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•Venetoclax resistance involves reduced mitochondrial priming and changes in BCL-2 family protein expression.•Venetoclax-resistant cells retain sensitivity to immunotherapeutic treatments.

Growing evidence suggests that gain or amplification [gain/amp(1q)] accumulates during disease progression of multiple myeloma (MM). Previous investigations have indicated that small gain/amp(1q) subclones present at the time of diagnosis may evolve into dominant clones upon MM relapse. However, the influence of a minor clone of gain/amp(1q) on MM survival, as well as the correlation between different clonal sizes of gain/amp(1q) and the chromosomal instability (CIN) of MM, remains poorly understood. In this study, we analyzed fluorescence in situ hybridization (FISH) results of 998 newly diagnosed MM (NDMM) patients. 513 patients were detected with gain/amp(1q) at diagnosis. Among these 513 patients, 55 had a minor clone (≤20%) of gain/amp(1q). Patients with a minor clone of gain/amp(1q) displayed similar survival outcomes compared to those without gain/amp(1q). Further analysis demonstrated patients with a minor clone of gain/amp(1q) exhibited a clonal architecture similar to those without gain/amp(1q). Lastly, our results showed a significant increase in the clonal size of the minor clone of gain/amp(1q), frequently observed in MM. These findings suggested that a minor clone of gain/amp(1q) might represent an earlier stage in the pathogenesis of gain/amp(1q) and propose a “two-step” process in the clonal size changes of gain/amp(1q) in MM.

Residual normal plasma cells (NPCs), which compete with tumor plasma cells, play an important role in multiple myeloma. However, large-scale cohort studies investigating residual NPCs, especially at the minimal residual disease (MRD) phase, are currently lacking. In this study, we conducted a comprehensive investigation into the clinical significance of residual NPCs throughout the entire disease course in 1363 myeloma patients from the NICHE cohort (NCT04645199). Our results revealed that myeloma patients with high baseline NPCs ratio (≥5%) exhibited distinct indolent features, characterized by lower tumor burden, reduced frequencies of cytopenia, immunoparesis, and high-risk cytogenetics. Importantly, high residual NPCs ratio at diagnosis or relapse was independently associated with favorable survival. High absolute percentages of NPCs at undetectable MRD were related with superior clinical benefit and immune reconstitution. At MRD-positive phases, grouping based on NPCs ratio (<50%, 50–90%, ≥90%) demonstrated better risk stratification compared to residual tumor log levels. Based on the time-dependent NPCs ratio trend, we developed a dynamic MRD model that classifies patients into three groups with diverse longitudinal trends, leading to distinct prognoses. Collectively, residual NPCs serves not only as a valuable complementary biomarker for risk stratification but also provides valuable insights on reclassifications and kinetics of MRD.

Single-cell analysis is of significant importance in delineating the exact phylogeny of the subclonal population and in discovering subtle diversification. So far, studies of intratumor heterogeneity and clonal evolution in multiple myeloma (MM) were largely focused on the bulk tumor population level. We performed quantitative multigene fluorescence in situ hybridization (QM-FISH) in 129 longitudinal samples of 57 MM patients. All the patients had newly diagnosed and relapsed paired samples. An expanded cohort of 188 MM patients underwent conventional FISH (cFISH) to validate the cytogenetic evolution in bulk tumor level. Forty-three of 57 patients (75.4%) harbored 3 or 4 cytogenetic clones at diagnosis. We delineated the phylogeny of the subclonal tumor population and derived the evolutionary architecture in each patient. Patients with clonal stabilization had a significantly improved overall survival (OS) than those with other evolutionary patterns (median OS, 71.2 months vs 39.7 months vs 35.2 months vs 25.5 months, for stable, differential, branching, and linear patterns, respectively; P = .001). A high degree of consistency and complementarity across QM-FISH and cFISH was observed in the evaluation of cytogenetic evolution patterns in MM. Survival after relapse was greater influenced by the presence of high-risk aberrations at relapse (hazard ratio = 2.07) rather than present at diagnosis (hazard ratio = 1.55). This study shows that QM-FISH is a valuable tool to elucidate the clonal architecture at the single-cell level. Clonal evolution pattern is of prognostic significance, highlighting the need for repeated cytogenetic evaluation in relapsed MM.

Single-cell analysis is of significant importance in delineating the exact phylogeny of the subclonal population and in discovering subtle diversification. So far, studies of intratumor heterogeneity and clonal evolution in multiple myeloma (MM) were largely focused on the bulk tumor population level. We performed quantitative multigene fluorescence in situ hybridization (QM-FISH) in 129 longitudinal samples of 57 MM patients. All the patients had newly diagnosed and relapsed paired samples. An expanded cohort of 188 MM patients underwent conventional FISH (cFISH) to validate the cytogenetic evolution in bulk tumor level. Forty-three of 57 patients (75.4%) harbored 3 or 4 cytogenetic clones at diagnosis. We delineated the phylogeny of the subclonal tumor population and derived the evolutionary architecture in each patient. Patients with clonal stabilization had a significantly improved overall survival (OS) than those with other evolutionary patterns (median OS, 71.2 months vs 39.7 months vs 35.2 months vs 25.5 months, for stable, differential, branching, and linear patterns, respectively; P= .001). A high degree of consistency and complementarity across QM-FISH and cFISH was observed in the evaluation of cytogenetic evolution patterns in MM. Survival after relapse was greater influenced by the presence of high-risk aberrations at relapse (hazard ratio = 2.07) rather than present at diagnosis (hazard ratio = 1.55). This study shows that QM-FISH is a valuable tool to elucidate the clonal architecture at the single-cell level. Clonal evolution pattern is of prognostic significance, highlighting the need for repeated cytogenetic evaluation in relapsed MM.

In order to systematically study the effects of electrodeposition parameters on the surface morphology, microstructure, mechanical properties, and abrasion resistance of metal matrix nanocoatings, pulse electrodeposited Ni-TiN nanocoatings were prepared; tests including scanning electron microscope (SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), X-ray diffraction (XRD), and friction wear testing machine were performed. The results indicate that the Ni-TiN nanocoatings produced at 4 A/dm2showed excellent micro-hardness value as high as 984.6 HV and at a TiN content of 8.65 wt%. The Ni-TiN nanocoatings fabricated at different pulse frequencies showed a (fcc) structure in different orientations. The average size of the Ni and TiN particles contained in the Ni-TiN nanocoatings manufactured at a 200 Hz pulse frequency was 87.1 ± 0.2 nm and 34.4 ± 0.2 nm, respectively. The micro-hardness and average abrasion loss of Ni-TiN nanocoatings produced at a 20% pulse duty cycle were 984.1 HV and 8.78 mg/mm2, respectively. In addition, the Ni-TiN nanocoating deposited with G-1 parameters (current density of 4 A/dm2, pulse frequency of 800 Hz, and pulse duty cycle of 20%) showed an uniform, fine, and compact microstructure.

High protein load is a feature of multiple myeloma (MM), making the disease exquisitely sensitive to proteasome inhibitor (PIs). Despite the success of PIs in improving patient outcome, the majority of patients develop resistance leading to progressive disease; thus, the need to investigate the mechanisms driving the drug sensitivity vs resistance. With the well-recognized chaperone function of 14-3-3 proteins, we evaluated their role in affecting proteasome activity and sensitivity to PIs by correlating expression of individual 14-3-3 gene and their sensitivity to PIs (bortezomib and carfilzomib) across a large panel of MM cell lines. We observed a significant positive correlation between 14-3-3ε expression and PI response in addition to a role for 14-3-3ε in promoting translation initiation and protein synthesis in MM cells through binding and inhibition of the TSC1/TSC2 complex, as well as directly interacting with and promoting phosphorylation of mTORC1. 14-3-3ε depletion caused up to a 50% reduction in protein synthesis, including a decrease in the intracellular abundance and secretion of the light chains in MM cells, whereas 14-3-3ε overexpression or addback in knockout cells resulted in a marked upregulation of protein synthesis and protein load. Importantly, the correlation among 14-3-3ε expression, PI sensitivity, and protein load was observed in primary MM cells from 2 independent data sets, and its lower expression was associated with poor outcome in patients with MM receiving a bortezomib-based therapy. Altogether, these observations suggest that 14-3-3ε is a predictor of clinical outcome and may serve as a potential target to modulate PI sensitivity in MM.

High protein load is a feature of multiple myeloma (MM), making the disease exquisitely sensitive to proteasome inhibitor (PIs). Despite the success of PIs in improving patient outcome, the majority of patients develop resistance leading to progressive disease; thus, the need to investigate the mechanisms driving the drug sensitivity vs resistance. With the well-recognized chaperone function of 14-3-3 proteins, we evaluated their role in affecting proteasome activity and sensitivity to PIs by correlating expression of individual 14-3-3 gene and their sensitivity to PIs (bortezomib and carfilzomib) across a large panel of MM cell lines. We observed a significant positive correlation between 14-3-3ε expression and PI response in addition to a role for 14-3-3ε in promoting translation initiation and protein synthesis in MM cells through binding and inhibition of the TSC1/TSC2 complex, as well as directly interacting with and promoting phosphorylation of mTORC1. 14-3-3ε depletion caused up to a 50% reduction in protein synthesis, including a decrease in the intracellular abundance and secretion of the light chains in MM cells, whereas 14-3-3ε overexpression or addback in knockout cells resulted in a marked upregulation of protein synthesis and protein load. Importantly, the correlation among 14-3-3ε expression, PI sensitivity, and protein load was observed in primary MM cells from 2 independent data sets, and its lower expression was associated with poor outcome in patients with MM receiving a bortezomib-based therapy. Altogether, these observations suggest that 14-3-3ε is a predictor of clinical outcome and may serve as a potential target to modulate PI sensitivity in MM.

Recent attempts have focused on identifying fewer magnitude of minimal residual disease (MRD) rather than exploring the biological and genetic features of the residual plasma cells (PCs). Here, a cohort of 193 patients with at least one cytogenetic abnormalities (CA) at diagnosis were analyzed, and interphase fluorescence in situ hybridization (iFISH) analyses were performed in patient-paired diagnostic and posttherapy samples. Persistent CA in residual PCs were observed for the majority of patients (63%), even detectable in 28/63 (44%) patients with MRD negativity (<10–4). The absence of CA in residual PCs was associated with prolonged survival regardless of MRD status. According to the change of the clonal size of specific CA, patients were clustered into five groups, reflecting different patterns of clone selection under therapy pressure. Therapy-induced clonal selection exerted a significant impact on survival (HR = 4.0; P< 0.001). According to the longitudinal cytogenetic studies at relapse, sequential cytogenetic dynamics were observed in most patients, and cytogenetic architecture of residual PCs could to some extent predict the evolutional pattern at relapse. Collectively, the repeat cytogenetic evaluation in residual PCs could not only serves as a good complementary tool for MRD detection, but also provides a better understanding of clinical response and clonal evolution.

Introduction

Background:The median overall survival (OS) in multiple myeloma (MM) is rapidly approaching 10 years. However, the prognosis of ultra-high risk MM (UHR-MM) remains very poor, the median overall survival (OS) is no more than 3 years. There is no consensus to define this population till now. Several prognostic factors with significant impact on survival have been discovered over time, with cytogenetic factors as the most potent. Nevertheless, there is little study to investigate the features of these UHR-MM, especially in Asian UHR-MM patients.

Background:Achieving undetectable minimal residual disease (MRD) has been considered a functional cure in multiple myeloma (MM), emphasizing the clinical importance of depth and duration of remission. Interestingly, a subset of myeloma patients presents with an MGUS-like status, characterized by persistent M-component or detectable MRD despite systematic treatment. Surprisingly, these patients exhibit an indolent disease course and experience unexpectedly long survival (PFS ≥ 5 years). Nevertheless, the specific genomic characteristics of their tumor cells, immune microenvironment, and clonal evolution patterns are still inadequately explored.

Introduction In multiple myeloma (MM), the leading cause of disease progression, exhibits intratumoral heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Previous studies have confirmed that clonal evolution frequently occurs at disease follow-up, and the patterns of clonal evolution between diagnosis and relapse correlates with patient outcomes. However, it remains unclear whether clonal evolution occurs as early as after induction therapy. Additionally, the mechanisms of malignant plasma cells (PCs) resistance after induction therapy have only been partly resolved. Here, we use single-cell RNA sequencing (scRNA-seq) to identify the clonal architecture at diagnosis and after induction therapy, and elucidate the resistance pathways occurs early after upfront therapy. Methods In this study, we analyzed single-cell RNA sequencing from 19 patients with newly diagnosed MM (NDMM), paired bone marrow (BM) samples after 2-4 cycles of proteasome inhibitor (PI) plus immunomodulatory drugs (IMiDS)-based induction therapy were collected and underwent scRNA-seq. By tracing transcriptional and cytogenetic PCs clones over time and performing differential expression analysis, we defined different patterns of clonal evolution and identified potential resistant pathways. Results In our cohort, 12 patients were identified with more than 30 PCs in the BM samples sequenced after induction therapy. Among them, our analysis of the transcriptional and cytogenetic clonal dynamics in MM patients identified three main trajectories: patients with sensitive PC clones or clone that responds to treatment with >90% of the malignant PCs replaced with seemingly health PCs (3/12 patients, 25%); in patients with a resistant clone that did not respond or only very partly responded to treatment, > 50% of the malignant PCs were found in the BM post-treatment (5/12 patients, 42%); and patients with clonal selection, indicating that the significant clone has been replaced by a small or undetectable clone at baseline (4/12 patients, 33%). For these four patients identified with clonal selection, one was observed with branching evolution, and the other three were observed with differential evolution. Transcriptional differences among sensitive clones, resistant clones, and selective clones were detected based on a pairwise comparison of the gene expressions. A large number of differentially expressed genes with reported MM resistant-related functions were observed in the resistant clones, including previously reported 1q-related genes such as CKS1B, HNRNPU, and H3F3A; cell cycle- and cell proliferation-related genes such as TUBA1B, STMN1, and HMGB2. For selective clones, an evident activation of the NF-kB signaling pathway was observed. Conclusions Together, our study confirms that clonal dynamics of the evolving PC clones may occur early after upfront therapy, and reveals that the acquisition of therapeutic resistant pathways is associated with early adaptation to treatment.

Background:

Venetoclax represents the first example of personalized medicine in multiple myeloma (MM), as it has meaningful clinical activity in patients harboring the t(11;14) translocation. This subgroup of patients generally displays upregulated BCL-2 expression and/or a higher BCL-2/BCL-X Lratio, reflecting an imbalance between cell survival (promoted by BCL-2) and cell death (promoted by BCL-X L). The Bellini study demonstrated significantly superior response rate and progression-free survival (PFS) with combination of Venetoclax and Bortezomib in relapsed myeloma, however, the overall survival in the arm with venetoclax was inferior. Part of the decrease in overall survival (OS) was considered to be related with increased incidence of infections, however, OS is also significantly impacted by response to subsequent therapies. Here, we investigated whether acquired venetoclax resistance could lead to global resistance to multiple subsequent anti-MM therapies and in turn can explain the decreased OS.

Rapid remission by induction therapy has long been recognized as an important predictor for long-time survival in acute leukemia. However, the impact of response kinetics on multiple myeloma (MM) seems to be different and remains unexplored. The relationship between response kinetics and outcome were assessed in 626 patients with newly diagnosed MM who were included in a prospective, nonrandomized clinical trial (BDH 2008/02). Patients were assigned to either immunomodulatory drug- or proteasome inhibitor–based therapy. The response depth, time to best response (TBR) and duration of best response (DBR) were collected. Depth of response was associated with superior outcomes, consistent with findings from other studies. However, the early responders (defined as TBR ≤3 months) showed significantly worse survival compared with late responders. We found that patients with rapid complete remission experienced inferior survivals comparable to those attaining a gradual partial remission. Moreover, 4 distinct response kinetics patterns were identified. Patients with gradual and sustained remission (“U-valley” pattern) experienced superior outcomes, whereas poor outcomes were observed in rapid and transient responders (“roller coaster” pattern) (median overall survival, 126 vs 30 months). The effects of response patterns on survival were confirmed in patients at different stages of disease and cytogenetic risk, including transplant-eligible patients and those attaining different extents of response depth. Collectively, our data indicated that slow and gradual response is a favorable prognostic factor in MM. In addition to response depth, the kinetic pattern of response is a simple and powerful predictor for survival even in the era of novel agents.

Rapid remission by induction therapy has long been recognized as an important predictor for long-time survival in acute leukemia. However, the impact of response kinetics on multiple myeloma (MM) seems to be different and remains unexplored. The relationship between response kinetics and outcome were assessed in 626 patients with newly diagnosed MM who were included in a prospective, nonrandomized clinical trial (BDH 2008/02). Patients were assigned to either immunomodulatory drug- or proteasome inhibitor–based therapy. The response depth, time to best response (TBR) and duration of best response (DBR) were collected. Depth of response was associated with superior outcomes, consistent with findings from other studies. However, the early responders (defined as TBR≤3 months) showed significantly worse survival compared with late responders. We found that patients with rapid complete remission experienced inferior survivals comparable to those attaining a gradual partial remission. Moreover, 4 distinct response kinetics patterns were identified. Patients with gradual and sustained remission (“U-valley” pattern) experienced superior outcomes, whereas poor outcomes were observed in rapid and transient responders (“roller coaster” pattern) (median overall survival, 126 vs 30 months). The effects of response patterns on survival were confirmed in patients at different stages of disease and cytogenetic risk, including transplant-eligible patients and those attaining different extents of response depth. Collectively, our data indicated that slow and gradual response is a favorable prognostic factor in MM. In addition to response depth, the kinetic pattern of response is a simple and powerful predictor for survival even in the era of novel agents.

Purpose:Most data on the prognostic impact of cytogenetic abnormalities come from the setting of newly diagnosed multiple myeloma, it remains unclear whether the dynamic changes of cytogenetic aberrations affect the prognostic evaluation in multiple myeloma.

Anderson: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

No relevant conflicts of interest to declare.

Background: Age is a pivotal prognostic factor for multiple myeloma (MM). The risk of evolving from MGUS and SMM to symptomatic MM steadily increases with age. And there are nuances in clinical manifestations and cytogenetic characteristics between young and old patients. The aim of this study is to delineate the clinical and laboratory features and determine the relative contribution of ISS, performance status and cytogenetic abnormalities in each age MM patients.

Background: Current definition of multi-hit multiple myeloma (MM) is based upon the number of high-risk cytogenetic abnormalities (CA). But we may overlook the influence of standard-risk CA and different concurrent patterns. In fact, standard-risk t(11;14) and del(13q) may bring extra danger when concurrent with other CA. And the concurrency of two secondary CA may do more harm to patients than that of one secondary CA with one primary CA. This study is to answer whether CA number or pattern exert an impact on outcomes of MM patients.

IntroductionsAlthough intratumor heterogeneity and clonal evolution have been inferred in multiple myeloma (MM), this was largely focused at the bulk tumor population level. Single-cell analysis is of significant importance in delineating the exact phylogeny of subclonal population and in discovering subtle diversification. Here, we identified the clonal architecture of different time points using multi-gene fluorescence in situ hybridization (mFISH) at single cell level, and explored the prognostic values of different clonal evolution patterns in MM.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Objective: To investigate the safety and efficacy of high-dose infusional gemcitabine combined with busulfan and cyclophosphamide (GBC) or melphalan (GBM) followed by autologous stem-cell transplantation (ASCT) in lymphoid malignancies.

Background and Objective:Multiple myeloma (MM) is characterized with significant cytogenetic changes and complex tumor microenvironment, thus patient survival is extremely heterogeneous. Various disease-related or patient-related factors affect the prognosis of patients. This study tried to analyze the prognostic indicators of patients with newly-treated MM, especially explored the prognosis of multiple cytogenetic abnormalities and the ratio of lymphocytes to monocytes (LMR). Additionally, we established a comprehensive prognostic model to help determine the patient prognosis.

Single-cell analysis is of significant importance in delineate the exact phylogeny of subclonal population and in discovering subtle diversification. So far studies of intratumor heterogeneity and clonal evolution in multiple myeloma (MM) were largely focused at the bulk tumor population level.

Real-world retrospective study of 46 patients with Macrofocal multiple myeloma (MFMM)

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

In this paper an adaptive control is designed for deterministic systems on the basis of the projection algorithm so that the quadratic loss function approaches its minimum at a rate of n-ε, ε > 0 and the parameter estimate converges to its true value with a near exponential rate.

The optimum point of an unknown function which is measured with noise and the unknown parameters in the measurement noise are estimated by a combined algorithm. The almost sure convergence and the convergence rate are established for both unconstrained and constrained problems.

In this paper, a deterministic predictive technique is introduced, which is based on the embedding theorem by Takens and the recently developed wavelet networks. Several economic time series are tested by using this technique. As a result, the predicted values correspond quite well with the actual values. It shows that some economic time series are predictable by using a deterministic approach. Furthermore, the effects of using smoothing techniques (e.g., moving average) upon the prediction results are also investigated since there inevitably exists noise in almost all economic time series. Our numerical results show that smoothing like moving average can improve the prediction results for some of our tested time series, and for others predictions without smoothing are even better than with smoothing. This implies that wavelet network is capable of drawing the underlying dynamics directly from noisy economic time series.

No relevant conflicts of interest to declare.

IntroductionMultiple myeloma (MM) is a kind of hematological malignancy which is characterized by high genetic heterogeneity. It has been proved that the existence and even the coexistence of numerical and structural cytogenetic abnormalities (CAs) play a critical role in the development and progression of MM. Hyperdiploidy (HD), as one of the two primary CAs of MM, can be observed in around half of the patients and is considered as a favorable prognostic factor. Nevertheless, its role in overcoming the negative effect of concomitant high-risk CAs remains controversial. Although the outbreak of novel drugs by the last decades, such as proteasome inhibitors (PIs) and Immunomodulatory drugs (IMiDs), has significantly improved the survival of patients, MM is still incurable and can relapse recurrently. The prognostic impact of HD in the era of novel agents and its impact on other CAs are unclear and under to be explored. Here, we report our results based on the Chinese population to provide some evidence for the above questions.

Background:Anti-CD19 chimeric antigen receptor (CAR) T-cell is a promising therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma. 29~37% of patients can achieve sustained complete remission (CR) after anti-CD19 CAR T-cell infusion, which means that approximately two-thirds of patients will eventually progress and have extremely poor survival. We conducted a pilot study to explore the safety and efficacy of CNCT19 (a second-generation anti-CD19 CAR T-cell) cellular immunotherapy in conjunction with high-dose chemotherapy and autologous stem-cell transplantation (HDT/ASCT). The preliminary results of the first 6 patients had been reported at the 61stASH Meeting (Liu et al., 784a). Here we reported the updated enrollment, safety, efficacy, and follow-up of this study. This trial was registered at www.chictr.org.cn as ChiCTR1900025419.

Background:In multiple myeloma (MM), impact of specific chromosomal translocations involving IgH (14q21 locus, including t(4;14), t(11;14), and t(14;16) etc.) has been explored extensively. However, over 15% MM patients harboring IgH translocation with undefined partners have long been ignored.

Lv: Juventas Cell Therapy Ltd.: Current Employment.