Myeloma Research Articles

MiR‑1343‑3p inhibits autophagy by directly targeting ATG7 in multiple myeloma cells.

Multiple myeloma (MM) is the second most common type of hematological malignancy globally. Despite application of several new drugs, such as daratumumab, bortezomib/lenalidomide/dexamethasone, in combination with hematopoietic stem cell transplantation, overall prognosis remains poor and the pathological mechanism of MM is still unknown. The present study used TargetScan to predict autophagy-related 7 (ATG7) as a candidate target gene of microRNA (miR)-1343-3p and confirmed the interaction between miR-1343-3p and the ATG7 3' untranslated region (3'UTR) using a dual-luciferase reporter assay. In U266 and RPMI-8226 MM cell lines, miR-1343-3p mimic transfection decreased mRNA and protein levels of ATG7, while miR-1343-3p inhibition increased ATG7 expression levels using reverse transcription-qPCR and western blot analysis. miR-1343-3p mimic transfection inhibited U266 and RPMI-8226 cell survival. Finally, miR-1343-3p regulated ATG7 and autophagy in MM cells using western blot analysis. The present findings suggested that miR-1343-3p may regulate ATG7 and autophagy by directly targeting the 3'UTR of ATG7. To the best of our knowledge, there are no direct data showing the roles of miR-1343-3p in development of MM; however, miR-1343-3p may be considered a potential target for MM treatment.

Anti-Tumor Activity of Indole: A Review

: Generally, heterocyclic compounds are included in a large class of pharmacologically active compounds. The indole scaffold in this category is widely distributed in nature and present in many active compounds, especially anti-cancer agents. Due to its unique physicochemical and biological properties, the indole platform has been considered a favorable scaffold in anti-cancer drug design and development. Various indole compounds (synthetic, semisynthetic, and natural) show remarkable anti-proliferative activity. According to the recent literature, this review describes the role of indole scaffolds as anti-cancer agents. Indole was reported to induce anti-tumor activity through multiple mechanisms, for example, Epidermal Growth Factor Receptors (EGFR), histone deacetylase (HDAC), kinase, DNA-topoisomerases, and tubulin inhibition. The current review focuses on some indole compounds with amazing effects against different types of cancers as there are too many FDA-approved drugs, for example, osimertinib, alectinib, and anlotinib in NSCLC treatment, panobinostat in multiple myeloma, midostaurin in acute myeloid leukemia treatment, etc. Moreover, several compounds are still in clinical trials to treat different cancer types. Additionally, there are some oxindole derivatives with potent inhibition against different types of tumors, such as ovarian cancer, colorectal cancer, and prostate cancer. Different series of oxindoles are promising and recommended for further studies due to their remarkable inhibition of tumor cells. Accordingly, the collection of data on a pharmacologically significant motif might aid researchers in further employing indoles in developing novel anti-cancer drugs with potentially fewer side effects and higher potency against this rapidly spreading disease.

Does immunohistochemical staining predict mobilization success in multiple myeloma patients?

BackgroundSo many risk factors for mobilization failure have been described so far. We aimed to identify the risk factors and search the possible effects of bone marrow fibrosis (BMF), CD56, c-myc, and cyclinD1 expression on mobilization. MethodsWe evaluated 189 patients with MM who were admitted for stem cell mobilization before autologous stem cell transplantation (ASCT) between 2015 and June 2021. Clinical, laboratory, treatment features, and survival outcomes were compared in patients who were successfully mobilized and who were not. ResultsMobilization failure rate was 11.1% (21) in our study group. Male gender, mobilization with only G-CSF, history of previous ASCT, lenalidomide exposure, and 2 lines of chemotherapy before stem cell mobilization were observed more commonly in mobilization failure group. There is no relationship between mobilization failure and BMF, CD56, c-myc, and cyclin D1 expression status in patients who received either only G-CSF or G-CSF+ chemotherapy for mobilization. Overall survival (OS) was not different in groups of patients who were successfully mobilized and who were not. Neutrophil engraftment was faster in patients who were transfused > 5 × 106/kg stem cells (p=0.015). ECOG performance status (p=0.004), c-myc expression (p=0.005), lenalidomide therapy before mobilization (p=0.032), and mobilization with G-CSF+chemotherapy was found to be predictive factors for OS. ConclusionEven though we could not find any predictive value of CD56, c-myc, and cyclin D1 expression on mobilization, c-myc was found to be associated with low OS. Further studies with large and homogenous study population would be more informative.

Radiotherapy and Increased Risk of Second Primary Cancers in Breast Cancer Survivors: An Epidemiological and Large Cohort Study

BackgroundRadiotherapy (RT) for breast cancer (BC) may raise the risk of second primary cancers (SPCs), a relationship inadequately studied. MethodsWe analyzed 248268 female BC patients from 9 SEER registries, 1988-2018 , identifying SPCs >5 years after initial treatment, comparing SPC risks between RT and non-RT cohorts using Fine-Gray and Poisson regressions. ResultsOf all participants, 55.4% received surgery and RT. The RT group had a higher SPC incidence, with excess incidence significantly dropped from 6.9% in 1990 to 0.2% in 2012. The 30-year SPC incidence was 24.69% in the RT cohort and 18.11% in the NRT cohort. RT increased the risk of SPCs(HR, 1.29 [95%CI,1.26-1.33];P<0.001), BC(HR, 1.58[1.52-1.64];P<0.001), cancer of respiratory system(HR, 1.21[1.13-1.30];P=0.013), skin cancer(HR, 1.26[1.10-1.44];P<0.001), leukemia(HR, 1.30[1.11-1.54];P=0.001), soft tissue cancer(HR, 1.78[1.34-2.37]; P<0.001), and eye & orbit cancer(HR, 2.21[1.02-4.80];P=0.044), except for reducing the risk of multiple myeloma (HR 0.76). Notably, RT-related risks(RR) for BC declined with increasing age and the year of BC diagnosed, increased with longer latency, but the dynamic RR for cancer of respiratory system presented the almost opposite trends. The RT cohort had higher standardized incidence ratios than the NRT cohort and general population. Although 15-year overall survival was similar between RT and NRT cohorts, SPC presence significantly lowered 30-year survival from 35.64% to 23.90%. ConclusionsRT might increase susceptibility to SPC in breast, respiratory system, skin, soft tissue, eye and orbit, and leukemia in BC survivors. Efforts should be made to timely diagnose SPCs based on their specific patterns to improve patient’s quality of life.

The future of medicine: Strategic insights into drug repurposing

The future of medicine is increasingly being shaped by innovative strategies that maximize the efficacy of existing therapeutics, one of the most promising being drug repurposing. Drug repurposing involves the identification of novel therapeutic applications for approved or investigational drugs, thereby circumventing the lengthy and costly processes associated with traditional drug development. This approach not only accelerates the delivery of treatments to patients but also optimizes existing resources, making it a compelling strategy in the face of rising healthcare costs and the urgent need for novel therapies. Recent advancements in genomics, bioinformatics, and high-throughput screening have revolutionized our ability to identify potential candidates for repurposing. These technologies facilitate the exploration of drug-target interactions across various diseases, enabling researchers to uncover unexpected therapeutic potentials. For instance, well-known medications originally developed for one condition have been found effective in treating others, such as the use of thalidomide for multiple myeloma and the repurposing of antifungal agents for cancer therapy.

Safety and Efficacy of Teclistamab in Patients With Relapsed or Refractory AL Amyloidosis

ABSTRACTIntroductionTeclistamab has demonstrated deep responses in patients with multiple myeloma in the MajesTEC‐1 study. However, the safety and efficacy of teclistamab in patients with AL amyloidosis are unknown.MethodsWe retrospectively analyzed patients with biopsy‐proven relapsed/refractory AL amyloidosis who were treated with teclistamab from December 2022 to February 2024 at the University of Pennsylvania. The data cutoff was 2/29/24. Adverse events (AE) were extracted from the electronic medical record. Patients were assessed for hematologic and organ response per consensus guidelines.ResultsEight patients were included in this case series: median age 63 (range 59–67), 75% female, 88% White. All eight patients achieved at least very good partial response (VGPR) and had normalization of free light chains (FLC), and six (75%) patients achieved undetectable FLC levels. Of the six patients with immunofixation completed, all six (100%) achieved hematologic complete response (hCR). The median time to hematologic VGPR and hCR was 13 days (range 12–18 days) and 88 days (range 32–150 days), respectively. The median duration of follow‐up was 8.5 months (range 1–14 months). Of the five patients with cardiac involvement, four (80%) achieved a cardiac response. Of the seven patients with renal involvement, two patients already achieved renal response prior to teclistamab, and of the remaining five, three (60%) achieved renal response. Six patients (75%) developed low‐grade cytokine release syndrome (CRS). No patients developed ICANS. Neutropenia and AKI both occurred in 25% of patients, respectively.ConclusionsIn this series of patients, teclistamab showed outstanding depth of response and was well‐tolerated. Teclistamab shows promise in treating patients with relapsed AL amyloidosis.

Predicting Structural Consequences of Antibody Light Chain N-Glycosylation in AL Amyloidosis

Background/Objectives: Antibody light chains form amyloid fibrils that lead to progressive tissue damage in amyloid light chain (AL) amyloidosis. The properties of each patient’s unique light chain appear to determine its propensity to form amyloid. One factor is N-glycosylation, which is more frequent in amyloid-associated light chains than in light chains from the normal immune repertoire. However, the mechanisms underlying this association are unknown. Here, we investigate the frequency and position within the light chain sequence of the N-glycosylation sequence motif, or sequon. Methods: Monoclonal light chains from AL amyloidosis and multiple myeloma were identified from the AL-Base repository. Polyclonal light chains were obtained from the Observed Antibody Space resource. We compared the fraction of light chains from each group harboring an N-glycosylation sequon, and the positions of these sequons within the sequences. Results: Sequons are enriched among AL-associated light chains derived from a subset of precursor germline genes. Sequons are observed at multiple positions, which differ between the two types of light chains, κ and λ, but are similar between light chains from AL amyloidosis and multiple myeloma. Positions of sequons map to residues with surface-exposed sidechains that are compatible with the folded structures of light chains. Within the known structures of λ AL amyloid fibrils, many residues where sequons are observed are buried, inconsistent with N-glycosylation. Conclusions: There is no clear structural rationale for why N-glycosylation of κ light chains is associated with AL amyloidosis. A better understanding of the roles of N-glycosylation in AL amyloidosis is required before it can be used as a marker for disease risk.

Clinical significance of complete remission and measurable residual disease in relapsed/refractory multiple myeloma patients treated with T-cell redirecting immunotherapy.

The impact of measurable residual disease (MRD) in relapse/refractory multiple myeloma (RRMM) patients treated with T-cell redirecting immunotherapy is uncertain. We analyzed MRD dynamics using next-generation flow in 201 patients treated in clinical trials with chimeric antigen receptor (CAR) T cells and T-cell engagers (TCE). Achieving MRD negativity at 10-6 was associated with 89% reduction in the risk of progression and/or death. Survival outcomes were improved in patients with sustained versus transient MRD negativity and were dismal in those who remained MRD positive. The intent-to-treat MRD negative rates were higher in patients treated with CAR T cells versus TCE. However, among patients achieving MRD negativity, there were no differences in survival outcomes when stratified according to treatment with CAR T cells versus TCE. In multivariate analysis including the number of prior lines of treatment, International Staging System, cytogenetic risk, extramedullary disease and type of T-cell redirecting immunotherapy, only the complete remission (CR) and MRD statuses showed independent prognostic value for progression-free and overall survival. In conclusion, our study shows that deep and sustained MRD negative CR is the most relevant prognostic factor and should be considered as the treatment endpoint in RRMM patients treated with CAR T cells and TCE.

The Association between Allergies and Hematologic Tumors — A Review

Introduction: Dysfunctions of the immune system in allergic diseases and hematological malignancies are the subject of many studies due to the mechanisms that link them. Chronic inflammation created in the immune response in an allergic reaction has been associated with developing neoplastic diseases. Aim of the study: This review examines the potential correlation between Allergies and Hematologic Tumors: acute lymphoblastic leukemia, childhood leukemias, non-Hodgkin and Hodgkin lymphomas. Material and methods: An English-language literature review was conducted, analyzing studies from the PubMed database up to October 2024 regarding the correlation between Allergies and Hematologic Tumors. The review was performed using the PubMed database, with 50 works used. Conclusions: The relationship between allergies and hematological tumors is unclear. According to some studies, this relationship does not exist; some state, however, that allergic diseases show correlations with hematological malignancies. The results of these studies do not provide a clear answer to whether this is a positive or negative relationship. Some studies suggest that allergies reduce the risk of hematological malignancies, while others contradict this, suggesting that allergies may increase the risk of hematological tumors. The results of studies showing an increased risk of hematological malignancies in people suffering from allergies can be due to the hypothesis of antigenic stimulation, which may explain the mechanism of correlation between those diseases. This hypothesis suggests that chronic immune stimulation predisposes to hematologic malignancies such as multiple myeloma, non-Hodgkin's lymphoma (NHL), and leukemia by promoting the development of randomly occurring pro-oncogenic mutations in actively dividing immune cells. Different results on this potential correlation showed that further studies are necessary.

CT-defined muscle density as a prognostic factor in multiple myeloma undergoing autologous stem cell therapy: a retrospective single center study.

Skeletal muscle quality assessment can be performed by cross-sectional imaging. Skeletal muscle density (SMD) identified to be of prognostic relevance of several clinically outcomes in patients with hematological diseases. The purpose of the present study was to establish the effect of SMD on overall survival (OS) and progression-free survival (PFS) in patients with multiple myeloma (MM). All patients with MM were retrospectively analyzed between 2009 and 2019. 127 patients were included into the analysis. Whole-body computed tomography (CT) was used to calculate skeletal muscle index (SMI), SMD, albumin-gauge score and intramuscular adipose tissue content (IMAC). Overall, 28 patients (22.0%) of the patient sample died. In the discrimination analysis muscle density was higher in non-survivors compared to survivors (mean 30.8 ± 12.5 versus 24.1 ± 15.8, p = 0.03) and IMAC was lower in non-survivors (-0.66 ± 1.8 versus -0.25 ± 0.21, p = 0.01). These differences, however, were not demonstrated in the logistic regression analysis, which could not show prognostic relevance for the investigated muscle density parameters on PFS or OS. CT-defined muscle density parameters have no prognostic relevance on survival in patients with MM undergoing autologous stem cell therapy, which was demonstrated in a comprehensive analysis. These results corroborate previous smaller studies that body composition might have a limited role in this tumor entity.

An analytical study of ophthalmological manifestations in hematological malignancies in a tertiary care centre, India

: The objective of the study was to describe the ophthalmological manifestations associated with various haematological malignancies at a tertiary care centre. This analytical cross-sectional study was conducted with 60 patients diagnosed with various types of haematological malignancies, including leukaemia, lymphomas, and multiple myeloma. Patients who had ocular media opacities which precluded fundus view like dense corneal opacity, cataracts, absolute glaucoma, and systemic conditions like hypertension, and diabetes were excluded from this study. All 60 patients underwent a comprehensive ocular examination and the collected data were analysed using IBM SPSS software version 25. Out of the 60 patients with haematological malignancies, 27 (45%) exhibited ocular features. Ocular involvement was more common in males (63%) and in the paediatric age group (1-10 years) (100%). Ocular findings were prevalent in leukaemia patients especially with chronic myeloid leukaemia showing the highest incidence (80%), compared to lymphomas and multiple myeloma. The most common ocular manifestations were in the posterior segment, such as retinal haemorrhages and Roth spots, observed across all age groups. Neurological involvement, specifically III and VI cranial nerve palsy, were also notable. At the time of presentation, the majority of patients with ocular features had good visual acuity, ranging from 6/6 to 6/9 (43%). With advancements in diagnostic and therapeutic methods, the survival rates for patients with haematological malignancies have considerably improved. This has led to an increase in the variability of ocular presentations. Consequently, routine ocular examination is essential at the time of diagnosis of haematological malignancies to prevent vision-threatening complications and improve the overall quality of life for these patients.

Clinical Spectrum of Monoclonal Protein and the Factors Associated with Lymphoplasmacytic Malignancies

Background: Monoclonal protein (MP) presents in various monoclonal gammopathies, ranging from benign conditions such as monoclonal gammopathy of undetermined significance (MGUS) to life-threatening conditions such as lymphoplasmacytic malignancies (LPMs), which include multiple myeloma (MM) and Waldenström macroglobulinemia (WM). Few studies have comprehensively assessed the clinical spectrum of MP and its factors associated with LPMs. This study aimed to determine the clinical spectrum of MP and identify factors associated with LPMs. Methods: This retrospective study included patients who were first tested for capillary electrophoresis (CEP) and identified as having MP between 2014 and 2023 at two university hospitals. Univariate (crude) and multivariate (adjusted) logistic regression analyses were performed to identify factors associated with LPMs. Results: Among the 1135 included patients with MP, 744 (65.6%) were diagnosed with LPMs and 391 (34.4%) with MGUS. Among the 391 patients with MGUS, 310 (79.3%) had at least 1 clinical association, including 204 with renal diseases, 35 with autoimmune diseases, 33 with chronic liver diseases, 22 with hematologic diseases, and 96 with other conditions. Multivariate analyses indicated that LPMs were associated with female sex (OR = 2.08), lower age (OR = 0.95), higher MP level (OR = 3.53), an abnormal FLC ratio (OR = 6.15), lower hemoglobin level (OR = 0.82), and higher total calcium level (OR = 1.81) (all p &lt; 0.05). Conclusions: This study provides insight into the distribution of MPs and their clinical association with MGUS and identifies factors related to LPM. These can help clinicians manage patients more effectively in the early stages of these conditions.

MRD-negative duration following latest line of therapy predicts long-term PFS in real-world multiple myeloma patients.

MRD-negative duration following latest line of therapy predicts long-term PFS in real-world multiple myeloma patients.

Abstract B010: Systematical evaluation on alternative splicing in immune-related therapy targets reveals innate and acquired therapy resistance mechanisms in multiple myeloma

Abstract Introduction: Although multiple myeloma (MM) is considered incurable, immune-related therapies are emerging as promising approaches to prolong patient survival. Alternative splicing (AS) has been identified as a mechanism causing therapy resistance to CD19 CAR-T in B-cell malignancies, but no systematic evaluation has been made on the impact towards MM immunotherapy targets. Methods: Utilizing two datasets (MMRF N=852 and IU N=122), we selected high-confidence targets based on high RNA expression (Log2(TPM+1)&amp;gt;3), low toxicity (nTPM&amp;gt;50 in &amp;lt;2 normal tissues and in &amp;lt;2 normal blood cells) and high target potential (&amp;gt;3 surfaceome databases or established immune-therapy targets). Known resistance mechanisms of other therapies, such as immunomodulatory drugs (IMiDs) were also included. AS analysis was conducted for all identified targets. Expression and AS events between patient samples and 19 MM cell lines from DepMap database were also measured. Results: 102 high-confidence targets were identified in MM samples including six existing immunotherapy targets (BCMA, SLAMF7, GPRC5D, CD79A/B and CD38). From these 102 genes, 361 significant AS events were subsequently identified (|dPSI|&amp;gt;0.2, FDR&amp;lt;0.05, &amp;gt;10 supporting reads in &amp;gt;25% samples). One event of interest included an aberrant exon inclusion event in the existing target FCRL5 in ∼10% of newly diagnosed and relapse patient samples, despite being treatment naïve. A cryptic exon between exon 3 and 4 of the canonical transcript was found with higher usage in MM (PSI&amp;gt;0.48) compared to 8 normal bone marrow plasma cell samples (=0.13). Inclusion of this exon led to the switch from three protein-coding transcript variants (FCRL5-201, -202, -203) to a transcript encoding a truncated protein after the first Ig domain (-206). The AS event in treatment-naïve patients may lead to the selection of this variant in treated patients as a mechanism of therapy resistance. Another key event was detected in CRBN, which encodes the target of IMiDs including lenalidomide. Serial samples in one patient treated with lenalidomide identified a novel splice junction in CRBN in the later sample (dPSI=0.2). The novel splice junction led to the skipping of exon 8 encoding the LON domain, which is essential for maintaining the functional conformation of the IMiD-binding site. Lack of exon 8 will disrupt LON domain integrity, indicating a potential AS-induced resistance mechanism. Interestingly, the novel splice junction was found in 70% relapsed samples (&amp;gt;10 supporting reads), 60% of which were with high exon skipping level (PSI&amp;lt;0.5). Conclusion: We have identified potential innate and acquired AS mechanisms that affect patient response towards immune-related therapies, highlighting the importance of conducting RNA-based diagnostics for MM patients. Citation Format: Enze Liu, Travis S Johnson, Parvathi Sudha, Habib Hamidi, Faiza Zafar, Vivek S Chopra, Rafat Abonour, Brian A Walker. Systematical evaluation on alternative splicing in immune-related therapy targets reveals innate and acquired therapy resistance mechanisms in multiple myeloma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B010.

A systematic literature review on clonal evolution events preceding relapse in multiple myeloma.

Despite considerable treatment advances, multiple myeloma (MM) remains an incurable hematological cancer due to treatment resistance. A systematic literature search was conducted to identify determinants for clonal evolution driving relapse and drug resistance in MM. A total of 631 non-duplicate publications were screened of which 28 articles were included for data extraction. Genetic alterations, mutational signatures, evolutionary trajectories, and non-genetic determinants were identified as key topics to characterize clonal evolution in relapsed MM. A variety of factors led to clonal diversification and increased tumor mutation burden, such as MAPK-Ras mutations and incremental changes related to chromosomal bands 1 and 17, while mutational signature analyses revealed that APOBEC activity and melphalan treatment leave a distinct impact on the clonal composition in MM genomes. To capture and dissect tumor heterogeneity, our review suggests combining methods or using technical approaches with high resolution to assess the impact of clonal evolution.

Pharmacokinetic Positron Emission Tomography Imaging of an Optimized CD38-Targeted 68Ga-Labeled Peptide in Multiple Myeloma: A Pilot Study.

Multiple myeloma (MM) is an incurable disease characterized by its clinical and prognostic heterogeneity. Despite conventional chemotherapy and autologous hematopoietic stem cell transplantation, the management of relapsed and refractory MM disease poses significant challenges, both medically and socioeconomically. CD38, highly expressed on the surface of MM cells, serves as a distinct tumor biological target in MM. Peptides offer advantages over antibodies, enabling precise tumor imaging and facilitating early tumor diagnosis and dynamic immunotherapy monitoring. In this study, we developed PF381, a CD38-targeted peptide, and investigated its role in diagnosis, biodistribution, and dosimetry through 68Ga-labeling for preclinical evaluation in tumor-bearing models. We screened a microchip-based combinatorial chemistry peptide library to obtain the amino acid sequence of PF381. Affinity for human CD38 was evaluated by SPRi. PF381 was conjugated with DOTA for radiolabeling with 68Ga, and the complex was characterized by HPLC. PET imaging was performed in murine tumor models after the administration of [68Ga]Ga-DOTA-PF381. Biodistribution analysis compared CD38-positive H929 and CD38-negative U266 tumors, and human radiation dosimetry was estimated. Tumor sections were stained for CD38 expression. SPRi showed that PF381 had a high affinity for CD38 with a KD of 2.49 × 10-8 M. HPLC measured a radiolabeling efficiency of 78.45 ± 7.91% for [68Ga]Ga-DOTA-PF381, with >98% radiochemical purity. PET imaging revealed rapid and persistent accumulation of radioactivity in CD38-positive H929 tumors, contrasting with negligible uptake in CD38-negative U266 tumors. Biodistribution confirmed higher uptake in H929 tumors (0.75 ± 0.03%ID/g) vs U266 (0.26 ± 0.08%ID/g, P < 0.001). The kidney received the highest radiation dose (3.57 × 10-02 mSv/MBq), with an effective dose of 1.41 × 10-02 mSv/MBq. Immunofluorescence imaging supported PET and biodistribution findings. We developed a novel peptide targeting CD38 and proved that 68Ga-labeled PF381 had rapid targeting and good tumor penetration capabilities. Therefore, 68Ga-labeled PF381 could achieve high sensitivity in vivo imaging for CD38-positive hematological malignancies.

M-protein-related necrobiotic granuloma in a multiple myeloma patient treated with daratumumab, lenalidomide and dexamethasone.

M-protein-related necrobiotic granuloma in a multiple myeloma patient treated with daratumumab, lenalidomide and dexamethasone.

Exploring the Relationship Between Daratumumab Treatment and Stem Cell Collection in Newly Diagnosed Multiple Myeloma (NDMM) Patients Undergoing Transplantation: Insights From a Single-Center Investigation

Exploring the Relationship Between Daratumumab Treatment and Stem Cell Collection in Newly Diagnosed Multiple Myeloma (NDMM) Patients Undergoing Transplantation: Insights From a Single-Center Investigation

Ixazomib, pomalidomide and dexamethasone in relapsed or refractory multiple myeloma characterized with high-risk cytogenetics: the IFM 2014-01 study.

Not available.

Natural killer cell biology and therapy in multiple myeloma: challenges and opportunities.

Despite therapeutic advancements, multiple myeloma (MM) remains incurable. NK cells have emerged as a promising option for the treatment of MM. NK cells are heterogenous and typically classified based on the relative expression of their surface markers (e.g., CD56 and CD16a). These cells elicit an antitumor response in the presence of low mutational burden and without neoantigen presentation via germline-encoded activating and inhibitory receptors that identify the markers of transformation present on the MM cells. Higher NK cell activity is associated with improved survival and prognosis, whereas lower activity is associated with advanced clinical stage and disease progression in MM. Moreover, not all NK cell phenotypes contribute equally toward the anti-MM effect; higher proportions of certain NK cell phenotypes result in better outcomes. In MM, the proportion, phenotype, and function of NK cells are drastically varied between different disease stages; this is further influenced by the bone marrow microenvironment, proportion of activating and inhibitory receptors on NK cells, expression of homing receptors, and bone marrow hypoxia. Antimyeloma therapies, such as autologous stem cell transplant, immunomodulation, proteasome inhibition, and checkpoint inhibition, further modulate the NK cell landscape in the patients. Thus, NK cells can naturally work in tandem with anti-MM therapies and be strategically modulated for improved anti-MM effect. This review article describes immunotypic and phenotypic differences in NK cells along with the functional changes in homeostatic and malignant states and provides expert insights on strategies to harness the potential of NK cells for improving outcomes in MM.