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The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.
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Linfoma de Células B , Macroglobulinemia de Waldenström , Humanos , Macroglobulinemia de Waldenström/terapia , Macroglobulinemia de Waldenström/tratamiento farmacológicoRESUMEN
Chimeric antigen receptor T (CAR T) cell and bispecific antibody therapies have shown unprecedented efficacy in heavily pretreated patients with multiple myeloma (MM). However, their use is associated with a significant risk of severe infections, which can be attributed to various factors such as hypogammaglobulinemia, neutropenia, lymphopenia, T-cell exhaustion, cytokine-release syndrome and immune-effector cell-associated neurotoxicity syndrome. As these therapies have been recently approved by regulatory agencies, it is crucial to establish practical guidelines for infection monitoring and prevention until robust data from prospective clinical trials become available. To address this issue, a panel of experienced investigators from the Academic Consortium to Overcome Multiple Myeloma through Innovative Trials (COMMIT) developed consensus recommendations for mitigating infections associated with CAR T-cell and bispecific antibody therapies in MM patients.
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Anticuerpos Biespecíficos , Leucopenia , Mieloma Múltiple , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/uso terapéutico , Linfocitos T , Mieloma Múltiple/tratamiento farmacológico , Estudios Prospectivos , Inmunoterapia Adoptiva/efectos adversos , Anticuerpos Biespecíficos/efectos adversos , Leucopenia/etiología , Antígeno de Maduración de Linfocitos BRESUMEN
Primary systemic light chain amyloidosis (SLCA) is characterized by production of light chains that get converted to amyloid fibrils with an affinity for visceral organs and causing organ dysfunction. The therapy for SLCA is directed to recovering the function of the affected organs by targeting the abnormal plasma cell clone and slowing deposition of amyloid fibrils. The NCCN Guidelines for SLCA provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated SLCA.
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Amiloide , Amiloidosis , Humanos , Amiloidosis/diagnóstico , Amiloidosis/terapia , Amiloidosis/etiología , Células PlasmáticasRESUMEN
The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.
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Mieloma Múltiple , Humanos , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Oncología Médica , Mieloma Múltiple/terapia , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológicoRESUMEN
BACKGROUND: Proteasome inhibitors (PIs), including carfilzomib, potentiate the activity of selinexor, a novel, first-in-class, oral selective inhibitor of nuclear export (SINE) compound, in preclinical models of multiple myeloma (MM). METHODS: The safety, efficacy, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of selinexor (80 or 100 mg) + carfilzomib (56 or 70 mg/m2) + dexamethasone (40 mg) (XKd) once weekly (QW) was evaluated in patients with relapsed refractory MM (RRMM) not refractory to carfilzomib. RESULTS: Thirty-two patients, median prior therapies 4 (range, 1-8), were enrolled. MM was triple-class refractory in 38% of patients and 53% of patients had high-risk cytogenetics del(17p), t(4;14), t(14;16) and/or gain 1q. Common treatment-related adverse events (all/Grade 3) were thrombocytopenia 72%/47% (G3 and G4), nausea 72%/6%, anaemia 53%/19% and fatigue 53%/9%, all expected and manageable with supportive care and dose modifications. MTD and RP2D were identified as selinexor 80 mg, carfilzomib 56 mg/m2, and dexamethasone 40 mg, all QW. The overall response rate was 78% including 14 (44%) ≥ very good partial responses. Median progression-free survival was 15 months. CONCLUSIONS: Weekly XKd is highly effective and well-tolerated. These data support further investigation of XKd in patients with MM.
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Dexametasona/administración & dosificación , Hidrazinas/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Oligopéptidos/administración & dosificación , Triazoles/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dexametasona/efectos adversos , Esquema de Medicación , Femenino , Humanos , Hidrazinas/efectos adversos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mieloma Múltiple/genética , Oligopéptidos/efectos adversos , Análisis de Supervivencia , Translocación Genética , Resultado del Tratamiento , Triazoles/efectos adversosRESUMEN
Patients with multiple myeloma are at increased risk of vascular thromboembolic events (VTEs). This post hoc analysis evaluated VTEs in the randomised phase 2 GRIFFIN study (ClinicalTrials.gov Identifier: NCT02874742) that investigated lenalidomide/bortezomib/dexamethasone (RVd) ± daratumumab (D). Patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplantation (ASCT) received D-RVd/RVd induction, high-dose therapy and ASCT, D-RVd/RVd consolidation and up to 2 years of lenalidomide maintenance therapy ± D. VTE prophylaxis was recommended (at least aspirin, ≥162 mg daily) in accordance with International Myeloma Working Group guidelines. In the safety population (D-RVd, n = 99; RVd, n = 102), VTEs occurred in 10.1% of D-RVd patients and 15.7% of RVd patients; grade 2-4 VTEs occurred in 9.1% and 14.7%, respectively. Median time to the first onset of VTE was longer for D-RVd versus RVd patients (305 days vs 119 days). Anti-thrombosis prophylaxis use was similar between arms (D-RVd, 84.8% vs RVd, 83.3%); among patients with VTEs, prophylaxis use at time of first VTE onset was 60.0% for D-RVd and 68.8% for RVd. In summary, the addition of daratumumab to RVd did not increase the incidence of VTEs, but the cumulative VTE incidence was relatively high in this cohort and anti-thrombotic prophylaxis use was suboptimal.
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Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Tromboembolia Venosa , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Aspirina/uso terapéutico , Bortezomib , Dexametasona , Lenalidomida , Mieloma Múltiple/terapia , Trasplante Autólogo , Tromboembolia Venosa/prevención & control , Tromboembolia Venosa/inducido químicamenteRESUMEN
Venous thromboembolism (VTE) is a major complication in all patients with cancer. Compared with the general population, patients with multiple myeloma (MM) have a 9-fold increase in VTE risk, likely because of their malignancy, its treatments, and other additional patient-related factors. In MM, thromboembolism events tend to occur within 6 months of treatment initiation, regardless of treatment regimen; however, the use of immunomodulatory agents such as thalidomide or lenalidomide, especially in combination with dexamethasone or multiagent chemotherapy, is known to create a significant risk for VTE. Currently, official recommendations for VTE prophylaxis in MM outlined in various national guidelines or multidisciplinary society panels are based on expert opinion, because data from randomized controlled trials are scarce. Large studies which have mainly focused on the efficacy of thromboprophylaxis in patients with cancer at higher risk for VTE either had a very low representation of patients with MM, or excluded them all together, limiting our ability to draw evidence-based conclusions on how to effectively protect MM population from VTE. In this brief perspective, we highlight some of the greatest challenges that have hampered the field concerning the availability of high-quality clinical trial data for the formulation of best VTE prophylaxis strategies in patients with newly diagnosed MM, as well as the rationale for the latest updates in the NCCN Guidelines on this topic.
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Mieloma Múltiple , Tromboembolia Venosa , Anticoagulantes/efectos adversos , Humanos , Lenalidomida/efectos adversos , Mieloma Múltiple/complicaciones , Mieloma Múltiple/tratamiento farmacológico , Factores de Riesgo , Talidomida/efectos adversos , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/etiología , Tromboembolia Venosa/prevención & controlRESUMEN
The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with various plasma cell neoplasms, including multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates/changes specific to the treatment of patients with multiple myeloma in the 2022 version of the guidelines.
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Mieloma Múltiple , Humanos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapiaRESUMEN
Despite the benign nature of monoclonal gammopathy of undetermined significance (MGUS), mounting data are associating MGUS with the development of organ dysfunction, specifically monoclonal gammopathy of renal significance (MGRS) and monoclonal gammopathy of neurological significance (MGNS), which could be associated with substantial morbidity. Emerging evidence suggests that patients with MGRS and MGNS could benefit from treatments used for myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia, depending on the underlying pathology. However, the treatment of MGRS and MGNS is not standardized, and potentially effective therapies might not be reimbursed because these conditions do not formally meet the criteria for malignant processes. The present review aims at establishing standards for the evaluation and management of MGRS and MGNS, which can facilitate the diagnosis of and provide therapeutic options for treating practitioners and patients affected by these conditions. The careful design and execution of clinical trials for patients with MGRS and MGNS are positively encouraged.
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Riñón/patología , Gammopatía Monoclonal de Relevancia Indeterminada/patología , Sistema Nervioso/patología , Animales , Manejo de la Enfermedad , Progresión de la Enfermedad , Humanos , Enfermedades Renales/diagnóstico , Enfermedades Renales/etiología , Enfermedades Renales/patología , Enfermedades Renales/terapia , Gammopatía Monoclonal de Relevancia Indeterminada/complicaciones , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Gammopatía Monoclonal de Relevancia Indeterminada/terapia , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/patología , Enfermedades del Sistema Nervioso/terapiaRESUMEN
Muhamed Baljevic, MD, considers the role of autologous stem cell transplantation for light chain amyloidosis in a peer perspective accompanying an article by Iuliana Vaxman, MD, and Angela Dispenzieri, MD.
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Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/terapia , Trasplante de Células Madre/métodos , Trasplante Autólogo/métodos , Supervivencia sin Enfermedad , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Acondicionamiento Pretrasplante/métodosRESUMEN
Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.
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Mieloma Múltiple , Médula Ósea , Humanos , Oncología Médica , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Células Plasmáticas , PlasmacitomaRESUMEN
The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, workup, treatment, follow-up, and supportive care for patients with monoclonal gammopathy of renal significance, solitary plasmacytoma, smoldering myeloma, and multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates and changes in the 1.2020 version of the NCCN Guidelines for Multiple Myeloma.
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Mieloma Múltiple , HumanosRESUMEN
The hepatocyte growth factor/c-MET pathway has been implicated in the pathobiology of multiple myeloma, and c-MET inhibitors induce myeloma cell apoptosis, suggesting that they could be useful clinically. We conducted a phase II study with the c-MET inhibitor tivantinib in patients with relapsed, or relapsed and refractory myeloma whose disease had progressed after one to four prior therapies. Tivantinib, 360 mg orally per dose, was administered twice daily continuously over a 4-week treatment cycle without a cap on the number of allowed cycles, barring undue toxicities or disease progression. Primary objectives were to determine the overall response rate and the toxicities of tivantinib in this patient population. Sixteen patients were enrolled in a two-stage design. Notable grade 3 and 4 hematological adverse events were limited to neutropenia in five and four patients, respectively. Nonhematological adverse events of grade 3 or higher included hypertension (in four patients); syncope, infection, and pain (two each); and fatigue, cough, and pulmonary embolism (one each). Four of 11 evaluable patients (36%) had stable disease as their best response, while the remainder showed disease progression. Overall, tivantinib as a single agent did not show promise for unselected relapsed/refractory myeloma patients. However, the ability to achieve stable disease does suggest that combination regimens incorporating targeted inhibitors in patients with c-MET pathway activation could be of interest.
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Mieloma Múltiple/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirrolidinonas/uso terapéutico , Quinolinas/uso terapéutico , Anciano , Supervivencia sin Enfermedad , Esquema de Medicación , Resistencia a Antineoplásicos , Fatiga/inducido químicamente , Femenino , Humanos , Hipertensión/inducido químicamente , Masculino , Persona de Mediana Edad , Mieloma Múltiple/metabolismo , Recurrencia Local de Neoplasia , Neutropenia/inducido químicamente , Dolor/inducido químicamente , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirrolidinonas/efectos adversos , Quinolinas/efectos adversos , Resultado del TratamientoRESUMEN
Telomeres are the capping ends of chromosomes that protect the loss of genetic material and prevent chromosomal instability. In human tissue-specific stem/progenitor cells, telomere length (TL) is maintained by the telomerase complex, which consists of a reverse transcriptase catalytic subunit (TERT) and an RNA template (TERC). Very short telomeres and loss-of-function mutations in the TERT and TERC genes have been reported in acute myeloid leukemia, but the role of telomeres in acute promyelocytic leukemia (APL) has not been well established. We report the results for a large cohort of 187 PML/RARα-positive APL patients. No germline mutations in the TERT or TERC genes were identified. Codon 279 and 1062 TERT polymorphisms were present at a frequency similar to that in the general population. TL measured in blood or marrow mononuclear cells at diagnosis was significantly shorter in the APL patients than in healthy volunteers, and shorter telomeres at diagnosis were significantly associated with high-risk disease. For patients who achieved complete remission, the median increase in TL from diagnosis to remission (delta TL) was 2.0 kilobase (kb), and we found delta TL to be the most powerful predictor of overall survival when compared with well-established risk factors for poor outcomes in APL.
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Codón , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/mortalidad , Polimorfismo Genético , Telomerasa/genética , Homeostasis del Telómero/genética , Adolescente , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , ARN/genética , Tasa de Supervivencia , Homeostasis del Telómero/efectos de los fármacosRESUMEN
Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA), which copresents with microangiopathic hemolytic anemia, thrombocytopenia, and kidney injury. While typical HUS is normally preceded by infections such as Shiga-toxin-producing Escherichia coli, atypical HUS (aHUS) has a genetic component that leads to dysregulation of the alternative complement pathway. We report a case of a 69-year-old female who developed aHUS after undergoing an elective knee surgery. Genetic testing revealed novel mutations affecting diacylglycerol kinase epsilon (DGKE) protein and complement factor I (CFI) that were not reported before as pathogenic. The patient was treated with eculizumab, leading to the complete resolution of TMA with no lasting organ damage.
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Objective: To identify the optimal dose of selinexor in combination with pomalidomide and dexamethasone (SPd). Methods: An analysis of efficacy and safety of 2 once-weekly selinexor regimens (60 mg and 40 mg) with pomalidomide and dexamethasone (SPd-60 and SPd-40, respectively) given to patients with relapsed/refractory multiple myeloma (RRMM) in the STOMP (NCT02343042) and XPORT-MM-028 (NCT04414475) trials. Results: Twenty-eight patients (60.7% males, median age 67.5 years) and 20 patients (35.0% males, median age 65.5 years) were analyzed in the SPd-40 and SPd-60 cohorts, respectively. Overall response rate was 50% (95% confidence interval [CI] 30.6-69.4%) and 65% (95% CI 40.8-84.6%), respectively. Very good partial response or better was reported in 28.6% (95% CI 13.2-48.7%) and 30.0% (95% CI 11.9-54.3%) of patients, respectively. Among 27 responders in both cohorts, the 12-month sustained response rate was 83.3% (95% CI 64.7-100.0%) for SPd-40 and 28.1% (95% CI 8.9-88.8%) for SPd-60. Median progression-free survival was 18.4 months (95% CI 6.5 months, not evaluable [NE]) and 9.5 months (95% CI 7.6 months-NE) for SPd-40 and SPd-60, respectively. Twenty-four-month survival rates were 64.2% (95% CI 47.7-86.3%) for SPd-40 and 51.1% (95% CI 29.9-87.5%) for SPd-60. Treatment-emergent adverse events (TEAEs) included neutropenia (all grades: SPd-40 64.3% versus SPd-60 75.0%), anemia (46.4% versus 65.0%), thrombocytopenia (42.9% versus 45.0%), fatigue (46.4% versus 75.0%), nausea (32.1% versus 70.0%) and diarrhea (28.6% versus 35.0%). Conclusion: The all-oral combination of SPd exhibited preliminary signs of efficacy and was generally tolerable in patients with RRMM. The overall risk-benefit profile favored the SPd-40 regimen.
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ABSTRACT: Clonal hematopoiesis (CH) is an age-associated phenomenon leading to an increased risk of both hematologic malignancy and nonmalignant organ dysfunction. Increasingly available genetic testing has made the incidental discovery of CH clinically common yet evidence-based guidelines and effective management strategies to prevent adverse CH health outcomes are lacking. To address this gap, the prospective CHIVE (clonal hematopoiesis and inflammation in the vasculature) registry and biorepository was created to identify and monitor individuals at risk, support multidisciplinary CH clinics, and refine taxonomy and standards of practice for CH risk mitigation. Data from the first 181 patients enrolled in this prospective registry recapitulate the molecular epidemiology of CH from biobank-scale retrospective studies, with DNMT3A, TET2, ASXL1, and TP53 as the most commonly mutated genes. Blood counts across all hematopoietic lineages trended lower in patients with CH. In addition, patients with CH had higher rates of end organ dysfunction, in particular chronic kidney disease. Among patients with CH, variant allele frequency was independently associated with the presence of cytopenias and progression to hematologic malignancy, whereas other common high-risk CH clone features were not clear. Notably, accumulation of multiple distinct high-risk clone features was also associated with cytopenias and hematologic malignancy progression, supporting a recently published CH risk score. Surprisingly, â¼30% of patients enrolled in CHIVE from CH clinics were adjudicated as not having clonal hematopoiesis of indeterminate potential, highlighting the need for molecular standards and purpose-built assays in this field. Maintenance of this well-annotated cohort and continued expansion of CHIVE to multiple institutions are underway and will be critical to understanding how to thoughtfully care for this patient population.
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Hematopoyesis Clonal , Inflamación , Humanos , Estudios Prospectivos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Sistema de Registros , Neoplasias Hematológicas/genética , Mutación , AdultoRESUMEN
Translocation t(11;17) is a well-recognized variant of acute promyelocytic leukemia (APL) and has also been identified in patients with mixed-lineage leukemia (MLL) non-APL acute myeloid leukemia. Here, we describe two patients bearing translocation t(11;17) presenting with a clinical diagnosis of de novo myelodysplastic syndrome (MDS): the first with sole karyotypic abnormality 46,XY,t(11;17)(p11.2; p13) and the second where it represented one of the two karyotypic abnormalities 46,XX,del(5)(q13q33)46,XX,del(5)(q13q33),t(11;17)(q24;q23). Molecular characterization of both cases failed to identify fusion transcripts involving MLL or PLZF-RARA and no collaborating somatic mutations commonly found among MDS patients were seen in either case, suggesting the presence of an as yet unidentified oncogenic fusion protein.
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Síndromes Mielodisplásicos/genética , Translocación Genética , Adulto , Médula Ósea/patología , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 17 , Femenino , Humanos , Cariotipificación , Leucemia Mieloide Aguda/patología , Leucemia Promielocítica Aguda/patología , Masculino , Metafase , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Pancitopenia/etiologíaRESUMEN
Competent T-cells with sufficient levels of fitness combat cancer formation and progression. In multiple myeloma (MM), T-cell exhaustion is caused by several factors including tumor burden, constant immune activation due to chronic disease, age, nutritional status, and certain MM treatments such as alkylating agents and proteasome inhibitors. Many currently used therapies, including bispecific T-cell engagers, anti-CD38 antibodies, proteasome inhibitors, and CART-cells, directly or indirectly depend on the anti-cancer activity of T-cells. Reduced T-cell fitness not only diminishes immune defenses, increasing patient susceptibility to opportunistic infections, but can impact effectiveness MM therapy effectiveness, bringing into focus sequencing strategies that could modulate T-cell fitness and potentially optimize overall benefit and clinical outcomes. Certain targeted agents used to treat MM, such as selective inhibitors of nuclear export (SINE) compounds, have the potential to mitigate T-cell exhaustion. Herein referred to as XPO1 inhibitors, SINE compounds inhibit the nuclear export protein exportin 1 (XPO1), which leads to nuclear retention and activation of tumor suppressor proteins and downregulation of oncoprotein expression. The XPO1 inhibitors selinexor and eltanexor reduced T-cell exhaustion in cell lines and animal models, suggesting their potential role in revitalizating these key effector cells. Additional clinical studies are needed to understand how T-cell fitness is impacted by diseases and therapeutic factors in MM, to potentially facilitate the optimal use of available treatments that depend on, and impact, T-cell function. This review summarizes the importance of T-cell fitness and the potential to optimize treatment using T-cell engaging therapies with a focus on XPO1 inhibitors.