most discussed, following bone protective treatment in MM is medication-related osteonecrosis of the jaw (MRONJ). The association of bone protective treatment to MM outcome has been intensively studied. However, the impact of MRONJ resulting from such treatment on MM prognosis and outcome is poorly understood. In this retrospective study, we therefore investigated the long-term effects of MRONJ. We used natural language processing (NLP) to screen individual data of 2389 MM patients to find 50 out of 52 patients with MRONJ matching our inclusion criteria. To further improve data quality, we then performed propensity score matching. In comparison to MM patients without MRONJ, we found a significantly longer overall survival (median 126 vs. 86 months) despite slightly worse clinical features.

Multiple myeloma (MM) is a cancerous condition characterized by the proliferation of plasma cells within the hematopoietic marrow, resulting in multiple osteolytic lesions. MM patients typically experience bone pain, kidney damage, fatigue due to anemia, and infections. Historically, MM was an incurable disease with a life expectancy of around three years after diagnosis. However, over the past two decades, the development of novel therapeutics has significantly improved patient outcomes, including response to treatment, remission duration, quality of life, and overall survival. These advancements include thalidomide and its derivatives, lenalidomide and pomalidomide, which exhibit diverse mechanisms of action against the plasma cell clone. Additionally, proteasome inhibitors such as bortezomib, ixazomib, and carfilzomib disrupt protein degradation, proving specifically toxic to cancerous plasma cells. Recent advancements also involve monoclonal antibodies targeting surface antigens, such as elotuzumab (anti-CS1) and daratumumab (anti-CD38), bispecific t-cell engagers such as teclistamab (anti-BCMA/CD3) and Chimeric antigen receptor T (CAR-T)-based strategies, with a growing focus on drugs that exhibit increasingly targeted action against neoplastic plasma cells and relevant effects on the tumor microenvironment.

Introduction: In patients with a clinical indication for autologous hematopoietic stem cell transplantation (ASCT), sufficient mobilization of CD34+ precursor cells into peripheral blood is essential to ensure adequate hematopoietic stem cell (HSC) collection prior to intensive therapy. However, with standard granulocyte-colony stimulating factor (G-CSF)-based mobilization schemes, an important minority of patients fail to mobilize sufficient (e.g., >10/µL) CD34+ cell counts into the peripheral blood and are considered as poor mobilizers (PM). Because failure to achieve sufficient CD34+ cell mobilization can negatively affect important clinical treatment endpoints, the use of plerixafor (PLX) was approved to increase CD34+ mobilization in PM patients. Methods: The German non-interventional, multicenter, open-label, prospective OPTIMOB study evaluated HSC mobilization strategies prior to planned ASCT in adult patients with hematologic malignancies (lymphomas or multiple myeloma [MM]) focusing on PM patients. PM patients were defined as follows: (1) never achieving ≥20 CD34+ cells/µL before 1st apheresis, (2) receiving PLX at any timepoint of mobilization, (3) their initially planned stem cell yield had to be reduced, or (4) they had not received apheresis due to low CD34+ count in peripheral blood. Results: 168 of 475 MM patients (35%) participating in the OPTIMOB study were classified as PM, and 155 of them (92%) received PLX (PM+PLX) during the study. PM patients were 40–78 years old, slightly more often male (n = 97, 58%), mostly newly diagnosed (n = 146, 87%) and received highly individualized previous treatments. Ninety-four of the PMs underwent chemotherapy mobilization (65%), and 51 patients (35%) received steady-state mobilization with G-CSF only during 1st mobilization attempt. 92% of the total PM population (n = 155) underwent apheresis, 78% of them (n = 117) achieved >2.0 × 106 CD34+ cells/kg body weight on the 1st day of apheresis. PM+PLX had a higher median total collection result than those PM patients without PLX support (7.2 vs. 5.7 × 106 CD34+ cells/kg body weight). In total, ASCT was performed in 136 PM+PLX (88%) versus 8 PM−PLX patients (62%). Conclusion: The OPTIMOB study showed that a considerable proportion of adult MM patients in Germany are PMs. Even though most of PMs were supported with PLX in the OPTIMOB study, PM-PLX also successfully mobilized HSCs, allowing ASCT in majority of all PMs. However, further analyses are required for treatment optimization in PMs.

Einleitung Natürliche Sprachverarbeitung (Natural Language Processing, NLP) umfasst eine Teildisziplin der künstlichen Intelligenz, die natürliche Sprache durch einen computerbasierten Algorithmus verarbeitet. So können Informationen aus unstrukturierten, narrativen Texten wie ärztlichen Dokumenten automatisiert extrahiert werden [1]. NLP wird bereits in vielen klinischen Bereichen angewandt. Bislang ist die Forschung über den Einsatz von künstlicher Intelligenz im Allgemeinen oder spezifisch die NLP betreffend beim Zervixkarzinom limitiert.

Abstract Purpose To investigate the trade-off between survival outcome and quality of life (QoL) in Multiple Myeloma (MM). Methods We developed a questionnaire that asked patients amongst others, whether they would choose a shortened time of progression-free survival (PFS) in favor of an increased QoL Results Of 194 MM patients who answered this question, 81 (42%) subjects were willing to accept a shorter PFS for better QoL. On the other hand, 92 (47%) preferred a longer PFS at the cost of reduced QoL. Twenty-one patients (11%) indicated to be undecided. Specific features were associated with the two main groups (“in favor QoL” vs “in favor PFS”). Patients who belonged to the “in favor QoL”-group tended to be in more advanced treatment lines when compared to the “in favor PFS-group” (P = 0.0001). Patients who preferred PFS were found to generally be more likely to hand over responsibility to their physicians (P = 0.01). No associations were found for other disease specific conditions including pain, gastrointestinal symptoms, fatigue or infection. Conclusion The results of our study highlight significant differences in patients’ preferences, thus underlining the importance of assessing individual patient needs in determining the endpoints of further research.

Belantamab mafodotin (Belamaf) is the first BCMA targeted therapy approved for the treatment of Multiple Myeloma patients with relapsed or refractory disease who have received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. This antibody-drug conjugate containing monomethyl auristatin F (MMAF) provides deep and durable remissions in this hard-to-treat MM population, but also induces significant ocular toxicity. This includes microcytic-like epithelial changes leading to transient blurred vision, dry eyes symptoms and loss of visual acuity. The underlying mechanisms are not yet fully understood, but clinical evidence from other ADC studies suggests that the cytotoxic payload MMAF is associated with the ocular toxicity observed. Of note, the cornea itself is not vascularized and does not express BCMA, thus, it remains an open question how toxic effects are transmitted to the cornea. It has been hypothesized that ADC may be transported via the vessels of the corneal limbus, but also transportation via the tear fluid is possible. To date, dose reduction of Belantamab Mafodotin is the only way to efficiently reduce ocular side effects of the treatment and no other mitigation strategies have been successfully established. We screened for soluble BCMA (sBCMA) in peripheral blood and tear fluid in seven healthy young volunteers and in 10 randomly selected MM patients from our institution. Tear fluid was collected using polyvinyl sponges and later eluted via high speed centrifugation. A commercially available human BCMA ELISA kit was used for BCMA quantification. Plasma samples were diluted within range of 1:40 to 1:500 and tear fluid was diluted 1:50 using dilution buffers provided according to manufacturer's instruction. In our healthy cohort, peripheral blood sBCMA (PBsBCMA) levels ranged from 10-20ng/ml with no difference between plasma and serum. Strikingly, we detected sBCMA in the tear fluid, but quantities were 10-fold reduced (0,5 to 3ng/ml). This, to the best of our knowledge, is the first report of sBCMA in human tear fluids (TFsBCMA), providing a novel potential transport mechanism of MMAF or of the ADC to the cornea epithelium. We next measured PBsBCMA and TFsBCMA levels in 10 MM patients from our institution and, likely reflecting their active and variable tumor burden, we found an increase not only in PBsBCMA (50-3500ng/ml) but also TFsBCMA load (3ng to 772ng/ml) compared to our healthy individuals. Interestingly, three patients with the highest TFsBCMA levels were treated with Belantamab Mafodotin at the timepoint of sampling, with a 50- to 100-fold increase compared to MM patients not treated with anti-BCMA therapy. The ongoing DREAMM-5 trial interrogates the addition of the gamma-secretase inhibitor Nirogacestat to minimize sBCMA levels in patients treated with Belantamab Mafodotin. Our novel finding of TFsBCMA suggests that it may be of additional value to also track TFsBCMA levels in these patients, and that such a strategy, lowering sBCMA levels, may not only increase treatment efficiency but may also hold potential to reduce ocular side effects under Belantamab Mafodotin therapy.

Introduction: Successful mobilization and collection of peripheral hematopoietic stem cells (HSCs) are necessary for lymphoma patients eligible for myeloablative chemotherapy with subsequent autologous stem cell transplantation (ASCT). Albeit G-CSF alone or combined with chemotherapy is well-established methods for HSC mobilization, up to 40% of the patients fail to mobilize (poor mobilizer, PM). Plerixafor (PLX) is commonly used in PM patients resulting in increased migration of HSCs into peripheral blood and thus improves the collection outcome. Methods: The prospective, multicenter, open-label, non-interventional OPTIMOB study assessed mobilization and collection parameter of patients with lymphoma or multiple myeloma to get deep insights in the treatment of those patients in clinical routine focusing on PM patients. PM was defined as follows: (1) no achievement of ≥20 CD34+ progenitor cells/µL before first apheresis, (2) PLX administration at any time point during the observational period, (3) reduction of the initially planned CD34+ progenitor cell yield as necessity due to failed mobilization or HSC collection, and (4) no performance of apheresis due to low CD34+ progenitor level. Primary objective of the study was to assess mobilization success by the proportion of PM patients achieving >2 × 106 CD34+ progenitor cells/kg body weight on the first day of apheresis. Here, the data of the lymphoma cohort are presented. Results: Out of 238 patients with lymphoma documented in the study, 32% were classified as PM. 87% of them received PLX. Demographic data revealed no obvious differences between PM and good mobilizing (GM) patients. All patients were treated highly individualized prior to mobilization. Majority of all PM patients were able to undergo apheresis (95%) and reached their individual requested CD34+ progenitor cell target (72%). 57% of the PM patients achieved >2.0 × 106 CD34+ progenitor cells/kg body weight on day 1 of apheresis and nearby 70% of them underwent ASCT. Median time to engraftment was similar in PM and GM patients of the lymphoma cohort. Conclusions: Majority of PM patients with lymphoma were successfully mobilized and underwent ASCT. Most of them received PLX during the study.

At the beginning of the COVID-19 pandemic, patients with primary and secondary immune disorders-including patients suffering from cancer-were generally regarded as a high-risk population in terms of COVID-19 disease severity and mortality. By now, scientific evidence indicates that there is substantial heterogeneity regarding the vulnerability towards COVID-19 in patients with immune disorders. In this review, we aimed to summarize the current knowledge about the effect of coexistent immune disorders on COVID-19 disease severity and vaccination response. In this context, we also regarded cancer as a secondary immune disorder. While patients with hematological malignancies displayed lower seroconversion rates after vaccination in some studies, a majority of cancer patients' risk factors for severe COVID-19 disease were either inherent (such as metastatic or progressive disease) or comparable to the general population (age, male gender and comorbidities such as kidney or liver disease). A deeper understanding is needed to better define patient subgroups at a higher risk for severe COVID-19 disease courses. At the same time, immune disorders as functional disease models offer further insights into the role of specific immune cells and cytokines when orchestrating the immune response towards SARS-CoV-2 infection. Longitudinal serological studies are urgently needed to determine the extent and the duration of SARS-CoV-2 immunity in the general population, as well as immune-compromised and oncological patients.

8000 Background: In medically fit patients with newly diagnosed (ND) multiple myeloma (MM), triplet or quadruplet induction regimens, high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) remain a standard of care. Carfilzomib (K), lenalidomide (R) and dexamethasone (d, KRd) induction/consolidation has proven exceptionally effective. Elotuzumab (E), an anti-SLAMF-7 monoclonal antibody bears favorable tolerability in relapsed/refractory MM while its role in NDMM remains unclear. Methods: Transplant-eligible (TE) NDMM patients (pts) up to 70 years (yrs) were randomized 1:1 to receive six cycles (C) of KRd or E-KRd, (chemomobilisation for ASCT after C3), single (tandem, if <CR/high risk NDMM) HDT/ASCT, followed by four consolidation C (KRd/E-KRd) and R or ER maintenance. Induction (IND, 28-day C) consisted of K on D1/2, 8/9 and 15/16 (20 mg/m² IV on D 1/2 in C1 and 36 mg/m² thereafter), R (25 mg PO, D1-21) and d (36/40 mg D 1, 8, 15, 22). E was given on D 1, 8, 15, and 22 (C1/C2) and on D 1 and 15 (C3-6; 10 mg/kg IV). After IND, pts underwent restaging when bone marrow was analyzed for minimal residual disease (MRD) by next-generation flow cytometry. The first co-primary endpoint of the study was the rate of pts who were in ≥ VGPR and were MRD negative. The study is registered as NCT03948035. Results: 579 pts (574 of whom received treatment) were randomized between 08/2018 and 10/2021 at 52 sites and included in the intent-to-treat analysis. Median age was 60 (range, 31-71) yrs.15.4% had ISS stage III disease. 108/459 evaluable pts (23.5%) had high-risk cytogenetics (del[17p]; t[4;14]; t[14;16]; ≥ 3 1q21 copies). 525/574 pts (91.5%) completed 6 IND cycles. MRD negativity and ≥ VGPR was achieved in 145 of E-KRd (49.8%) and 102 (35.4%) of KRd patients, respectively (p=.0005). 212 (72.9%) of E-KRd versus 177 (62.5%) of KRd patients experienced treatment-emergent AEs (TEAEs) of ≥ grade 3. Febrile neutropenia occurred in 26 (6.4%) E-KRd versus 14 (4.9%) KRd pts. Grade 3/4 thrombocytopenia was seen in 36 (12.4%) E-KRd and 30 (10.6%) KRd pts. Pneumonia occurred in 24 E-KRd (8.2%) and 18 KRd (6.4%) pts. Grade 3/4 cardiac events occurred in 16 E-KRd (5.5%) and of grades 3 to 5 in 16 (5.7%) of KRd pts. 12 E-KRd (4%) and 9 KRd (3.2%) pts had COVID-19 infections with one grade 5 event each (0.3% and 0.4%, respectively). Three pts on E-KRd (1.0%) versus 7 on KRd (2.5%) died on induction due to infections (N=3), MM progression (2), AML (1), a cardiac event (N=1), other (N=3). Conclusions: In this study, the addition of elotuzumab to KRd significantly improved the rate of early, deep (≥ VGPR) MRD-negative remission in TE NDMM. E-KRd pts had slightly more TEAEs. Events were mainly hematotoxicity. To the best of our knowledge, this is the first study to show a benefit for the addition of elotuzumab to a front-line regimen. Clinical trial information: NCT03948035 .