Multiple Myeloma
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Yoshihide Kakimoto ◽  
Miyako Hoshino ◽  
Mikiko Hashimoto ◽  
Masaya Hiraizumi ◽  
Kohei Shimizu ◽  

Alfred Garfall ◽  
Adam Cohen ◽  
Edward Stadtmauer ◽  
Sandra Susanibar-Adaniya ◽  
Dan Vogl ◽  

2021 ◽  
Yanqing Zhang ◽  
Jiaqi Pan ◽  
Xi Chen ◽  
Lianjie Wang ◽  
Liyan Chen ◽  

Aim: Increased serum ferritin (SF) indicates an adverse prognosis in patients with hematologic malignancies. However, its prognostic significance in multiple myeloma (MM) remains unknown. Patients & methods: The impact of SF levels on outcomes in patients with MM was retrospectively analyzed and dynamically assessed. Results: At initial diagnosis, 188 out of 295 patients (63.7%) had high SF that correlated with poor prognosis factors including adverse overall survival and progression-free survival. SF expression was dynamically observed at different time points and SF levels significantly decreased after treatment induction. In addition, SF expression significantly increased at disease progression or relapse. Conclusion: SF can be used as a prognostic factor at initial diagnosis and relapse in patients with MM.

Haematologica ◽  
2021 ◽  
Marcelo Capra ◽  
Thomas Martin ◽  
Philippe Moreau ◽  
Ross Baker ◽  
Ludek Pour ◽  

Renal impairment (RI) is common in patients with multiple myeloma (MM) and new therapies that can improve renal function are needed. The Phase 3 IKEMA study (NCT03275285) investigated isatuximab (Isa) with carfilzomib and dexamethasone (Kd) vs Kd in relapsed MM. This subgroup analysis examined results from patients with RI, defined as estimated glomerular filtration rate

2021 ◽  
Emilie Logie ◽  
Louis Maes ◽  
Joris Van Meenen ◽  
Peter HL De Rijk ◽  
Mojca Strazisar ◽  

Ferroptosis is a lipid peroxidation-dependent mechanism of regulated cell death known to suppress tumor proliferation and progression. Although several genetic and protein hallmarks have been identified in ferroptotic cell death, it remains challenging to fully characterize ferroptosis signaling pathways and to find suitable biomarkers. Moreover, changes taking place in the epigenome of ferroptotic cells remain poorly studied. In this context, we aimed to investigate the role of chromatin remodeler forkhead box protein A1 (FOXA1) in RSL3-treated multiple myeloma cells because, similar to ferroptosis, this transcription factor has been associated with changes in the lipid metabolism, DNA damage, and epithelial-to-mesenchymal transition (EMT). RNA sequencing and Western blot analysis revealed that FOXA1 expression is consistently upregulated upon ferroptosis induction in different in vitro and in vivo disease models. In silico motif analysis and transcription factor enrichment analysis further suggested that ferroptosis-mediated FOXA1 expression is orchestrated by specificity protein 1 (Sp1), a transcription factor known to be influenced by lipid peroxidation. Remarkably, FOXA1 upregulation in ferroptotic myeloma cells did not alter hormone signaling or EMT, two key downstream signaling pathways of FOXA1. CUT&RUN genome-wide transcriptional binding site profiling showed that GPX4-inhibition by RSL3 triggered loss of binding of FOXA1 to pericentromeric regions in multiple myeloma cells, suggesting that this transcription factor is possibly involved in genomic instability, DNA damage, or cellular senescence under ferroptotic conditions.

2021 ◽  
Vol 9 (1) ◽  
Hong Ding ◽  
Juan Xu ◽  
Zhimei Lin ◽  
Jingcao Huang ◽  
Fangfang Wang ◽  

AbstractMultiple myeloma (MM) is a treatable plasma cell cancer with no cure. Clinical evidence shows that the status of minimal residual disease (MRD) after treatment is an independent prognostic factor of MM. MRD indicates the depth of post-therapeutic remission. In this review article, we outlined the major clinical trials that have determined the prognostic value of MRD in MM. We also reviewed different methods that were used for MM MRD assessment. Most important, we reviewed our current understanding of MM MRD biology. MRD studies strongly indicate that MRD is not a uniform declination of whole MM tumor population. Rather, MM MRD exhibits unique signatures of cytogenetic aberration and gene expression profiles, unlike those of MM cells before therapy. Diagnostic high-risk MM and low-risk MM exhibited a diversity of MRD features. Clonal evaluation may occur at the MRD stage in MM. The dynamics from the diagnostic MM to MRD correlate with the disease prognosis. Lastly, on the aspect of omics, we performed data-based analysis to address the biological features underlying the course of diagnostic-to-MRD MM. To summarize, the MRD stage of disease represents a critical step in MM pathogenesis and progression. Demonstration of MM MRD biology should help us to deal with the curative difficulties.

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5154
Klaus Podar ◽  
Xavier Leleu

Despite the challenges imposed by the COVID-19 pandemic, exciting therapeutic progress continues to be made in MM. New drug approvals for relapsed/refractory (RR)MM in 2020/2021 include the second CD38 monoclonal antibody, isatuximab, the first BCMA-targeting therapy and first-in-class antibody–drug conjugate (ADC) belantamab mafodotin, the first BCMA-targeting CAR T cell product Idecabtagen-Vicleucel (bb2121, Ide-Cel), the first in-class XPO-1 inhibitor selinexor, as well as the first-in-class anti-tumor peptide-drug conjugate, melflufen. The present introductory article of the Special Issue on “Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond” summarizes the most recent registration trials and emerging immunotherapies in RRMM, gives an overview on latest insights on MM genomics and on tumor-induced changes within the MM microenvironment, and presents some of the most promising rationally derived future therapeutic strategies.

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258487
Agoston Gyula Szabo ◽  
Tobias Wirenfeldt Klausen ◽  
Mette Bøegh Levring ◽  
Birgitte Preiss ◽  
Carsten Helleberg ◽  

Most patients cannot be included in randomized clinical trials. We report real-world outcomes of all Danish patients with multiple myeloma (MM) treated with daratumumab-based regimens until 1 January 2019. Methods Information of 635 patients treated with daratumumab was collected retrospectively and included lines of therapy (LOT), hematologic responses according to the International Myeloma Working Group recommendations, time to next treatment (TNT) and the cause of discontinuation of treatment. Baseline characteristics were acquired from the validated Danish Multiple Myeloma Registry (DMMR). Results Daratumumab was administrated as monotherapy (Da-mono) in 27.7%, in combination with immunomodulatory drugs (Da-IMiD) in 57.3%, in combination with proteasome inhibitors (Da-PI) in 11.2% and in other combinations (Da-other) in 3.8% of patients. The median number of lines of therapy given before daratumumab was 5 for Da-mono, 3 for Da-IMiD, 4 for Da-PI, and 2 for Da-other. In Da-mono, overall response rate (ORR) was 44.9% and median time to next treatment (mTNT) was 4.9 months. In Da-IMiD, ORR was 80.5%, and mTNT was 16.1 months. In Da-PI, OOR was 60.6% and mTNT was 5.3 months. In patients treated with Da-other, OOR was 54,2% and mTNT was 5.6 months. The use of daratumumab in early LOT was associated with longer TNT (p<0.0001). Patients with amplification 1q had outcome comparable to standard risk patients, while patients with t(4;14), t(14;16) or del17p had worse outcome (p = 0.0001). Multivariate analysis indicated that timing of treatment (timing of daratumumab in the sequence of all LOT that the patients received throughout the course of their disease) was the most important factor for outcome (p<0.0001). Conclusion The real-world outcomes of multiple myeloma patients treated with daratumumab are worse than the results of clinical trials. Outcomes achieved with daratumumab were best when daratumumab was used in combination with IMIDs and in early LOT. Patients with high-risk CA had worse outcomes, but patients with amp1q had similar outcomes to standard-risk patients.

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5131
David F. Moreno ◽  
Laura Rosiñol ◽  
María Teresa Cibeira ◽  
Joan Bladé ◽  
Carlos Fernández de Larrea

Monoclonal gammopathy of undetermined significance (MGUS) is defined as the presence of a monoclonal protein (M-protein) produced by a small amount of plasma cells. The majority of patients remain asymptomatic; however, a fraction of them develop clinical manifestations related to the monoclonal gammopathy despite not fulfilling criteria of multiple myeloma or other lymphoproliferative disorder. These patients constitute an emerging clinical issue coined as monoclonal gammopathy of clinical significance (MGCS). The mechanisms involved are poorly understood, and literature is scarce regarding management. The clinical spectrum involves symptoms related to renal, neurologic, skin, ocular, or bleeding manifestations, requiring a multidisciplinary approach. Treatment strategies rely on the basis of symptomatic disease and the M-protein isotype. In this review, we focus on MGCS other than renal, as the latter was earliest recognized and better known. We review the literature and discuss management from diagnosis to treatment based on illustrative cases from daily practice.

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1455
Alessandra Romano ◽  
Nunziatina Laura Parrinello ◽  
Marina Parisi ◽  
Vittorio Del Fabro ◽  
Angelo Curtopelle ◽  

Background Myeloid dysfunction is an emerging hallmark of microenvironment changes occurring in multiple myeloma (MM). Our previous work showed that FcγRI/CD64 overexpression in neutrophils of newly diagnosed MM patients is associated to inferior outcomes, reduced oxidative bursts and phagocytosis, with an increased risk of bacterial infections. Pomalidomide is a novel immune-modulatory drug approved for relapsed/refractory patients (RRMM), with drug-related neutropenia as major limitation to treatment. Patients and methods Herein, we describe a prospective analysis of 51 consecutive RRMM patients treated with pomalidomide and dexamethasone (PomDex) from March 2015 through December 2016, associated with secondary prophylaxis with filgrastim (G-CSF) in case of neutrophil count <1500 cells/μL. Neutrophil function was investigated by flow cytometry, including the phagocytosis, oxidative bursts, and median fluorescence intensity of FcγRI-CD64. Controls included a group of newly diagnosed symptomatic MM (NDMM), asymptomatic (smoldering myeloma, MGUS) and healthy subjects referred to our Center in the same time-frame. Results Compared to controls, RRMM neutrophils had higher expression of FcγRI/CD64 and lower phagocytic activity and oxidative bursts. We maintained median leukocyte counts higher than 3.5· 10^9/L for 6 cycles, and median neutrophil counts higher than 1.5 · 10^9/L, with only 6 (11%) patients developing grade 3–4 infections, without pomalidomide dose reduction. After 4 cycles of PomDex, FcγRI/CD64 was further increased in neutrophils, and phagocytic activity and oxidative bursts recovered independently from filgrastim exposure and the quality of hematological responses. Similarly, in NDMM patients, lenalidomide but not bortezomib upregulated FcγRI/CD64 expression, improving phagocytic activity and oxidative bursta as tested in vitro. Conclusions Our combined biological and clinical data provide new information on the ability of pomalidomide and lenalidomide to modulate the functional activity of neutrophils, despite their chronic activation due to FcγRI/CD64 overexpression.

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