Daratumumab and antineoplastic therapy versus antineoplastic therapy only for adults with newly diagnosed multiple myeloma ineligible for transplant.

BACKGROUND: Multiple myeloma (MM) is a haematological malignancy that is characterised by proliferation of malignant plasma cells in the bone marrow. For adults ineligible to receive high-dose chemotherapy and autologous stem cell transplant, the recommended treatment combinations in first-line therapy generally consist of combinations of alkylating agents, immunomodulatory drugs, and proteasome inhibitors. Daratumumab is a CD38-targeting, human IgG1k monoclonal antibody recently developed and approved for the treatment of people diagnosed with MM. Multiple myeloma cells uniformly over-express CD-38, a 46-kDa type II transmembrane glycoprotein, making myeloma cells a specific target for daratumumab. OBJECTIVES: To determine the benefits and harms of daratumumab in addition to antineoplastic therapy compared to antineoplastic therapy only for adults with newly diagnosed MM who are ineligible for transplant. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, EU Clinical Trials Register, ClinicalTrials.gov, WHO ICTRP, and conference proceedings from 2010 to September 2023. SELECTION CRITERIA: We included randomised controlled trials that compared treatment with daratumumab added to antineoplastic therapy versus the same antineoplastic therapy alone in adult participants with a confirmed diagnosis of MM. We excluded quasi-randomised trials and trials with less than 80% adult participants, unless there were subgroup analyses of adults with MM. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the results of the search strategies for eligibility. We documented the process of study selection in a flowchart as recommended by the PRISMA statement. We evaluated the risk of bias in included studies with RoB 1 and assessed the certainty of the evidence using GRADE. We followed standard Cochrane methodological procedures. MAIN RESULTS: We included four open-label, two-armed randomised controlled trials (34 publications) involving a total of 1783 participants. The ALCYONE, MAIA, and OCTANS trials were multicentre trials conducted worldwide in middle- and high-income countries. The AMaRC 03-16 trial was conducted in one high-income country, Australia. The mean age of participants was 69 to 74 years, and the proportion of female participants was between 40% and 54%. All trials evaluated antineoplastic therapies with or without daratumumab. In the ALCYONE and OCTANS trials, daratumumab was combined with bortezomib and melphalan-prednisone. In the AMaRC 03-16 study, it was combined with bortezomib, cyclophosphamide, and dexamethasone, and in the MAIA study, it was combined with lenalidomide and dexamethasone. None of the included studies was blinded (high risk of performance and detection bias). One study was published as abstract only, therefore the risk of bias for most criteria was unclear. The other three studies were published as full texts. Apart from blinding, the risk of bias was low for these studies. Overall survival Treatment with daratumumab probably increases overall survival when compared to the same treatment without daratumumab (hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.53 to 0.76, 2 studies, 1443 participants, moderate-certainty evidence). After a follow-up period of 36 months, 695 per 1000 participants survived in the control group, whereas 792 per 1000 participants survived in the daratumumab group (95% CI 758 to 825). Progression-free survival Treatment with daratumumab probably increases progression-free survival when compared to treatment without daratumumab (HR 0.48, 95% CI 0.39 to 0.58, 3 studies, 1663 participants, moderate-certainty evidence). After a follow-up period of 24 months, progression-free survival was reached in 494 per 1000 participants in the control group versus 713 per 1000 participants in the daratumumab group (95% CI 664 to 760). Quality of life Treatment with daratumumab may result in a very small increase in quality of life after 12 months, evaluated on the EORTC QLQ-C30 global health status scale (GHS), when compared to treatment without daratumumab (mean difference 2.19, 95% CI -0.13 to 4.51, 3 studies, 1096 participants, low-certainty evidence). The scale is from 0 to 100, with a higher value indicating a better quality of life. On-study mortality Treatment with daratumumab probably decreases on-study mortality when compared to treatment without daratumumab (risk ratio (RR) 0.72, 95% CI 0.62 to 0.83, 3 studies, 1644 participants, moderate-certainty evidence). After the longest follow-up available (12 to 72 months), 366 per 1000 participants in the control group and 264 per 1000 participants in the daratumumab group died (95% CI 227 to 304). Serious adverse events Treatment with daratumumab probably increases serious adverse events when compared to treatment without daratumumab (RR 1.18, 95% CI 1.02 to 1.37, 3 studies, 1644 participants, moderate-certainty evidence). After the longest follow-up available (12 to 72 months), 505 per 1000 participants in the control group versus 596 per 1000 participants in the daratumumab group experienced serious adverse events (95% CI 515 to 692). Adverse events (Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3) Treatment with daratumumab probably results in little to no difference in adverse events (CTCAE grade ≥ 3) when compared to treatment without daratumumab (RR 1.01, 95% CI 0.99 to 1.02, 3 studies, 1644 participants, moderate-certainty evidence). After the longest follow-up available (12 to 72 months), 953 per 1000 participants in the control group versus 963 per 1000 participants in the daratumumab group experienced adverse events (CTCAE grade ≥ 3) (95% CI 943 to 972). Treatment with daratumumab probably increases the risk of infections (CTCAE grade ≥ 3) when compared to treatment without daratumumab (RR 1.52, 95% CI 1.30 to 1.78, 3 studies, 1644 participants, moderate-certainty evidence). After the longest follow-up available (12 to 72 months), 224 per 1000 participants in the control group versus 340 per 1000 participants in the daratumumab group experienced infections (CTCAE grade ≥ 3) (95% CI 291 to 399). AUTHORS' CONCLUSIONS: Overall analysis of four studies showed a potential benefit for daratumumab in terms of overall survival and progression-free survival and a slight potential benefit in quality of life. Participants treated with daratumumab probably experience increased serious adverse events. There were likely no differences between groups in adverse events (CTCAE grade ≥ 3); however, there are probably more infections (CTCAE grade ≥ 3) in participants treated with daratumumab. We identified six ongoing studies which might strengthen the certainty of evidence in a future update of this review.

Pre-Clinical Assessment of SAR442257, a CD38/CD3xCD28 Trispecific T Cell Engager in Treatment of Relapsed/Refractory Multiple Myeloma.

Current treatment strategies for multiple myeloma (MM) are highly effective, but most patients develop relapsed/refractory disease (RRMM). The anti-CD38/CD3xCD28 trispecific antibody SAR442257 targets CD38 and CD28 on MM cells and co-stimulates CD3 and CD28 on T cells (TCs). We evaluated different key aspects such as MM cells and T cells avidity interaction, tumor killing, and biomarkers for drug potency in three distinct cohorts of RRMM patients. We found that a significantly higher proportion of RRMM patients (86%) exhibited aberrant co-expression of CD28 compared to newly diagnosed MM (NDMM) patients (19%). Furthermore, SAR442257 mediated significantly higher TC activation, resulting in enhanced MM killing compared to bispecific functional knockout controls for all relapse cohorts (Pearson's r = 0.7). Finally, patients refractory to anti-CD38 therapy had higher levels of TGF-ß (up to 20-fold) compared to other cohorts. This can limit the activity of SAR442257. Vactoserib, a TGF-ß inhibitor, was able to mitigate this effect and restore sensitivity to SAR442257 in these experiments. In conclusion, SAR442257 has high potential for enhancing TC cytotoxicity by co-targeting CD38 and CD28 on MM and CD3/CD28 on T cells.

The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma.

Acquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IGH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing (WGS) data from 1173 MM samples. Integrating molecular time and structural variants (SV) within early chromosomal duplications, we indeed identified pre-gain deletions in 9.4% of HY patients without IGH translocations, challenging HY as the earliest somatic event. Remarkably, these deletions affected tumor suppressor genes (TSG) and/or oncogenes in 2.4% of HY patients without IGH translocations, supporting their role in MM pathogenesis. Furthermore, our study points to post-gain deletions as novel driver mechanisms in MM. Using multi-omics approaches to investigate their biological impact, we found associations with poor clinical outcome in newly diagnosed patients and profound effects on both oncogene and TSG activity, despite the diploid gene status. Overall, this study provides novel insights into the temporal dynamics of genomic alterations in MM.

Clinical and serological characterization of acute pleuropericarditis suggests an autoinflammatory pathogenesis and highlights risk factors for recurrent attacks.

PURPOSE: We describe the manifestations and course of patients with pleuropericarditis (PP). Serum parameters were analyzed to evaluate the contribution of autoimmune and autoinflammatory mechanisms to PP pathogenesis. Finally, we outline risk factors for recurrent PP attacks. METHODS: Electronic medical records of the University Hospital Heidelberg were screened for PP diagnosis between the years 2009 and 2021. A total of 164 patients were detected and compared to patients suffering from systemic lupus erythematosus (SLE)-associated PP. Follow-up data were collected until January 2023. RESULTS: In 57.3% of a total of 164 PP cases, no trigger was identified (idiopathic PP). The clinical manifestations were similar in subgroups with different triggers (idiopathic, post-cardiac injury and post-infectious). None of the patients in the idiopathic-PP (i-PP) group fulfilled the diagnostic criteria of an autoimmune disease and the i-PP group could be clearly discriminated by clinical, epidemiological and serological means from the control cohort of SLE-associated PP. After a median follow-up of 1048 days, the majority of PP patients (72.7%) had at least one PP relapse. Univariate analyses showed that CRP, SAA (serum amyloid A), troponin T, NT-BNP and post-cardiac injury were negatively correlated, while the presence of fever and an idiopathic trigger were positively correlated with recurrence of PP. Multivariate analyses showed that fever, an idiopathic trigger and low SAA values were risk factors for PP recurrence. CONCLUSION: This study highlights that most cases of PP are idiopathic and PP cases with various triggers have an identical clinical phenotype. Our data suggest that the clinical, epidemiological and serological characteristics of idiopathic PP considerably differ from patients with PP caused by autoimmune disease like SLE. We further demonstrate that PP has a high risk of recurrence and identify factors associated with this risk, allowing for a targeted secondary prophylaxis.

High-throughput electron tomography identifies centriole over-elongation as an early event in plasma cell disorders.

Plasma cell disorders are clonal outgrowths of pre-malignant or malignant plasma cells, characterized by extensive chromosomal aberrations. Centrosome abnormalities are a major driver of chromosomal instability in cancer but their origin, incidence, and composition in primary tumor cells is poorly understood. Using cutting-edge, semi-automated high-throughput electron tomography, we characterized at nanoscale 1386 centrioles in CD138pos plasma cells from eight healthy donors and 21 patients with plasma cell disorders, and 722 centrioles from different control populations. In plasma cells from healthy individuals, over-elongated centrioles accumulated with age. In plasma cell disorders, centriole over-elongation was notably frequent in early, pre-malignant disease stages, became less pronounced in overt multiple myeloma, and almost entirely disappeared in aggressive plasma cell leukemia. Centrioles in other types of patient-derived B cell neoplasms showed no over-elongation. In contrast to current belief, centriole length appears to be highly variable in long-lived, healthy plasma cells, and over-elongation and structural aberrations are common in this cell type. Our data suggest that structural centrosome aberrations accumulate with age in healthy CD138pos plasma cells and may thus play an important role in early aneuploidization as an oncogenic driver in plasma cell disorders.

Resolving the spatial architecture of myeloma and its microenvironment at the single-cell level.

In multiple myeloma spatial differences in the subclonal architecture, molecular signatures and composition of the microenvironment remain poorly characterized. To address this shortcoming, we perform multi-region sequencing on paired random bone marrow and focal lesion samples from 17 newly diagnosed patients. Using single-cell RNA- and ATAC-seq we find a median of 6 tumor subclones per patient and unique subclones in focal lesions. Genetically identical subclones display different levels of spatial transcriptional plasticity, including nearly identical profiles and pronounced heterogeneity at different sites, which can include differential expression of immunotherapy targets, such as CD20 and CD38. Macrophages are significantly depleted in the microenvironment of focal lesions. We observe proportional changes in the T-cell repertoire but no site-specific expansion of T-cell clones in intramedullary lesions. In conclusion, our results demonstrate the relevance of considering spatial heterogeneity in multiple myeloma with potential implications for models of cell-cell interactions and disease progression.

Application of an artificial intelligence-based tool in [18F]FDG PET/CT for the assessment of bone marrow involvement in multiple myeloma.

PURPOSE: [18F]FDG PET/CT is an imaging modality of high performance in multiple myeloma (MM). Nevertheless, the inter-observer reproducibility in PET/CT scan interpretation may be hampered by the different patterns of bone marrow (BM) infiltration in the disease. Although many approaches have been recently developed to address the issue of standardization, none can yet be considered a standard method in the interpretation of PET/CT. We herein aim to validate a novel three-dimensional deep learning-based tool on PET/CT images for automated assessment of the intensity of BM metabolism in MM patients. MATERIALS AND METHODS: Whole-body [18F]FDG PET/CT scans of 35 consecutive, previously untreated MM patients were studied. All patients were investigated in the context of an open-label, multicenter, randomized, active-controlled, phase 3 trial (GMMG-HD7). Qualitative (visual) analysis classified the PET/CT scans into three groups based on the presence and number of focal [18F]FDG-avid lesions as well as the degree of diffuse [18F]FDG uptake in the BM. The proposed automated method for BM metabolism assessment is based on an initial CT-based segmentation of the skeleton, its transfer to the SUV PET images, the subsequent application of different SUV thresholds, and refinement of the resulting regions using postprocessing. In the present analysis, six different SUV thresholds (Approaches 1-6) were applied for the definition of pathological tracer uptake in the skeleton [Approach 1: liver SUVmedian × 1.1 (axial skeleton), gluteal muscles SUVmedian × 4 (extremities). Approach 2: liver SUVmedian × 1.5 (axial skeleton), gluteal muscles SUVmedian × 4 (extremities). Approach 3: liver SUVmedian × 2 (axial skeleton), gluteal muscles SUVmedian × 4 (extremities). Approach 4: ≥ 2.5. Approach 5: ≥ 2.5 (axial skeleton), ≥ 2.0 (extremities). Approach 6: SUVmax liver]. Using the resulting masks, subsequent calculations of the whole-body metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in each patient were performed. A correlation analysis was performed between the automated PET values and the results of the visual PET/CT analysis as well as the histopathological, cytogenetical, and clinical data of the patients. RESULTS: BM segmentation and calculation of MTV and TLG after the application of the deep learning tool were feasible in all patients. A significant positive correlation (p < 0.05) was observed between the results of the visual analysis of the PET/CT scans for the three patient groups and the MTV and TLG values after the employment of all six [18F]FDG uptake thresholds. In addition, there were significant differences between the three patient groups with regard to their MTV and TLG values for all applied thresholds of pathological tracer uptake. Furthermore, we could demonstrate a significant, moderate, positive correlation of BM plasma cell infiltration and plasma levels of ß2-microglobulin with the automated quantitative PET/CT parameters MTV and TLG after utilization of Approaches 1, 2, 4, and 5. CONCLUSIONS: The automated, volumetric, whole-body PET/CT assessment of the BM metabolic activity in MM is feasible with the herein applied method and correlates with clinically relevant parameters in the disease. This methodology offers a potentially reliable tool in the direction of optimization and standardization of PET/CT interpretation in MM. Based on the present promising findings, the deep learning-based approach will be further evaluated in future prospective studies with larger patient cohorts.

Resolving therapy resistance mechanisms in multiple myeloma by multiomics subclone analysis.

Intratumor heterogeneity as a clinical challenge becomes most evident after several treatment lines, when multidrug-resistant subclones accumulate. To address this challenge, the characterization of resistance mechanisms at the subclonal level is key to identify common vulnerabilities. In this study, we integrate whole-genome sequencing, single-cell (sc) transcriptomics (scRNA sequencing), and chromatin accessibility (scATAC sequencing) together with mitochondrial DNA mutations to define subclonal architecture and evolution for longitudinal samples from 15 patients with relapsed or refractory multiple myeloma. We assess transcriptomic and epigenomic changes to resolve the multifactorial nature of therapy resistance and relate it to the parallel occurrence of different mechanisms: (1) preexisting epigenetic profiles of subclones associated with survival advantages, (2) converging phenotypic adaptation of genetically distinct subclones, and (3) subclone-specific interactions of myeloma and bone marrow microenvironment cells. Our study showcases how an integrative multiomics analysis can be applied to track and characterize distinct multidrug-resistant subclones over time for the identification of molecular targets against them.

Idecabtagene Vicleucel Is Well Tolerated and Effective in Relapsed/Refractory Myeloma Patients with Prior Allogeneic Stem Cell Transplantation.

BCMA-specific chimeric-antigen receptor (CAR-) T cell therapy has led to high response rates and durable remissions in patients with relapsed refractory multiple myeloma. However, little data are available for patients after prior allogeneic stem cell transplantation (allo-SCT) in whom T cells are chimeric. In this study, we aimed to assess the safety and efficacy of patient-derived donor CAR-T therapy in myeloma patients with prior allo-SCT, particularly with regard to graft-versus-host disease (GVHD). We report a comprehensive clinical analysis of 3 patients who had previously undergone allo-SCT for high-risk myeloma and were treated with idecabtagene vicleucel (ide-cel) at our institution. Ide-cel was well tolerated, with no clinically relevant immune effector cell-associated neurotoxicity syndrome or cytokine release syndrome observed in any patient. Importantly, no new GVHD was observed, even though all patients had a history of GVHD. All patients responded to treatment with at least a very good partial remission. Two patients relapsed within 6 months, and 1 patient was still in stringent complete remission at the time of this report. Our findings demonstrate that treatment with ide-cel is feasible, very well tolerated, and effective in patients with relapsed/refractory multiple myeloma after prior allo-SCT.

Impact of novel agent therapies on immune cell subsets and infectious complications in patients with relapsed/refractory multiple myeloma.

Introduction: Infections are a leading cause of morbidity and mortality in patients with multiple myeloma (MM). Methods: To examine the effects of modern second-generation novel agent therapy on immune cell subsets, in particular CD4+-T-cells, and infectious complications in patients with relapsed/refractory MM (RRMM), we conducted a prospective cohort study in 112 RRMM patients. Results: Substantially decreased CD4+-T-cells <200/µl before initiation of relapse therapy were detected in 27.7% of patients and were associated with a higher number of previous lines of therapy. Relapse therapy with carfilzomib or pomalidomide showed a significant further decrease of CD4+-T-cells. All novel agents led to a significant decrease of B-cell counts. Overall, infections were frequent with 21.3% of patients requiring antibacterial therapy within the first 3 months of relapse therapy, 5.6% requiring hospitalization. However, in the setting of standard antimicrobial prophylaxis in RRMM patients with very low CD4+-T-cells, no significant association of CD4+T-cell count and an increased risk of infection could be detected. Discussion: Our findings imply that reduced CD4+-T-cell numbers and infections are common in patients with RRMM. We also demonstrate an association with the number of previous therapies and certain substances suggesting an increased need for personalized prophylaxis strategies for opportunistic infections in this patient cohort.

Characterizing the role of the immune microenvironment in multiple myeloma progression at a single-cell level.

Early alterations within the bone marrow microenvironment that contribute to the progression of multiple myeloma (MM) from its precursor stages could be the key to identifying novel therapeutic approaches. However, the intrinsic variability in cellular populations between patients and the differences in sample processing and analysis methods have made it difficult to identify consistent changes between data sets. Here, we used single-cell RNA sequencing of bone marrow cells from precursor stages, monoclonal gammopathy of unknown significance, smoldering MM, and newly diagnosed MM and analyzed our data in combination with a previously published data set that used a similar patient population and sample processing. Despite the vast interpatient heterogeneity, some alterations were consistently observed in both data sets. We identified changes in immune cell populations as the disease progressed, which were characterized by a substantial decrease in memory and naïve CD4 T cells, and an increase in CD8+ effector T cells and T-regulatory cells. These alterations were further accompanied by an enrichment of nonclonal memory B cells and an increase in CD14 and CD16 monocytes in MM compared with its precursor stages. These results provide crucial information on the immune changes associated with the progression to clinical MM and can help to develop immune-based strategies for patient stratification and early therapeutic intervention.

Proceedings from the Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup Workshop on Immune and Cellular Therapy in Multiple Myeloma.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup conducted a workshop on Immune and Cellular Therapy in Multiple Myeloma on January 7, 2022. This workshop included presentations by basic, translational, and clinical researchers with expertise in plasma cell dyscrasias. Four main topics were discussed: platforms for myeloma disease evaluation, insights into pathophysiology, therapeutic target and resistance mechanisms, and cellular therapy for multiple myeloma. Here we provide a comprehensive summary of these workshop presentations.

Midkine Promotes Metastasis and Therapeutic Resistance via mTOR/RPS6 in Uveal Melanoma.

Uveal melanoma is a rare form of melanoma that originates in the eye, exerts widespread therapeutic resistance, and displays an inherent propensity for hepatic metastases. Because metastatic disease is characterized by poor survival, there is an unmet clinical need to identify new therapeutic targets in uveal melanoma. Here, we show that the pleiotropic cytokine midkine is expressed in uveal melanoma. Midkine expression in primary uveal melanoma significantly correlates with poor survival and is elevated in patients that develop metastatic disease. Monosomy 3 and histopathologic staging parameters are associated with midkine expression. In addition, we demonstrate that midkine promotes survival, migration across a barrier of hepatic sinusoid endothelial cells and resistance to AKT/mTOR inhibition. Furthermore, midkine is secreted and mediates mTOR activation by maintaining phosphorylation of the mTOR target RPS6 in uveal melanoma cells. Therefore, midkine is identified as a uveal melanoma cell survival factor that drives metastasis and therapeutic resistance, and could be exploited as a biomarker as well as a new therapeutic target. IMPLICATIONS: Midkine is identified as a survival factor that drives liver metastasis and therapeutic resistance in melanoma of the eye.

Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single-cell transcriptomics.

Virtually all patients with multiple myeloma become unresponsive to treatment over time. Relapsed/refractory multiple myeloma (RRMM) is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations and profound changes of the bone marrow microenvironment (BME). However, the molecular mechanisms that drive drug resistance remain elusive. Here, we analyze the heterogeneous tumor cell population and its complex interaction network with the BME of 20 RRMM patients by single cell RNA-sequencing before/after treatment. Subclones with chromosome 1q-gain express a specific transcriptomic signature and frequently expand during treatment. Furthermore, RRMM cells shape an immune suppressive BME by upregulation of inflammatory cytokines and close interaction with the myeloid compartment. It is characterized by the accumulation of PD1+ γδ T-cells and tumor-associated macrophages as well as the depletion of hematopoietic progenitors. Thus, our study resolves transcriptional features of subclones in RRMM and mechanisms of microenvironmental reprogramming with implications for clinical decision-making.

Pathway-Directed Therapy in Multiple Myeloma.

Multiple Myeloma (MM) is a malignant plasma cell disorder with an unmet medical need, in particular for relapsed and refractory patients. Molecules within deregulated signaling pathways, including the RAS/RAF/MEK/ERK, but also the PI3K/AKT-pathway belong to the most promising evolving therapeutic targets. Rationally derived compounds hold great therapeutic promise to target tumor-specific abnormalities rather than general MM-associated vulnerabilities. This paradigm is probably best depicted by targeting mutated BRAF: while well-tolerated, remarkable responses have been achieved in selected patients by inhibition of BRAFV600E alone or in combination with MEK. Targeting of AKT has also shown promising results in a subset of patients as monotherapy or to resensitize MM-cells to conventional treatment. Approaches to target transcription factors, convergence points of signaling cascades such as p53 or c-MYC, are emerging as yet another exciting strategy for pathway-directed therapy. Informed by our increasing knowledge on the impact of signaling pathways in MM pathophysiology, rationally derived Precision-Medicine trials are ongoing. Their results are likely to once more fundamentally change treatment strategies in MM.

[Current Recommendations for the First-Line Therapy of Symptomatic Multiple Myeloma]. / Erstlinientherapie des behandlungsbedürftigen Multiplen Myeloms ­ Aktuelle Empfehlungen.

Due to the introduction of novel therapeutic agents, the prognosis of Multiple Myeloma has greatly improved over the last decades. The current standard for fit patients is a bortezomib-based induction therapy, followed by high-dose chemotherapy and autologous stem cell transplantation and lenalidomide-based maintenance therapy. For older, non-transplant-eligible patients, daratumumab in combination with bortezomib or lenalidomide offers a well-tolerated, effective treatment option. Despite large improvements, there is still no cure for most myeloma patients, the aim of therapy is therefore to reach a deep remission to prevent lasting damage followed by a continuous maintenance therapy to uphold the remission and prolong overall survival.

Evaluation of Pd→B Interactions in Diphosphinoborane Complexes and Impact on Inner-Sphere Reductive Elimination.

The dative Pd→B interaction in a series of R DPBR' Pd0 and PdII complexes (R DPBR' =(o-PR2 C6 H4 )2 BR', diphosphinoborane) was analyzed using XRD, 11 B NMR spectroscopy and NBO/NLMO calculations. The borane acceptor discriminates between the oxidation state PdII and Pd0 , stabilizing the latter. Reaction of lithium amides with [(R DPBR' )PdII (4-NO2 C6 H4 )I] chemoselectively yields the C-N coupling product. DFT modelling indicates no significant impact of PdII →B coordination on the inner-sphere reductive elimination rate.

Synthesis and structures of gallaarsenes LGaAsGa(X)L featuring a Ga-As double bond.

Three equivalents of LGa {L = HC[C(Me)N(2,6-i-Pr2C6H3)]2} react with AsX3 (X = Cl, Br) by insertion into two As-X bonds, followed by the elimination of LGaX2 and formation of LGaAsGa(Cl)L (1) and LGaAsGa(Br)L (2). According to single crystal X-ray analysis, 1 and 2 each exhibit one Ga-As single bond and one Ga-As double bond. The π-bonding contribution (9.71 kcal mol-11 and 9.44 kcal mol-12) was proved by variable temperature (VT) 1H NMR spectroscopy, while the electronic structure of 1' was studied by quantum chemical calculations.

Comprehensive Study on Reactions of Group 13 Diyls with Tetraorganodipentelanes.

L1Ga {L1 = HC[C(Me)N(2,6- iPr2C6H3)]2} reversibly reacts with E2Ph4 (E = Sb, Bi) in a temperature-dependent equilibrium reaction with insertion into the E-E bond and formation of L1Ga(EPh2)2 (E = Sb 1, Bi 2). Analogous findings were observed in the reactions of L2Ga {L2 = (C6H11)2NC[N(2,6- iPr2C6H3)]2} with E2R4 (R = Ph, Et), yielding L2Ga(EPh2)2 (E = Sb 3, Bi 4) and L2Ga(EEt2)2 (E = Sb 5, Bi 6). 1-3 and 5 were isolated by fractional crystallization at low temperature, whereas 4 and 6 could not be isolated in their pure form even at low temperature. In contrast, reactions of [Cp*Al]4 (Cp* = C5Me5) with Sb2R4 (R = Ph, Et) and Bi2Et4 did not proceed with insertion into the E-E bonds but with formation of (Cp*Al)3E2 (E = Sb, 7; Bi, 8), whereas the reaction with Bi2Ph4 yielded metallic bismuth. 8 was also formed in the reaction of [Cp*Al]4 and BiEt3 at ambient temperature, whereas the analogous reaction of [Cp*Al]4 with SbEt3 did not yield 7 even under drastic reaction conditions (120 °C, 3 days). In contrast, Cp*Ga and Sb2R4 (R = Ph, Et) were found to react only at elevated temperature (120 °C) with formation of antimony metal.