Currently, there is limited understanding regarding the prognostic significance of time to progression (TTP) after first remission in multiple myeloma (MM).

We conducted a retrospective analysis of clinical data from 209 patients with MM. These patients were categorized into ≤ 6 months, ≤ 12 months, ≤ 24 months, > 24 months, 6-12 months, and 12-24 months subgroups based on TTP.

Patients in ≤ 12 months group exhibited shorter median overall survival (OS) and OS-1 compared to those in ≤ 24 months group (61.73 vs 96.10 months, P = 0.02; 54.00 vs 74.17 months, P = 0.048). ≤ 6 months group exhibited shorter median OS and OS-1 compared to 6-12 months group (33.63 vs 79.60 months, P = 0.022; 19.93 vs 65.17 months, P = 0.015). Patients in 6-12 months group had shorter median OS and OS-1 compared to those in 12-24 months group (79.60 vs 100.43 months, P < 0.001; 65.17 vs 77.17 months, P = 0.012).No significant difference in OS was observed between patients in 12-24 months and > 24 months groups. For patients who experienced progression within 12 or 24 months after remission, undergoing autologous hematopoietic stem cell transplantation (ASCT) after progression conferred a median OS and OS-2 advantage over receiving post-progression chemotherapy. Multivariable analysis confirmed that TTP was an independent predictor for OS in patients with MM.

Patients with MM who experience earlier disease progression within 12 months after remission have a worse prognosis, and post-progression ASCT can improve their survival outcomes.

Changes in metabolic activity in tumor cells is one of the hallmarks of cancer. Cancer cells exhibit the Warburg effect with high glucose consumption for their energy needs. This provides the basis for imaging using 18F-2-deoxy-D-glucose for positron emission tomography to assess tumor burden and response to therapy. We postulated that metabolically active tumors may compete with the brain for glucose uptake and evaluated glucose uptake in the brain and liver in patients with multiple myeloma in various states of response and relapse. The ratio of brain to liver glucose activity (B2LR) mirrors disease activity in myeloma, predicts the presence of extramedullary disease and is also predictive of a short response to chimeric antigen receptor T cell therapy. Patients with a low B2LR also have an inferior survival compared to patients with persistently higher B2LR values. Our simple metabolic ratio has prognostic implications in myeloma and other tumors.

Pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) increases the sensitivity of multiple myeloma (MM) cells to bortezomib by upregulating lysosome-associated membrane protein 2 (LAMP2), while their clinical role in MM patients is unclear. This study aimed to assess the intercorrelation between PHLPP and LAMP2, as well as their associations with treatment response and survival in MM patients who received induction treatment with bortezomib.

A total of 59 MM patients who received induction treatment with bortezomib were included. PHLPP and LAMP2 were detected by quantitative polymerase chain reaction in bone marrow plasma cells that were collected before treatment. Treatment response, progression-free survival (PFS), and overall survival (OS) were assessed.

PHLPP was positively correlated with LAMP2, whether they were considered as continuous variables (r = 0.469, P < 0.001) or categorized as high and low expressions (P = 0.003). PHLPP and LAMP2 were elevated in patients who achieved complete remission (CR) versus those who did not, as well as in patients who achieved partial remission (PR) and above versus those who had less than PR (all P < 0.05). By chi-square test, high PHLPP (cut by the median) was linked with the achievement of PR and above (P = 0.015), and high LAMP2 (cut by the median) was related to the achievement of CR (P = 0.030). High PHLPP (P = 0.016) and LAMP2 (P = 0.037) were associated with prolonged PFS, but not OS (both P > 0.05).

PHLPP is positively correlated with LAMP2, and their high expressions predict favorable treatment response and PFS in MM patients who receive induction treatment with bortezomib.

Background: Several thrombotic risk assessment models have been proposed for identifying patients with a high risk of thrombosis (the IMPEDE venous thromboembolism (VTE), SAVED, and PRISM scores) in multiple myeloma (MM). Recently, adding a biomarker (D-dimer) for the IMPEDE VTE score has shown that it can boost the detection power of IMPEDED VTE. However, data from studies comparing these models in MM are scarce. Even real-world data arguing the utility of thrombotic risk assessment models in MM from low- or middle-income countries like Türkiye are lacking. Methods: We aimed to show the possibility of detecting VTE using the IMPEDED VTE score in our cohort by retrospectively screening MM patients. Therefore, we aimed to compare the IMPEDE VTE, SAVED and IMPEDED VTE scoring models. Results: We conducted a retrospective analysis of 455 MM patients from three centers in Bursa, Türkiye, evaluating the incidence of VTE within six months of the treatment. The IMPEDED VTE score showed superior predictive accuracy (c-statistic of 0.701), compared to the IMPEDE VTE (0.618) and SAVED (0.633) scores, demonstrating the added value of D-dimer as a biomarker. The cumulative incidence of VTE in the cohort was 10.7%, comparable to rates observed in real-world studies. Conclusions: Despite the interventions and thrombotic risk assessment models, thrombosis remains a high-risk entity. Personalized risk assessment tools, such as IMPEDED VTE, could be used to manage thrombotic risk in MM patients, particularly in resource-limited settings. Albeit the thromboprophylaxis (51.6%), our findings support the utility of biomarker-enhanced models for better VTE-risk stratification, particularly in resource-limited settings.

Patients with multiple myeloma (MM) without high-risk cytogenetic abnormalities are classified as having standard-risk MM (SRMM), and data focusing on their outcomes after autologous hematopoietic stem cell transplantation (autoHCT) are limited. We sought to evaluate survival outcomes for patients with SRMM receiving autoHCT, and to elucidate factors that impact these outcomes. This was a single-center retrospective analysis that included consecutive MM patients who received upfront autoHCT between 2013 and 2021, had available cytogenetic information and had no high-risk chromosomal abnormalities on fluorescence in situ hybridization, defined as t(4;14), t(14;16), del(17p) or 1q21 gain or amplification. A total of 1000 SRMM patients were included, with a median age of 61 years (range 25 to 83), and 61% were male (n = 612). The most common induction regimens were bortezomib/lenalidomide/dexamethasone (VRD; n = 398, 40%) and carfilzomib/lenalidomide/dexamethasone (KRD; n = 212, 21%), and the majority (87%) received single-agent melphalan as conditioning. After induction and before autoHCT, 16% and 57% achieved ≥complete response (CR) and ≥very good partial response (VGPR), respectively. At day 100 post autoHCT, 37% and 77% achieved ≥CR and ≥VGPR, respectively. Sixty-two percent and 89% of patients achieved ≥ CR and ≥VGPR as best response post-transplant. A minimal residual disease (MRD) negative response pre- and post-transplantation was achieved in 43% (401/936) and 64% (199/311) of patients, respectively. After a median follow-up of 42.1 months, the median progression-free survival (PFS) for the entire cohort was 68.3 months (95% CI 60.1 to 72.1), and the median overall survival (OS) was not reached (95% CI 102.3-not reached). The 5-year PFS and OS rates were 55% and 83%, respectively. In multivariable analysis, achieving MRD-negative CR prior to autoHCT (HR 0.65 [95% CI 0.44 to 0.97], P = .033) or as best response (0.52 [0.34 to 0.78], P = .002), and use of post-transplant maintenance (0.69 [0.52 to 0.93], P = .013) and lenalidomide-based combination maintenance (0.68 [0.48 to 0.96], P = .030) were associated with improved PFS, whereas use of an induction regimen other than KRD was associated with worse PFS (1.50 [1.04 to 2.17], P = .031). For OS, post-transplant maintenance (0.48 [0.32 to 0.70], P < .001) was associated with better survival in multivariable analysis, whereas R-ISS stage III, compared with stage I, (2.34 [1.01 to 5.43], P = .047) was associated with worse OS. Patients with SRMM who received upfront autoHCT had a median PFS of >5.5 years, and median OS was not reached. These results highlight the favorable outcomes with upfront autoHCT for patients with SRMM, serving as a benchmark for future therapeutic approaches in this subgroup of MM patients.

This review aims to address the subgroup of patients with newly diagnosed multiple myeloma (NDMM) who have high-risk multiple myeloma (HRMM) and continue to experience poor outcomes despite recent therapeutic advances. We will explore various clinical, biochemical, imaging, genetic, and dynamic features associated with high-risk status, along with the different risk stratification tools developed to identify HRMM patients.

Although numerous parameters for defining HRMM have been proposed, a universally accepted definition remains absent. Studies have shown diverse treatment responses and varying outcomes in HRMM patients, prompting the development of tailored therapeutic approaches. Emerging evidence supports the need for refined definitions and more targeted strategies to improve HRMM management. HRMM patients represent an unmet need in NDMM treatment, and a standardized definition for HRMM is crucial for advancing research and clinical care. This review discusses current and future treatment options, the necessity for a consistent HRMM definition, and the importance of clinical trials focused on this high-risk group to bridge existing treatment gaps.

In the MAIA study (median follow-up, 56.2 months), daratumumab plus lenalidomide and dexamethasone (D-Rd) significantly improved progression-free survival (PFS) and overall survival versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible newly diagnosed multiple myeloma (NDMM). In this post hoc analysis of clinically important subgroups in MAIA (median follow-up, 64.5 months), transplant-ineligible patients with NDMM were randomized 1:1 to D-Rd or Rd. The primary endpoint was PFS; secondary endpoints included overall response rate (ORR) and measurable residual disease (MRD)-negativity rate (10-5). PFS favored D-Rd versus Rd in most subgroups, including patients aged ≥75 years (HR, 0.59; 95% CI, 0.44-0.79), frail patients (HR, 0.64; 95% CI, 0.48-0.85), patients with high-risk cytogenetics (HR, 0.59; 95% CI, 0.44-0.80), and patients with isolated gain(1q21) (HR, 0.36; 95% CI, 0.19-0.67). ORRs, MRD-negativity rates, and sustained (≥12 months) MRD-negativity rates were higher with D-Rd versus Rd across subgroups. In patients aged ≥75 years, rates of grade 3/4 and serious treatment-emergent adverse events (TEAEs) were similar for D-Rd and Rd, but discontinuation due to TEAEs was lower for D-Rd. Results support use of D-Rd for high-risk patients, supporting D-Rd as a standard of care for transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as NCT02252172.

1q gain/amplification (1q+) is the most common cytogenetic abnormality (CA), with a frequency of 30-50% in patients with newly diagnosed multiple myeloma (NDMM). Although accumulating evidence supports 1q+ as a "high-risk" CA (HRCA), several issues remain to be addressed to understand its true prognostic property. We retrospectively analyzed a cohort of 934 patients with NDMM from three centers in China, who had baseline data available for 1q+ [including 1q21 gain (3 copies) and amplification (> 3 copies)] detected by fluorescence in situ hybridization in isolated CD138+ cells, and who received first-line treatment with novel agents including proteasome inhibitors, immunomodulatory drugs, or both. Minimal residue disease (MRD) was assessed using next-generation flow cytometry. In this cohort, 1q+ patients accounted for 53% of all patients. 1q+ patients were characterized by larger tumor burden, more advanced diseases, adverse complications, and frequent concurrence of other CAs (particularly HRCAs) at diagnosis. Concurrence of HRCAs [del(17p), t(4;14), and t(14;16); known as double-hit MM], but not standard-risk CA, markedly worsened the outcome of 1q+ patients, compared to those with 1q+ only (progression-free survival/PFS: hazard ratio/HR 1.63, 95% confidence interval/CI 1.21-2.20, P = 0.0013; overall survival/OS: HR 1.96, 95% CI 1.40-2.74, P < 0.0001). 1q+ modulated the risk levels defined by the Revised International Staging System (R-ISS). Although the overall response rate was not significantly different between patients with or without 1q+, fewer 1q+ patients achieved complete response or better and minimal residue disease negativity (MRD-). MRD- attainment substantially prolonged PFS (HR 4.03, 95% CI 2.59-6.29, P < 0.0001) and OS (HR 3.72, 95% CI 2.24-6.19, P < 0.0001) of 1q+ patients. While 1q+ patients had relatively shorter MRD- duration, sustained MRD- significantly improved the PFS and OS of 1q+ patients. Together, 1q+ is an HRCA and a major component of double-hit MM, while the risk-adapted and MRD-tailored therapy may best help manage this high-risk population.

Multiple myeloma (MM) is a malignancy where drug resistance often leads to relapse or refractory disease. Chemokine receptor 5 (CCR5) has emerged as a novel therapeutic target. However, the role of CCR5-antagonist Maraviroc (MVC) in M2 macrophage polarization and its potential to enhance Bortezomib sensitivity in MM has not been fully explored.

We used human bone marrow samples, RPMI 8226 cells, and THP-1 monocytes to investigate CCL3/CCR5 axis. ELISA measured CCL3/CCR5 levels. Knockdown/overexpression vectors modulated expression. Cell proliferation, apoptosis, and macrophage polarization were assessed using CCK8, flow cytometry, and transwell assays. QRT-PCR analyzed CCL3 expression, and western blotting examined PI3K/AKT/RhoA signaling. CCR5 was targeted via siRNAs or MVC. NOD/SCID mouse model evaluated CCL3/CCR5 effects on macrophage polarization and MVC's impact on Bortezomib efficacy.

CCL3, CCR5, and M2 macrophage markers are upregulated in MM patients, with CCL3/CCR5 expression correlating with M2 macrophage polarization. Myeloma-secreted CCL3 and paracrine CCR5 significantly promoted M2 macrophage polarization by activating PI3K/AKT/RhoA signaling, which in turn enhanced myeloma proliferation, inhibited apoptosis, and reduced Bortezomib sensitivity. MVC inhibited M2 macrophage polarization and improved Bortezomib sensitivity in vitro and xenograft mouse myeloma models.

MVC reduced macrophage polarization and enhanced Bortezomib sensitivity in MM cells.

t(11;14) is considered a standard risk factor in multiple myeloma (MM). However, recent studies suggested that its impact in the context of novel agents remained controversial.

This retrospective analysis examined the clinical profiles of 375 newly diagnosed patients with MM and compared the outcomes between those with t(11;14) and those with normal cytogenetics.

The median progression-free survival (PFS) of the 84 patients with t(11;14) was 36 months (95% confidence interval (CI), 23.5-48.5), which was significantly shorter than the median PFS of 65 months (95% CI, 23.0-107.0) for the 59 patients with normal cytogenetics (p = 0.011). Median overall survival (OS) was not reached in either group (p = 0.977). When combined with 1q21 + , t(11;14) showed a trend toward poorer PFS (median PFS: 36 vs. 65 months; p = 0.130). In the presence of high-risk cytogenetics (HRCAs), t(11;14) was associated with a worse PFS (median PFS: 9 vs. 38 months, p = 0.015) and a trend toward shorter OS (median OS: 33 vs. 49 months, p = 0.096). Multivariate analysis indicated that t(11;14) was a poor prognostic factor for PFS. 1q21 + was a detrimental prognostic factor, particularly in the t(11;14) group. Autologous stem cell transplantation (ASCT) may be a beneficial treatment option for patients with t(11;14).

In this study, patients with MM with t(11;14) demonstrated poorer PFS than those with normal cytogenetics. Further investigations are required to evaluate the impact of t(11;14) in patients newly diagnosed with MM in the era of novel agents.

Osteolytic lesions and pathological fractures are hallmark manifestations of multiple myeloma (MM), profoundly influencing the quality of life and self-care ability of MM patients. By analyzing transcriptome data and single-cell RNA-seq data from our center and the GEO database, a subset of MM cells with high expression levels of chemokine CXCL7 was identified. This subset of MM cells possesses a high capacity for proliferation and activation of osteoclast signaling pathway. CXCL7 might be a crucial regulator of osteolytic damage in MM. Subsequently, the association between the expression level of CXCL7 and pathological fractures in patients was investigated, and the impact of CXCL7 on MM proliferation was confirmed both in vivo and in vitro. A mouse xenograft tumor model was established through intravenous injection of myeloma cell lines based on the homing ability of plasma cells. Moreover, the mechanism by which CXCL7 promotes the activation of osteoclast signaling pathways in MM was explored. Our findings reveal that elevated CXCL7 levels significantly enhance MM cell proliferation, increasing the risk of pathological fractures in MM patients. Additionally, our mouse xenograft tumor model demonstrated that CXCL7 can induce femoral fractures and reduce bone mineral density. Concurrently, it was discovered that CXCL7 could activate the JAK/STAT3 pathway via CXCR2 and upregulate the expression levels of MMP13 and C-myc, facilitating MM cell proliferation and activation of the osteoclast signaling pathway. Our study offers novel insights into the pathogenic mechanism of osteolytic lesions and implies that targeting CXCL7 may present a new therapeutic avenue for MM.

Chromosome 1q copy number variations, collectively termed +1q, are 1 of the most common cytogenetic abnormalities in multiple myeloma. 1q abnormalities are associated with overexpression of a high-risk gene signature promoting cell proliferation, apoptosis resistance, genomic instability, and treatment resistance, and acquisition or expansion of +1q subclones mediate disease development and relapse. While there remains significant controversy as to whether the presence of +1q is itself an independent driver of poor prognosis or is simply a marker of other high-risk features, +1q has recently been incorporated into multiple prognostic scoring models as a new high-risk cytogenetic abnormality. In this review, we present possible underlying genetic mechanisms of high-risk disease in +1q myeloma, implications for subclonal development, its role in modifying the tumor microenvironment, current evidence for clinical significance in newly-diagnosed and relapsed patients, and current controversies in +1q classification and prognostication.

To develop a whole-body low-dose CT (WBLDCT) deep learning model and determine its accuracy in predicting the presence of cytogenetic abnormalities in multiple myeloma (MM).

WBLDCTs of MM patients performed within a year of diagnosis were included. Cytogenetic assessments of clonal plasma cells via fluorescent in situ hybridization (FISH) were used to risk-stratify patients as high-risk (HR) or standard-risk (SR). Presence of any of del(17p), t(14;16), t(4;14), and t(14;20) on FISH was defined as HR. The dataset was evenly divided into five groups (folds) at the individual patient level for model training. Mean and standard deviation (SD) of the area under the receiver operating curve (AUROC) across the folds were recorded.

One hundred fifty-one patients with MM were included in the study. The model performed best for t(4;14), mean (SD) AUROC of 0.874 (0.073). The lowest AUROC was observed for trisomies: AUROC of 0.717 (0.058). Two- and 5-year survival rates for HR cytogenetics were 87% and 71%, respectively, compared to 91% and 79% for SR cytogenetics. Survival predictions by the WBLDCT deep learning model revealed 2- and 5-year survival rates for patients with HR cytogenetics as 87% and 71%, respectively, compared to 92% and 81% for SR cytogenetics.

A deep learning model trained on WBLDCT scans predicted the presence of cytogenetic abnormalities used for risk stratification in MM. Assessment of the model's performance revealed good to excellent classification of the various cytogenetic abnormalities.

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1q21gain/amp is the most common in patients with multiple myeloma. However, there is limited research on the prognostic heterogeneity of 1q21+, and the prognostic of the 1q21 copy remains controversial. In this study, we primarily conducted a retrospective analysis of the prognostic significance of 1q21 gain/amp in 375 newly diagnosed multiple myeloma patients. 1q21 + was detected in 164 (43.7%) patients, including 103 (27.5%) with 3 copies and 61 (16.3%) with ≥ 4 copies. Patients with 1q21 + were more likely to be accompanied by anemia, hypercalcemia, t(4;14), and t(14;16). Compared with 1q21-, the progression-free survival (PFS) and overall survival (OS) of 1q21 + are shorter(p <0.0001; p = 0.036). The PFS of 1q21 amp was shorter than 1q21 gain (p = 0.0072). When accompanied by other high-risk abnormalities, 1q21 + was associated with earlier disease progression (all p<0.05). There were no significant differences in survival outcomes among patients with 1q21 gain alone, 1q21 amp alone, and FISH-. Autologous stem cell transplantation can prolong the survival of 1q21 + patients (p = 0.00062). A predictive scoring system based on 1q21 gain, 1q21 amp, del(17p), t(14;16), ISS II/III, and high LDH categorizes patients into three groups: low-risk (44.8%), intermediate-risk (38.9%), and high-risk (16.3%) (p < 0.0001; p < 0.0001). 1q21 + showed a relatively poor prognosis when coexisted with other high-risk cytogenetic abnormalities, especially 1q21 amp. The risk scoring system based on 1q21 copies is a potential risk stratification tool for multiple myeloma.

Despite tremendous advancements in multiple myeloma (MM) therapeutics, outcomes remain heterogeneous, heavily influenced by clinical and cytogenetic factors. Among these, deletion of the short arm of chromosome 17 (del(17p)) is a strong predictor of poor prognosis. The aim of this study was to evaluate real-world outcomes in patients with newly diagnosed MM (NDMM) with del(17p) undergoing upfront autologous hematopoietic stem cell transplantation (auto-HCT). We conducted a single-center retrospective analysis of patients with NDMM who underwent upfront auto-HCT at MD Anderson Cancer Center between 2008 and 2018. Primary endpoints were progression-free survival (PFS) and overall survival (OS), with secondary endpoints being hematological response and measurable residual disease (MRD) status postauto-HCT. MRD status in the bone marrow biopsy was evaluated using 8-color next-generation flow cytometry with a sensitivity of 1/10-5 cells. One hundred and fifteen patients were included (55% male). Median age at auto-HCT was 62 years (range 34 to 83). The median del(17p) clone size was 20%, with 51 (53%) patients having clone sizes >20% and 15 (15%) patients having clone sizes >55%. Additional high-risk cytogenetic abnormalities included t(4;14) in 15 (13%) patients, t(14;16) in 8 (7%) patients, and 1q21+ in 25 (22%) patients. After induction, 10% of patients achieved ≥ CR, and 50% achieved ≥ VGPR, with 25% having MRD-negative ≥ VGPR. Post-transplant, 42% achieved ≥ CR, and 83% achieved ≥ VGPR as best response, with 55% (48/87) having MRD-negative ≥ VGPR. With a median follow-up of 31.4 months (range 3.1 to 199.1), median PFS and OS for the entire cohort were 19.9 and 71.5 months, respectively, and 5-year OS was 53%. Concurrent del(17p) and t(4;14) were associated with significantly worse outcomes, with median PFS and OS of 11.5 and 22.4 months, respectively. In multivariable analysis (MVA), female sex was associated with worse PFS (HR [95% CI] 2.87 [1.75 to 4.72], P < .001), while MRD negative CR post-transplant (0.35 [0.18 to 0.68], P = .002) and maintenance therapy (0.46 [0.27 to 0.77], P = 0.003) were associated with better PFS. In MVA for OS, female sex (2.22 [1.18 to 4.17], P = 0.013) and the presence of t(4;14) (2.55 [1.09 to 5.95], P = 0.030) were associated with worse OS, whereas Karnofsky Performance Status of ≥90 (0.47 [0.23 to 0.94], P = 0.034) was associated with better OS. This study affirms del(17p) as a high-risk abnormality with unfavorable outcomes despite modern therapies. The co-occurrence of del(17p) and t(4;14) was associated with particularly poor outcomes. Novel approaches are needed for this high-risk subgroup.

Multiple myeloma (MM) is a heterogeneous disease, with MM patients experiencing different clinical outcomes depending on the disease's biological features. Novel insights into the molecular mechanisms of MM have led to the introduction of sophisticated drugs, which dramatically improved patient treatment and survival. To date, young patients with newly diagnosed MM could experience a median overall survival (OS) of 10 years. Nevertheless, a small proportion of patients still undergoes early disease progression and death. Indeed, cases defined as ultra-high-risk MM (uHRMM) and high-risk MM (HRMM) are destined for a worse outcome, with an OS of 2-3 and 3-5 years, respectively. In this regard, current risk stratification systems failed to identify this subset of patients better. The application of existing risk models has led to the identification of extremely heterogeneous categories of patients, and they have not taken into account biological and clinical differences. The concept of HRMM was initially formalised in 2015. Since then, a great effort has been made to identify those parameters whose presence pone MM patients at higher risk of developing an early relapse. The simultaneous presence of 2 or more unfavourable cytogenetic abnormalities, the identification of an extramedullary disease or the detection of circulating plasma cells, as well as high-risk gene expression profiling (GEP) signature, have shown to be well related to a worse outcome and are going to be incorporated into new prognostic systems. The introduction of the Individualised Risk Model for Multiple Myeloma (IRMMa) marks a significant advancement in the management of HRMM by integrating genomic and clinical data to tailor treatment strategies. This model demonstrates improved prognostic accuracy compared to traditional staging systems and emphasises the importance of personalised treatment approaches. The implementation of these advanced tools is essential for enhancing precision medicine in MM and improving outcomes for patients in high-risk categories.

Multiple myeloma (MM) patients with chromosome 1q gain (1q+) are clinically and biologically heterogeneous. The underlying molecular mechanisms are still under investigation, while the identification of targets for effective therapy of this subgroup of MM patients is urgently needed. We aimed to investigate the clinical significance and the regulatory mechanisms of insulin-like growth factor 2 messenger RNA (mRNA) binding protein 1 (IGF2BP1), a N6-methyladenosine (m6A) reader, in MM patients with 1q+. We found that MM patients with 1q+ exhibit a significantly higher level of IGF2BP1 mRNA than controls, while higher IGF2BP1 expression predicted a worse prognosis in MM patients with 1q+. IGF2BP1 overexpression promoted cell proliferation and G1-to-S phase transition of the cell cycle in NCI-H929 cells. Through comprehensive in silico analyses of existing public datasets and in-house generated high-throughput sequencing datasets, along with in vitro experiments, we identified CDC5L as a target of IGFBP1, which can bind to the m6A sites of CDC5L mRNA to up-regulate its protein abundance. Higher CDC5L expression also predicted a worse prognosis of MM patients with 1q+. Moreover, both knockdown and mutation of CDC5L attenuated the pro-proliferative effect of IGF2BP1. Furthermore, IGF2BP1 inhibitor BTYNB effectively inhibited CDC5L expression in MM cells with 1q+ and suppressed the proliferation of these cells in vitro and in vivo. Therefore, IGF2BP1 acts as a post-transcriptional enhancer of CDC5L in an m6A-dependent manner to promote the proliferation of MM cells with 1q+. Our work identified a novel IGF2BP1-CDC5L axis and provided new insight into developing targeted therapeutics for MM patients with 1q+.

Despite advancements in treatment, multiple myeloma (MM) remains a challenging hematologic malignancy. It is crucial to stratify risk and perform prognostic assessment with various markers, including the expression of cluster of differentiation 56 (CD56) and cluster of differentiation 117 (CD117). However, the relationship of these markers with MM-related survival remains unclear. In this context, the objective of this study was to investigate the prognostic implications of CD56 and CD117 expression and associated clinical features in MM patients.

The population of this retrospective single-center study consisted of adult MM patients whose CD56 and CD117 expression levels were analyzed. Patients were divided into four groups according to their immunophenotypes: CD56+CD117-, CD56-CD117+, CD56+CD117+, and CD56-CD117-. These groups were compared in terms of demographic and clinical characteristics, response to treatment, and survival outcomes.

Of the 168 MM patients included in the study, CD56 positivity, CD117 positivity, CD56 and CD117 double positivity, and CD56 and CD117 double negativity were observed in 57.1%, 38.1%, 21.4%, and 26.2%, respectively. Patients with double positivity had significantly higher cytogenetic risk and significantly lower overall response rate (ORR) compared to other patients (p<0.001 for both). ORR and overall survival (OS) were significantly lower in CD56-positive patients than in CD56-negative patients (p=0.017 and p=0.004, respectively). Mortality rates were significantly higher in CD56-positive and CD117-positive patients than in double-negative patients (p<0.001 and p=0.002, respectively). Double-negative patients had significantly lower ORR and OS and higher mortality than others (p=0.001, p=0.002, and p<0.001, respectively). High cytogenetic risk was found to be an independent predictor of shorter OS (p>0.001).

This study’s findings revealed that MM patients with CD56 and CD117 double positivity had poorer prognosis, lower ORR, shorter OS, and higher mortality.

While 1q21+ was common genetic alteration and found to have adverse effect on prognosis, the underlying genes remain unclear. Identification of related genes may provide additional help for rational intervention. The microarray dataset GSE2658 associated with MM was downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were obtained, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to annotate their functions. The hub genes were derived from the combined results of up-regulated DEGs and weighted gene coexpression network analysis (WGCNA). The receiver operating characteristic (ROC) curves of hub genes were plotted to evaluate correlation with 1q21+. Survival analysis and drug-gene interaction of hub genes were performed separately to find the prognostic value and potential targeted drugs. A total of 55 DEGs were identified. GO and KEGG pathway analyses suggested that the DEGs were related to several pathways of cell proliferation. NVL, IL6R, DUSP23 were proven to be highly correlated with 1q21+ and have adverse effects on prognosis. IL6R, DUSP23 were matched to known interaction-drug. This study revealed potential roles of hub genes in the pathogenesis and progression of MM with 1q21+, further investigations are needed to elucidate the mechanisms.

Autologous hematopoietic cell transplantation (AHCT) is a commonly used treatment in multiple myeloma (MM). However, real-world global demographic and outcome data are scarce. We collected data on baseline characteristics and outcomes from 61 725 patients with newly diagnosed MM who underwent upfront AHCT between 2013 and 2017 from nine national/international registries. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), relapse incidence (RI) and non-relapse mortality (NRM). Median OS amounted to 90.2 months (95% CI 88.2-93.6) and median PFS 36.5 months (95% CI 36.1-37.0). At 24 months, cumulative RI was 33% (95% CI 32.5%-33.4%) and NRM was 2.5% (95% CI 2.3%-2.6%). In the multivariate analysis, superior outcomes were associated with younger age, IgG subtype, complete hematological response at auto-HCT, Karnofsky score of 100%, international staging scoring (ISS) stage 1, HCT-comorbidity index (CI) 0, standard cytogenetic risk, auto-HCT in recent years, and use of lenalidomide maintenance. There were differences in the baseline characteristics and outcomes between registries. While the NRM was 1%-3% at 12 months worldwide, the OS at 36 months was 69%-84%, RI at 12 months was 12%-24% and PFS at 36 months was 43%-63%. The variability in these outcomes is attributable to differences in patient and disease characteristics as well as the use of maintenance and macroeconomic factors. In conclusion, worldwide data indicate that AHCT in MM is a safe and effective therapy with an NRM of 1%-3% with considerable regional differences in OS, PFS, RI, and patient characteristics. Maintenance treatment post-AHCT had a beneficial effect on OS.

Multiple myeloma (MM) is a heterogeneous disease with a small subset of high-risk patients having poor prognoses. Identifying these patients is crucial for treatment management and strategic decisions. In this study, we developed a novel computational framework to define prognostic gene signatures by selecting genes with expression driven by clonal copy number alterations. We applied this framework to MM and developed a clonal gene signature (CGS) consisting of 22 genes and evaluated in five independent datasets. The CGS provided significant prognostic values after adjusting for well-established factors including cytogenetic abnormalities, International Staging System (ISS), and Revised ISS (R-ISS). Importantly, CGS demonstrated higher performance in identifying high-risk patients compared to the GEP70 and SKY92 signatures recommended for prognostic stratification of MM. CGS can further stratify patients into subgroups with significantly differential prognoses when applied to the high- and low-risk groups identified by GEP70 and SKY92. Additionally, CGS scores are significantly associated with patient response to dexamethasone, a commonly used treatment for MM. In summary, we proposed a computational framework that requires only gene expression data to identify CGSs for prognosis prediction. CGS provides a useful biomarker for improving prognostic stratification in MM, especially for identifying the highest-risk patients.

Multiple myeloma is currently treated with a one-size-fits-all approach despite significant heterogeneity in patient outcomes and disease molecular constitution. A personalised approach would tailor therapy to unique patient or disease characteristics.

Well established prognostic biomarkers such as cytogenetic risk and patient frailty status are being evaluated as potential predictive biomarkers. Specifically, treatment intensity can be augmented in high-risk patients or conversely attenuated in those at lower risk or lower ability to withstand treatment toxicities. Alternatively, targeted therapy can be rationally designed to exploit vulnerable pathways in myeloma cells as identified using predictive biomarkers. The t(11;14) translocation, found in approximately 15-20% of myeloma cases, is a leading biomarker for response to BCL-2 inhibitors such as venetoclax.

Active research efforts exploring venetoclax combination therapies, as well as new generation BCL-2 inhibitors are underway. Following the development of venetoclax, numerous other cellular pathways are under investigation as candidate predictive biomarkers to rationally inform newer targeted therapies in myeloma.

We developed a new predictive staging system to explore the heterogeneity of survival in newly diagnosed multiple myeloma (NDMM) patients in the real world.

In this retrospective study, we evaluated the predictive value of cytogenetic abnormal and clinical data in 375 patients with NDMM at our center. Established a weighted MM prognostic scoring system risk model and validated its predicted PFS and OS by external cohort.

Elevated lactate dehydrogenase levels (1 point), international staging system stage II/III (1 point), 1q21+ ≥ 52.75% (0.5 point), del (17p) ≥ 3.5% (0.5 point), and t (14;16) ≥ 35.25% (1 point) had independent prognostic significance. Patients were further divided into three risk groups: low (I) (score 0-0.5, 16.5%), intermediate (II) (score 1, 46.7%), and high (III) (score 1.5-3, 36.8%). In the training cohort, the 3-year PFS was 79.5% vs. 65.3% vs. 40.3% (p < 0.001), and the 3-year OS was 87.7% vs.70.1% vs. 55% (p < 0.001) for the three risk groups. In the external validation cohort, the 3-year PFS was 85.5% vs.61.2% vs. 43.1% (p < 0.001) and the 3-year OS was 91.4% vs.83.5% vs. 56.9% (p < 0.001) for the three risk groups.

The risk stratification of this model shows good discrimination and calibration, and its application in clinical practice can improve the risk assessment of patients with NDMM and guide personalized treatment strategies.

Multiple myeloma (MM) is a common hematological malignancy. Autologous hematopoietic stem cell transplantation (auto-HSCT) can significantly improve the prognosis of patients with MM, but a variety of complications may occur after transplantation. Retroperitoneal fibrosis (RPF) is a rare cause of obstructive nephropathy. Because there are no specific symptoms at the time of onset and the course of the disease is often insidious, special laboratory and instrumental examination methods are usually needed to confirm the diagnosis. This article describes the clinical case of a 50-year-old female patient diagnosed with multiple myeloma. She developed postoperative acute kidney injury (AKI) more than 20 days after transplantation and was subsequently diagnosed with retroperitoneal fibrosis. After multidisciplinary collaboration, early transurethral vesicoureteral stent placement was performed, the obstruction was relieved, and her renal function returned to normal. Reports of retroperitoneal fibrosis after multiple myeloma transplantation are relatively rare. This case report advances our understanding of these 2 diseases, and the correlation between MM and RPF warrants further exploration.

This study aims to identify clinical laboratory parameters for the diagnosis of newly diagnosed multiple myeloma (NDMM), establish optimal cutoffs for early screening, and develop a diagnostic model for precise diagnosis.

The study conducted a retrospective analysis of 279 NDMM patients and 553 healthy subjects at Zhejiang Province People's Hospital between January 2008 and June 2023. Multifactor LR was employed to explore clinical laboratory indicators with diagnostic value for NDMM, determine optimal cutoff values and contract a diagnostic model. The diagnostic efficacy and clinical utility were evaluated using receiver operating characteristic curves (ROC), sensitivity, specificity, and other indicators.

Multifactor analysis revealed that hemoglobin (Hb), albumin (Alb), and platelet distribution width (PDW) were significant diagnostic factors for NDMM. Optimal cutoff values for Hb, Alb, and PDW in MM diagnosis were determined, and the results showed a significant increase in the probability of NDMM diagnosis when Alb was below 39.3 g/L, Hb was below 11.6 g/dL, and PDW was below 14.1 fL. The diagnostic model constructed from the development cohort demonstrated a high area under the ROC curve of 0.960 (95% CI 0.942-0.978) and exhibited good sensitivity (0.860), specificity (0.957). The area under the curve (AUC) value of the diagnostic model in the external validation cohort was 0.979, confirming its good diagnostic efficacy and generalization.

The optimal cutoff values for Hb, Alb, and PDW and the diagnostic model designed in the study provided good accuracy and sensitivity for the initial screening and diagnosis of NDMM.

Multiple myeloma (MM) stands as the second most prevalent hematological malignancy, constituting approximately 10% of all hematological malignancies. Current guidelines recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible MM patients. This study seeks to delineate factors influencing post-ASCT outcomes in MM patients. Our cohort comprised 150 MM patients from Taipei Veterans General Hospital, with progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. A Cox proportional hazards model was employed to discern potential predictive factors for survival. ASCT age ≥ 65 (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.08-3.47) and the presence of extramedullary disease (HR 2.53, 95% CI 1.53-4.19) negatively impacted PFS. Conversely, treatment response ≥ VGPR before ASCT (HR 0.52, 95% CI 0.31-0.87) and total CD34+ cells collected ≥ 4 × 106 cells/kg on the first stem cell harvesting (HR 0.52, 95% CI 0.32-0.87) were positively associated with PFS. For OS, patients with ISS stage III (HR 2.06, 95% CI 1.05-4.04), the presence of extramedullary disease (HR 3.92, 95% CI 2.03-7.58), light chain ratio ≥ 100 before ASCT (HR 7.08, 95% CI 1.45-34.59), post-ASCT cytomegalovirus infection (HR 9.43, 95% CI 3.09-28.84), and a lower conditioning melphalan dose (< 140 mg/m2; HR 2.75, 95% CI 1.23-6.17) experienced shorter OS. In contrast, post-ASCT day + 15 absolute monocyte counts (D15 AMC) > 500/µl (HR 0.36, 95% CI 0.17-0.79) and post-ASCT day + 15 platelet counts (D15 PLT) > 80,000/µl (HR 0.48, 95% CI 0.24-0.94) were correlated with improved OS. Significantly, early PLT and AMC recovery on day + 15 predicting longer OS represents a novel finding not previously reported. Other factors also align with previous studies. Our study provides real-world insights for post-ASCT outcome prediction beyond clinical trials.

Immunoglobin-related (AL) amyloidosis is the production of amyloidogenic immunoglobulin light chains from clonal plasma cells or, rarely, B-cell lymphomas with plasmacytic differentiation. Amyloid deposition causes progressive end organ destruction with profound morbidity.

We present a rare case of a lambda light chain AL amyloidoma localized to a thoracic vertebra of an 87-year-old woman who had a remote history of an unspecified non-Hodgkin B-cell lymphoma (NHL). Our patient presented with upper extremity neuropathy and was found by MRI to have a malignant-appearing lesion throughout the T1 vertebra. Initial biopsy showed amyloid deposition and staging evaluation found localized disease. Prior to planned surgery and radiation the following year, she had worsening neuropathy including multiple falls. Repeat MRI confirmed lesion progression with concern for cord compression. Urgent surgical resection was performed. Histology showed numerous plasma cells with abundant amyloid deposition that was found by amyloid typing to be lambda light chain. An incidental B-cell rich lymphoid aggregate was also seen in a bone marrow fragment that required additional immunohistochemical evaluation, showing the aggregate to be benign while revealing the plasma cells to be positive for cyclin D1. She received localized radiation and has been asymptomatic.

Amyloidosis and plasma cell neoplasms require appropriate staging evaluation. The cyclin D1-positive plasma cells raises the possibility of the t(11;14)/IGH::CCND1 translocation that portends better prognosis and therapeutic response with venetoclax.

Amyloidomas are uncommon and may present in nearly any site, requiring a high index of clinical suspicion for proper diagnosis.

Multiple myeloma (MM) exhibits significant heterogeneity in its presentation, genetics, and treatment response. Despite therapeutic advances, some patients continue to relapse early (ER, <18-months) and rapidly cycle through therapies. Myriad prognostic factors have been identified and incorporated into risk stratification models; however, these produce discordant, often three-tiered outputs that fail to identify many patients destined for ER. Treatment strategies are increasingly focused on disease biology and trials enriched for high-risk (HR)MM, but consensus on the minimum required testing and a succinct, specific, and clinically meaningful definition for HRMM remains elusive. We review the risk-factors, definitions, and future directions for HRMM.

The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]). Patients received 4 induction cycles (D-RVd/RVd), high-dose therapy/transplant, 2 consolidation cycles (D-RVd/RVd), and lenalidomide±daratumumab maintenance (≤ 2 years). Minimal residual disease-negativity (10-5) rates were higher for D-RVd versus RVd in patients ≥ 65 years (67.9% vs 17.9%), with HRCAs (54.8% vs 32.4%), and with gain/amp(1q21) (61.8% vs 28.6%). D-RVd showed a trend toward improved progression-free survival versus RVd (hazard ratio [95% confidence interval]) in patients ≥ 65 years (0.29 [0.06-1.48]), with HRCAs (0.38 [0.14-1.01]), and with gain/amp(1q21) (0.42 [0.14-1.27]). In the functional high-risk subgroup (not MRD negative at the end of consolidation), the hazard ratio was 0.82 (0.35-1.89). Among patients ≥ 65 years, grade 3/4 treatment-emergent adverse event (TEAE) rates were higher for D-RVd versus RVd (88.9% vs 77.8%), as were TEAEs leading to discontinuation of ≥ 1 treatment component (37.0% vs 25.9%). One D-RVd patient died due to an unrelated TEAE. These results support the addition of daratumumab to RVd in transplant-eligible patients with high-risk NDMM. Video Abstract.

Given the high heterogeneity in survival for patients with multiple myeloma, it would be clinically useful to quantitatively predict the individual survival instead of attributing patients to two to four risk groups as in current models, for example, revised International Staging System (R-ISS), R2-ISS, or Mayo-2022-score.

Our aim was to develop a quantitative prediction tool for individual patient's 3-/5-year overall survival (OS) probability. We integrated established clinical and molecular risk factors into a comprehensive prognostic model and evaluated and validated its risk discrimination capabilities versus R-ISS, R2-ISS, and Mayo-2022-score.

A nomogram for estimating OS probabilities was built on the basis of a Cox regression model. It allows one to translate the individual risk profile of a patient into 3-/5-year OS probabilities by attributing points to each prognostic factor and summing up all points. The nomogram was externally validated regarding discrimination and calibration. There was no obvious bias or overfitting of the prognostic index on the validation cohort. Resampling-based and external evaluation showed good calibration. The c-index of the model was similar on the training (0.76) and validation cohort (0.75) and significantly higher than for the R-ISS (P < .001) or R2-ISS (P < .01).

In summary, we developed and validated individual quantitative nomogram-based OS prediction. Continuous risk assessment integrating molecular prognostic factors is superior to R-ISS, R2-ISS, or Mayo-2022-score alone.

The ELOQUENT-3 trial demonstrated the superiority of the combination of elotuzumab, pomalidomide, and dexamethasone (EloPd) in terms of efficacy and safety, compared to Pd in relapsed/refractory multiple myeloma (RRMM), who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor. The present study is an 18-month follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloPd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 17.7 months, 213 patients (66.4%) experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 7.5 and 19.2 months, respectively. The updated multivariate analysis showed a significant reduction of PFS benefit magnitude both in advanced International Staging System (ISS) (II and III) stages and previous exposure to daratumumab cases. Instead, advanced ISS (II and III) stages and more than 2 previous lines of therapy maintained an independent prognostic impact on OS. Major adverse events included grade three-fourths neutropenia (24.9%), anemia (13.4%), lymphocytopenia (15.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 19.3% and 8.7%, respectively. A slight increase in the incidence of neutropenia and lymphocytopenia was registered with longer follow-up. In conclusion, our real-world study still confirms that EloPd is a safe and possible therapeutic choice for RRMM. Nevertheless, novel strategies are desirable for those patients exposed to daratumumab.

Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; n = 395) randomizing VAD induction (vincristin/adriamycin/dexamthasone)/tandem-transplantation/thalidomide-maintenance vs. PAD induction (bortezomib/adriamycin/dexamethasone)/tandem transplantation/bortezomib maintenance, we discern how chromosomal aberrations determine long-term prognosis by different patterns of association with proliferation and treatment-dependent response, whether responses achieved by different regimens are equal regarding prognosis, and whether subpopulations of patients could be defined as treatable without upfront "novel agents" in cases of limited resources, e.g., in low- or middle-income countries. Serum parameters and risk factors were assessed in 395 patients. CD138-purified plasma cells were subjected to fluorescence in situ hybridization (n = 354) and gene expression profiling (n = 204). We found chromosomal aberrations to be associated in four patterns with survival, proliferation, and response: deletion (del) del17p13, del8p21, del13q14, (gain) 1q21+, and translocation t(4;14) (all adverse) associate with higher proliferation. Of these, del17p is associated with an adverse response (pattern 1), and 1q21+, t(4;14), and del13q14 with a treatment-dependent better response (pattern 2). Hyperdiploidy associates with lower proliferation without impacting response or survival (pattern 3). Translocation t(11;14) has no association with survival but a treatment-dependent adverse response (pattern 4). Significantly fewer patients reach a near-complete response or better with "conventional" (VAD) vs. bortezomib-based treatment after induction or high-dose melphalan. These patients, however, show significantly better median progression-free and overall survival. Molecularly, patients responding to the two regimens differ in gene expression, indicating distinct biological properties of the responding myeloma cells. Patients with normal renal function (89.4%), low cytogenetic risk (72.5%), or low proliferation rate (37.9%) neither benefit in progression-free nor overall survival from bortezomib-based upfront treatment. We conclude that response level, the treatment by which it is achieved, and molecular background determine long-term prognosis. Chromosomal aberrations are associated in four patterns with proliferation and treatment-dependent responses. Associations with faster and deeper responses can be deceptive in the case of prognostically adverse aberrations 1q21+ and t(4;14). Far from advocating a return to "outdated" treatments, if resources do not permit state-of-the-art-treatment, normal renal function and/or molecular profiling identifies patient subpopulations doing well without upfront "novel agents".