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Multiple myeloma (MM) is a hematological malignancy and poses significant therapeutic challenges. This review synthesizes evidence from pivotal clinical trials to guide induction treatment for transplant-eligible (TE), newly diagnosed MM (NDMM) patients. Emphasizing the evolution from three-drug to four-drug induction therapies, we highlight the integration of monoclonal antibodies, particularly CD38 recombinant monoclonal antibody agents, into treatment regimens. This analysis includes a comprehensive literature review of research from major databases and conferences conducted between 2010 and 2023, culminating in the detailed evaluation of 47 studies. The findings underscore the superiority of quadruple regimens in TE NDMM, notably those incorporating daratumumab, in achieving superior responses including progression-free survival (PFS), minimal residual disease (MRD) negativity, objective response rate (ORR), and overall survival (OS) when compared to triple-drug regimens. As treatment regimens evolve with additional agents, the improved outcomes with treatment-related adverse events should be carefully balanced. This review advocates for a paradigm shift towards quadruple induction therapies for TE NDMM, offers a detailed insight into the current landscape of MM treatment, and reinforces a new standard of care. [ABSTRACT FROM AUTHOR]

Our main objective was to identify abundantly expressed tyrosine kinases in multiple myeloma (MM) as potential therapeutic targets. We first compared the transcriptomes of malignant plasma cells from newly diagnosed MM patients who were risk-categorized based on the patientspecific EMC-92/SKY-92 gene expression signature values vs. normal plasma cells from healthy volunteers using archived datasets from the HOVON65/GMMG-HD4 randomized Phase 3 study evaluating the clinical efficacy of bortezomib induction/maintenance versus classic cytotoxic drugs and thalidomide maintenance. In particular, ERBB1/EGFR was significantly overexpressed in MM cells in comparison to normal control plasma cells, and it was differentially overexpressed in MM cells from high-risk patients. Amplified expression of EGFR/ERBB1 mRNA in MM cells was positively correlated with increased expression levels of mRNAs for several DNA binding proteins and transcription factors with known upregulating activity on EGFR/ERBB1 gene expression. MM patients with the highest ERBB1/EGFR expression level had significantly shorter PFS and OS times than patients with the lowest ERBB1/EGFR expression level. High expression levels of EGFR/ERBB1 were associated with significantly increased hazard ratios for unfavorable PFS and OS outcomes in both univariate and multivariate Cox proportional hazards models. The impact of high EGFR/ERBB1 expression on the PFS and OS outcomes remained significant even after accounting for the prognostic effects of other covariates. These results regarding the prognostic effect of EGFR/ERBB1 expression were validated using the MMRF-CoMMpass RNAseq dataset generated in patients treated with more recently applied drug combinations included in contemporary induction regimens. Our findings provide new insights regarding the molecular mechanism and potential clinical significance of upregulated EGFR/ERBB1 expression in MM. [ABSTRACT FROM AUTHOR]

: Background-smoldering multiple myeloma (SMM) risk of progression to multiple myeloma (MM) is highly heterogeneous and several models have been suggested to predict this risk. Lakshman et al. recently proposed a model based on three biomarkers: bone marrow plasma cell (BMPC) percentage > 20%, free light chain ratio (FLCr) > 20 and serum M protein > 20 g/L. The goal of our study was to test this "20/20/20" model in our population and to determine if similar results could be obtained in another cohort of SMM patients. Method-we conducted a retrospective, single center study with 89 patients diagnosed with SMM between January 2008 and December 2019. Results-all three tested biomarkers were associated with an increased risk of progression: BMPC percentage ≥ 20% (hazard ratio [HR]: 4.28 [95%C.I., 1.90-9.61]; p < 0.001), serum M protein ≥ 20 g/L (HR: 4.20 [95%C.I., 1.90-15.53]; p = 0.032) and FLCr ≥ 20 (HR: 3.25 [95%C.I., 1.09-9.71]; p = 0.035). The estimated median time to progression (TTP) was not reached for the low and intermediate risk groups and was 29.1 months (95%C.I., 3.9-54.4) in the high-risk group (p = 0.006). Conclusions-the 20/20/20 risk stratification model adequately predicted progression in our population and is easy to use in various clinical settings. [ABSTRACT FROM AUTHOR]

Elotuzumab is the first monoclonal antibody approved for the treatment of relapsed-refractory multiple myeloma (MM) in combination with lenalidomide, an immunodulatory drug, and dexamethasone. We report on a multiply pre-treated MM patient with disease progression due to appearance of new focal lesions on imaging modalities, who was started on a combination treatment of elotuzumab, lenalidomide, and dexamethasone. After completion of three cycles of the new therapy the patient responded very well with a major decline of serological myeloma activity parameters serum monoclonal protein, kappa light chains, free light chains (FLC) ratio. The patient was also monitored with the functional imaging modalities 18F-FDG PET/CT and diffusion weighted imaging (DWI), which exhibited a mismatch of almost complete metabolic remission on positron emission tomography/computed tomography (PET/CT) with 18F-fluoro-2-deoxy-d-glucose (18F-FDG) (consistent with the serological response), and signal elevation persistence on DWI. This case demonstrates the potentially superior performance of 18F-FDG PET/CT over DWI in early response evaluation of combined treatment with a monoclonal antibody, an immunomodulatory drug, and dexamethasone in MM. [ABSTRACT FROM AUTHOR]

The p53 pathway is inactivated in the majority of human cancers. Although this perturbation frequently occurs through the mutation or deletion of p53 itself, there are other mechanisms that can attenuate the pathway and contribute to tumorigenesis. For example, overexpression of important p53 negative regulators, such as murine double minute 2 (MDM2) or murine double minute 4 (MDM4), epigenetic deregulation, or even alterations in TP53 mRNA splicing. In this work, we will review the different mechanisms of p53 pathway inhibition in cancer with special focus on multiple myeloma (MM), the second most common hematological malignancy, with low incidence of p53 mutations/deletions but growing evidence of indirect p53 pathway deregulation. Translational implications for MM and cancer prognosis and treatment are also reviewed. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is the second most frequent hematological cancer and is characterized by the clonal proliferation of malignant plasma cells. Genome-wide expression profiling (GEP) analysis with DNA microarrays has emerged as a powerful tool for biomedical research, generating a huge amount of data. Microarray analyses have improved our understanding of MM disease and have led to important clinical applications. In MM, GEP has been used to stratify patients, define risk, identify therapeutic targets, predict treatment response, and understand drug resistance. In this study, we built a gene risk score for 267 genes using RNA-seq data that demonstrated a prognostic value in two independent cohorts (n = 674 and n = 76) of newly diagnosed MM patients treated with high-dose Melphalan and autologous stem cell transplantation. High-risk patients were associated with the expression of genes involved in several major pathways implicated in MM pathophysiology, including interferon response, cell proliferation, hypoxia, IL-6 signaling pathway, stem cell genes, MYC, and epigenetic deregulation. The RNA-seq-based risk score was correlated with specific MM somatic mutation profiles and responses to targeted treatment including EZH2, MELK, TOPK/PBK, and Aurora kinase inhibitors, outlining potential utility for precision medicine strategies in MM. [ABSTRACT FROM AUTHOR]

Immunomodulatory drugs (IMiDs) are effective in the treatment of multiple myeloma (MM), myelodysplastic syndrome with deletion of chromosome 5q and other haematological malignancies. Recent studies showed that IMiDs bind to cereblon (CRBN), a substrate receptor of the CRL4–CRBN complex, to induce the ubiquitination and degradation of IKZF1 and IKZF3 in MM cells, contributing to their anti-myeloma activity. We aimed to determine whether the CRL4–CRBN complex proteins' expression predicts the prognosis of MM patients treated with IMiDs. Here, we evaluated the expression of CRL4–CRBN complex proteins and their downstream targets with immunohistochemistry (IHC) staining in 130 bone marrow samples from MM patients treated with thalidomide or lenalidomide-based regimens. We found that the expression of CRBN and CUL4A was associated with the superior IMiD-based treatment response (p = 0.007 and p = 0.007, respectively). Moreover, the CUL4A expression was associated with improved PFS (HR = 0.66, 95% CI 0.44–0.99; p = 0.046) and DDB1 expression showed a negative impact on OS both in the univariate (HR = 2.75, 95% CI 1.65–4.61; p = 0.001) and the multivariate (HR 3.67; 95% CI 1.79–7.49; p < 0.001) analysis. Overall, our data suggest that the expression of DDB1, CUL4A and CRBN assessed by IHC predicts the clinical course of MM patients and identifies patients with a high probability of responding to IMiD-based therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: In this review we have summarized the history, the current use, and the future possibilities of alkylator treatment in multiple myeloma. Alkylators have for decades been part of the standard of care of myeloma treatment, but still new alkylators and new use of old alkylators are making its way into myeloma guidelines of today. A large number of novel treatments for myeloma have been developed and approved; however, alkylating drugs continue to be part of standard regimens. Additionally, novel alkylators are currently being developed. We performed a non-systematized literary search for relevant papers and communications at large conferences, as well as exploiting the authors' knowledge of the field, to review the history, current use and novel concepts around the traditional alkylators cyclophosphamide, bendamustine and melphalan and current data on the newly developed pro-drug melflufen. Even in the era of targeted treatment and personalized medicine, alkylating drugs continue to be part of the standard-of-care in myeloma, and new alkylators are coming to the market. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM) is a neoplastic disease of plasma cells, characterized by a complex array of clinical manifestations. Despite extensive efforts and progress in the care of MM patients, the disease is still fatal because of de novo or acquired resistance of malignant cells to standard chemotherapies. In turn, new therapies and/or combination therapies are urgently needed. Reactive oxygen species (ROS) are unstable and highly reactive chemical molecules, able to alter the main structural components of cells, such as proteins and lipids, and thus, modifying cell fates. ROS levels are tightly controlled in normal cells both for their production and degradation. In turn, an unbalance of the redox status might be exploited to induce cell death. This is indeed the case for myeloma cells even those that are resistant, opening new perspectives for refractory or relapsed MM patients. Multiple myeloma (MM) is a common hematological disease characterized by the accumulation of clonal malignant plasma cells in the bone marrow. Over the past two decades, new therapeutic strategies have significantly improved the treatment outcome and patients survival. Nevertheless, most MM patients relapse underlying the need of new therapeutic approaches. Plasma cells are prone to produce large amounts of immunoglobulins causing the production of intracellular ROS. Although adapted to high level of ROS, MM cells die when exposed to drugs increasing ROS production either directly or by inhibiting antioxidant enzymes. In this review, we discuss the efficacy of ROS-generating drugs for inducing MM cell death and counteracting acquired drug resistance specifically toward proteasome inhibitors. [ABSTRACT FROM AUTHOR]

Aim of the study is to compare the agreement between whole-body low-dose computed tomography (WBLDCT) and magnetic resonance imaging (WBMRI) in the evaluation of bone marrow involvement in patients with multiple myeloma (MM). Patients with biopsy-proven MM, who underwent both WBLDCT and WBMRI were retrospectively enrolled. After identifying the presence of focal bone involvement (focal infiltration pattern), the whole skeleton was divided into five anatomic districts (skull, spine, sternum and ribs, pelvis, and limbs). Patients were grouped according to the number and location of the lytic lesions (<5, 5–20, and >20) and Durie and Salmon staging system. The agreement between CT and MRI regarding focal pattern, staging, lesion number, and distribution was assessed using the Cohen Kappa statistics. The majority of patients showed focal involvement. According to the distribution of the focal lesions and Durie Salmon staging, the agreement between CT and MRI was substantial or almost perfect (all κ > 0.60). The agreement increased proportionally with the number of lesions in the pelvis and spine (κ = 0.373 to κ = 0.564, and κ = 0.469–0.624), while for the skull the agreement proportionally decreased without reaching a statistically significant difference (p > 0.05). In conclusion, WBLDCT showed an almost perfect agreement in the evaluation of focal involvement, staging, lesion number, and distribution of bone involvement in comparison with WBMRI. [ABSTRACT FROM AUTHOR]

The present study was designed to assess the additional value of 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) to magnetic resonance imaging (MRI) in the treatment response assessment of multiple myeloma (MM). We performed a meta-analysis of all available studies to compare the detectability of treatment response of [18F]FDG PET/CT and MRI in treated MM. We defined detecting a good therapeutic effect as positive, and residual disease as negative. We determined the sensitivities and specificities across studies, calculated the positive and negative likelihood ratios (LR), and made summary receiver operating characteristic curves (SROC) using hierarchical regression models. The pooled analysis included six studies that comprised 278 patients. The respective performance characteristics (95% confidence interval (CI)) of [18F]FDG PET/CT and MRI were as follows: sensitivity of 80% (56% to 94%) and 25% (19% to 31%); specificity of 58% (44% to 71%) and 83% (71% to 91%); diagnostic odds ratio (DOR) of 6.0 (3.0–12.0) and 1.7 (0.7–2.7); positive LR of 1.8 (1.3–2.4) and 1.4 (0.7–2.7); and negative LR of 0.33 (0.21–0.53) and 0.81 (0.62–1.1). In the respective SROC curves, the area under the curve was 0.77 (SE, 0.038) and 0.59 (SE, 0.079) and the Q* index was 0.71 and 0.57. Compared with MRI, [18F]FDG PET/CT had higher sensitivity and better DOR and SROC curves. Compared with MRI, [18F]FDG PET/CT had greater ability to detect the treatment assessment of MM. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a plasma cell disorder that is on the rise throughout the world, especially in the US, Australia, and Western Europe. In the US, MM accounts for almost 2% of cancer diagnoses and over 2% of cancer deaths (more than double the global proportion). Incidence has risen by 126% globally and over 40% in the US since 1990, while global mortality has risen by 94% and US mortality has fallen by 18%. The 5 year survival in the US has more than doubled over the past decades with the introduction of new targeted therapies and transplant techniques. Risk factors for MM include age (average age of diagnosis is 69), race (African Americans are over double as likely to be diagnosed), sex (men are at a 1.5× risk), and family history. Diagnosis includes serum or urine electrophoresis and free light-chain assay but requires bone marrow biopsy. It is distinguished from smoldering myeloma and monoclonal gammopathy of undetermined significance by a high (>3 g/dL) level of M-protein (monoclonal light chains) and the presence of CRAB (Hypercalcemia, Renal failure, Anemia, Bone pain) symptoms, which include hypercalcemia, renal failure, anemia, and bone pain, suggesting an end-organ damage. International staging system staging involves beta 2 microglobulin and albumin levels, while the revised system considers prognostic factors such as lactate dehydrogenase levels and chromosomal abnormalities. Front-line management includes induction regimen, maintenance therapy and hematopoietic cell transplantation for eligible patients and bisphosphonates or bone-stimulating agents for the prevention of skeletal events. Treatment for relapsed disease includes newly approved monoclonal antibodies like the CD38-targeting daratumumab, proteasome inhibitors, immunomodulating agents, and investigational therapies such as B cell maturation antigen Chimeric antigen receptor T cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Smoldering multiple myeloma is a heterogenous precursor state of multiple myeloma—both the time until progression and the cause of progression vary within this subgroup. While the number of focal lesions in whole-body MRI (magnetic resonance imaging) is known to be of prognostic value, we investigated whether additional parameters like the size or growth dynamics of focal lesions or precisely quantified diffuse infiltration are connected to risk and cause of progression. We found that both the size and dynamics of focal lesions correlate with progression to multiple myeloma and with existence/appearance of corresponding osteolytic lesions in near-term computed tomography (CT) scans. Furthermore, a score combining intensity and extent of diffuse infiltration showed connections with risk of progression and decrease in hemoglobin. We conclude that these parameters from whole-body MRI can help to predict the clinical course of disease in smoldering multiple myeloma (SMM) patients, with implications for diagnostic follow-up and possibly more specified therapeutic approaches in the future. The purpose of this study was to analyze size and growth dynamics of focal lesions (FL) as well as to quantify diffuse infiltration (DI) in untreated smoldering multiple myeloma (SMM) patients and correlate those MRI features with timepoint and cause of progression. We investigated 199 whole-body magnetic resonance imaging (wb-MRI) scans originating from longitudinal imaging of 60 SMM patients and 39 computed tomography (CT) scans for corresponding osteolytic lesions (OL) in 17 patients. All FLs >5 mm were manually segmented to quantify volume and growth dynamics, and DI was scored, rating four compartments separately in T1- and fat-saturated T2-weighted images. The majority of patients with at least two FLs showed substantial spatial heterogeneity in growth dynamics. The volume of the largest FL (p = 0.001, c-index 0.72), the speed of growth of the fastest growing FL (p = 0.003, c-index 0.75), the DI score (DIS, p = 0.014, c-index 0.67), and its dynamic over time (DIS dynamic, p < 0.001, c-index 0.67) all significantly correlated with the time to progression. Size and growth dynamics of FLs correlated significantly with presence/appearance of OL in CT within 2 years after the respective MRI assessment (p = 0.016 and p = 0.022). DIS correlated with decrease of hemoglobin (p < 0.001). In conclusion, size and growth dynamics of FLs correlate with prognosis and local bone destruction. Connections between MRI findings and progression patterns (fast growing FL—OL; DIS—hemoglobin decrease) might enable more precise diagnostic and therapeutic approaches for SMM patients in the future. [ABSTRACT FROM AUTHOR]

Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant therapeutic modalities in oncology. Antibody-drug conjugates, bispecific antibodies, peptides, cell, and gene-therapies are emerging to address the unmet patient need. Advancement in the discovery and development platforms, identification of novel targets, and emergence of new technologies have greatly expanded the treatment options for patients. Here, we provide an overview of various therapeutic modalities and the current treatment options in oncology, and an in-depth discussion of the therapeutics in the preclinical stage for the treatment of breast cancer, lung cancer, and multiple myeloma. [ABSTRACT FROM AUTHOR]

Some genetic abnormalities of multiple myeloma (MM) detected more than two decades ago remain major prognostic factors. In recent years, the introduction of cutting-edge genomic methodologies has enabled the extensive deciphering of genomic events in MM. Although none of the alterations newly discovered have significantly improved the stratification of the outcome of patients with MM, some of them, point mutations in particular, are promising targets for the development of personalized medicine. This review summarizes the main genetic abnormalities described in MM together with their prognostic impact, and the therapeutic approaches potentially aimed at abrogating the undesirable pathogenic effect of each alteration. [ABSTRACT FROM AUTHOR]

The International Myeloma Working Group (IMWG) recently introduced the evaluation of minimal residual disease (MRD) within the multiple myeloma (MM) response criteria, and MRD negativity assessed inside and outside the bone marrow is currently considered the most powerful predictor of favorable long-term outcomes. However, MRD evaluation has thus far relied on flow-cytometry or molecular-based methods, despite the limitations associated with the patchy infiltration of bone marrow (BM) plasma cells and the presence of extra-medullary (EMD). On the contrary, imaging-based sensitive response assessment through the use of functional rather than morphological whole-body (WB) imaging techniques, such as positron emission tomography with computed tomography (PET/CT) and magnetic resonance imaging (MRI), likely is a promising strategy to overcome these limitations in evaluating response to therapy and in the assessment of the MRD status in MM patients. However, despite the significant advances in the development and availability of novel functional imaging techniques for MRD evaluation, a worldwide standardization of imaging criteria for acquisition, interpretation, and reporting is yet to be determined and will be object of future investigations. [ABSTRACT FROM AUTHOR]