RESUMEN
Venetoclax is a highly potent, selective BCL2 inhibitor capable of inducing apoptosis in cells dependent on BCL2 for survival. Most myeloma is MCL1-dependent; however, a subset of myeloma enriched for translocation t(11;14) is codependent on BCL2 and thus sensitive to venetoclax. The biology underlying this heterogeneity remains poorly understood. We show that knockdown of cyclin D1 does not induce resistance to venetoclax, arguing against a direct role for cyclin D1 in venetoclax sensitivity. To identify other factors contributing to venetoclax response, we studied a panel of 31 myeloma cell lines and 25 patient samples tested for venetoclax sensitivity. In cell lines, we corroborated our previous observation that BIM binding to BCL2 correlates with venetoclax response and further showed that knockout of BIM results in decreased venetoclax sensitivity. RNA-sequencing analysis identified expression of B-cell genes as enriched in venetoclax-sensitive myeloma, although no single gene consistently delineated sensitive and resistant cells. However, a panel of cell surface makers correlated well with ex vivo prediction of venetoclax response in 21 patient samples and may serve as a biomarker independent of t(11;14). Assay for transposase-accessible chromatin sequencing of myeloma cell lines also identified an epigenetic program in venetoclax-sensitive cells that was more similar to B cells than that of venetoclax-resistant cells, as well as enrichment for basic leucine zipper domain-binding motifs such as BATF. Together, these data indicate that remnants of B-cell biology are associated with BCL2 dependency and point to novel biomarkers of venetoclax-sensitive myeloma independent of t(11;14).
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Linfocitos B/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Epigénesis Genética/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Mieloma Múltiple , Sulfonamidas/farmacología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Línea Celular Tumoral , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 11/metabolismo , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 14/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Técnicas de Silenciamiento del Gen , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Translocación Genética/efectos de los fármacosRESUMEN
LAY SUMMARY: Elderly patients with myeloma derive benefits from transplantation similar to those for younger patients. Age should not be the sole criterion for determining transplant eligibility. Performance status assessment and other tools for assessing comorbidities such as the Charlson comorbidity score may potentially help in determining transplant eligibility and will allow us to move away from our heavy reliance on numerical age.
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Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Trasplante AutólogoRESUMEN
PURPOSE OF REVIEW: The aim of this article is to review the diagnosis and risk stratification of smoldering myeloma (SMM), describe recently published data regarding the early treatment of SMM, and to provide practical strategies on how to manage patients with SMM in the clinic. RECENT FINDINGS: Recently published data from the ECOG E3A06 and GEM-CESAR studies supporting early intervention for certain subsets of high-risk SMM patients will be presented, and the relevance of these findings in relation to real-life application will be explored. SUMMARY: Accurate risk-stratification and standard of care for SMM is evolving, and here we summarize the pertinent clinical data and provide recommendations for clinical management of SMM patients.
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Mieloma Múltiple Quiescente/diagnóstico , Mieloma Múltiple Quiescente/tratamiento farmacológico , Anciano , Ensayos Clínicos Fase III como Asunto , Dexametasona/administración & dosificación , Femenino , Humanos , Lenalidomida/administración & dosificación , Lenalidomida/uso terapéutico , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
The development of effective monoclonal antibodies for the treatment of myeloma has been a long journey of clinical and drug development. Identification of the right target antigen was a critical part of the process. CD38 as a target has been considered for some time, but clinically, daratumumab, a CD38 monoclonal antibody, was the first to be tested, and it has delivered the best clinical responses as a single agent to date. Its proven safety and efficacy in combination with other antimyeloma agents have led to several US Food and Drug Administration approvals for treating myeloma. Furthermore, the results of early trials in the induction therapy setting have demonstrated a beneficial role when it is added to the existing induction regimens. This review summarizes the importance of CD38 as a target and examines the clinical development of the CD38 monoclonal antibody daratumumab and its clinical significance in combination regimens in both patients with relapsed/refractory myeloma and patients with newly diagnosed myeloma.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , ADP-Ribosil Ciclasa 1/inmunología , ADP-Ribosil Ciclasa 1/metabolismo , Amiloidosis/tratamiento farmacológico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/farmacología , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos , Humanos , Inmunoterapia/métodos , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/metabolismo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder characterized by circulating plasma cells and a poor prognosis. Although patients who have pPCL benefit from the use of stem cell transplantation (SCT) and novel agents, their prognosis remains inferior to that of patients who have myeloma. METHODS: This was a retrospective analysis of 38 consecutive patients with pPCL who were diagnosed between October 2005 and July 2016 and were registered in the Winship Cancer Institute of Emory University database. Baseline characteristics as well as data about treatment and survival outcomes were collected. RESULTS: The median patient age at diagnosis was 58 years. All patients received a bortezomib-based induction regimen, and 92% received both bortezomib and an immunomodulatory drug (thalidomide or lenalidomide); in addition, 74% of patients underwent autologous SCT (ASCT), and 61% received maintenance therapy. The best response to first-line therapy was a partial response or better in 87% of patients, and 45% had a complete response (CR). The achievement of ≥CR was a predictor for prolonged progression-free survival (PFS) and overall survival (OS). The median PFS was 20 months, and the median OS was 33 months. PFS was prolonged in patients who underwent ASCT compared with those who did not undergo ASCT (25 vs 6 months; P = .004), and patients who received maintenance therapy after ASCT had prolonged median PFS (27 vs 11 months; P = .03) and a trend toward prolonged OS (median, 38 vs 22 months; P = .06) compared with those who did not receive maintenance therapy. CONCLUSIONS: The current data support the use of regimens combining novel agents in the upfront treatment of patients with pPCL as well as the role of ASCT and maintenance therapy for long-term disease control.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia de Células Plasmáticas/mortalidad , Leucemia de Células Plasmáticas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Bortezomib/uso terapéutico , Quimioterapia Adyuvante , Drogas en Investigación/uso terapéutico , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia de Células Plasmáticas/diagnóstico , Leucemia de Células Plasmáticas/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Talidomida/uso terapéutico , Terapias en Investigación , Trasplante Autólogo , Resultado del TratamientoRESUMEN
BACKGROUND: The efficacy of daratumumab (DARA) both as a monotherapy and in combination with standard-of-care regimens in multiple myeloma (MM) has been established in clinical trials. This article presents a retrospective analysis of the safety and efficacy of DARA in combination with pomalidomide (POM) and dexamethasone (ie, daratumumab, pomalidomide, and dexamethasone [DARA-POM-D]) and, more importantly, the long-term follow-up of a cohort that was naive to DARA and POM as well as a cohort in which the utility of re-treatment was evaluated among patients who were DARA- and/or POM-refractory. METHODS: Thirty-four consecutive patients with relapsed and/or refractory MM treated with DARA-POM-D at the Winship Cancer Institute of Emory University from January 2015 through July 2016 were included in the analysis. The study was approved by Emory University's institutional review board. All received prior proteasome inhibitors and immunomodulatory drugs (IMiDs) and were refractory to their last line of therapy. RESULTS: All patients were lenalidomide-refractory, and 91% were bortezomib-refractory. Two cohorts were identified on the basis of prior exposure to DARA and/or POM. Cohort 1 (12 patients) was DARA- and POM-naive, and cohort 2 (22 patients) was DARA- and/or POM-refractory. A subgroup of 12 patients in cohort 2 (cohort 3) was DARA- and POM-refractory. The combination's tolerability was consistent with the results of the published phase 1b study (EQUULES) that evaluated the combination and no new safety signals were observed. The overall response rates (ORRs) were 91.7%, 40.9%, and 33.3% in cohorts 1, 2, and 3, respectively. Deep responses, including 4 stringent complete responses, were observed in cohort 1. In cohort 2, the ORR comprised 8 partial responses (PRs) and 1 very good PR. The median progression-free survival (PFS) was not reached in cohort 1 at a median follow-up of 41 months, and it was 3.2 months in cohort 2. DARA-POM-D not only was effective in DARA- and POM-naive patients but also produced clinical responses in a third of patients re-treated with these drugs. CONCLUSIONS: A better than quadrupled PFS benefit observed in cohort 1 in comparison with the previously reported benefit in the EQUULEUS trial (which led to US Food and Drug Administration approval of the DARA-POM-D combination) highlights the fact that the introduction of monoclonal antibody combination strategies and IMiDs as earlier lines of therapeutic options potentially could deliver better clinical outcomes. One-third of patients refractory to separate lines of DARA and/or POM responded when they were re-treated with a combination, and this resulted in survival benefits equivalent to those of other antimyeloma agents/combinations available for DARA-refractory patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Talidomida/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bortezomib/uso terapéutico , Estudios de Cohortes , Dexametasona/administración & dosificación , Femenino , Humanos , Lenalidomida/uso terapéutico , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estudios Retrospectivos , Talidomida/administración & dosificación , Resultado del TratamientoRESUMEN
High-dose therapy (HDT) and autologous stem cell transplantation (ASCT) are established components in the treatment of multiple myeloma; however, undergoing transplantation usually requires hematopoietic support, which poses a challenge among patients who are unwilling to receive blood products. Most transplant centers decline HDT/ASCT to these patients because of safety concerns. Here, the authors' institutional data on safety, engraftment parameters, and survival outcomes after bloodless ASCT (BL-ASCT) are examined among patients with myeloma. This retrospective case-control study included patients who underwent BL-ASCT and Transfusion-supported ASCT (TS-ASCT) at Emory University Hospital between August 2006 and August 2016. In total, 24 patients who underwent BL-ASCT and 70 who underwent TS-ASCT were included. The median time for neutrophil engraftment, platelet engraftment and the median length of hospital stay all were equivalent for both groups. There were no transplant-related cardiovascular complications or mortality in either the BL-ASCT group or the TS-ASCT group. The median progression-free survival was 36 months and 44 months in the BL-ASCT and TS-ASCT groups, respectively (P = .277), and the median OS was not reached in either group at a median follow-up of 59 months after ASCT (P = .627). There was no transplant-related mortality at the 100-day or 1-year mark in either group. BL-ASCT is safe and feasible; transplant-related mortality, cardiovascular and hematologic complications are similar to those associated with TS-ASCT. Furthermore, BL-ASCT can yield similar engraftment and survival parameters comparable to those observed with TS-ASCT.
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Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Trasplante de Células Madre/métodos , Adulto , Anciano , Amiloidosis/mortalidad , Amiloidosis/terapia , Transfusión Sanguínea , Enfermedades Cardiovasculares/etiología , Estudios de Casos y Controles , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Trasplante de Células Madre/efectos adversos , Trasplante de Células Madre/mortalidad , Análisis de Supervivencia , Trasplante Autólogo/efectos adversos , Trasplante Autólogo/métodos , Trasplante Autólogo/mortalidad , Resultado del TratamientoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Resistencia a Antineoplásicos , Terapia Molecular Dirigida , Mieloma Múltiple/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Terapia Recuperativa , Sulfonamidas/uso terapéutico , Adulto , Anciano , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 11/ultraestructura , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 14/ultraestructura , Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Selección de Paciente , Pronóstico , Supervivencia sin Progresión , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Translocación GenéticaRESUMEN
PURPOSE: The incidence of multiple myeloma (MM) is two to three times higher in Black patients compared with other races, making it the most common hematologic malignancy in this patient population. Current treatment guidelines recommend the combination of a proteasome inhibitor, an immunomodulatory agent, and a corticosteroid as preferred induction therapy. Bortezomib use comes with the risk of peripheral neuropathy (PN) and potential need for dose reduction, therapy interruption, and additional supportive medications. Known risk factors for bortezomib-induced peripheral neuropathy (BIPN) include diabetes mellitus, previous thalidomide, advanced age, and obesity. We aimed to determine the potential association between Black race and incidence of BIPN. PATIENTS AND METHODS: We identified a cohort of 748 patients with newly diagnosed MM who received induction with bortezomib, lenalidomide, and dexamethasone from 2007 to 2016. One hundred forty Black patients were matched with 140 non-Black patients on age, sex, BMI, and route of bortezomib administration. Incidence of BIPN was a binary event defined as new use of a neuropathy medication, bortezomib dose reduction, dose omission, or discontinuation because of PN. RESULTS: The incidence of BIPN was higher in Black patients (46%) compared with non-Black patients (34%; P = .05) in both univariate (odds ratio [OR], 1.61; 95% CI, 1.00 to 2.61; P = .052) and multivariable analyses (OR, 1.64; 95% CI, 1.01 to 2.67; P = .047). No significant differences in BIPN were seen when stratified by route of administration. CONCLUSION: These data indicate that Black race is an independent risk factor for the development of BIPN. Additional prevention strategies, close monitoring, and appropriate supportive care measures are warranted for these patients.
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Mieloma Múltiple , Enfermedades del Sistema Nervioso Periférico , Humanos , Bortezomib/efectos adversos , Lenalidomida/efectos adversos , Mieloma Múltiple/complicaciones , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/etnología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/etnología , Talidomida/efectos adversos , Negro o AfroamericanoRESUMEN
We characterized virus-neutralization and spike-binding antibody profiles in myeloma patients following monovalent or bivalent-SARS-CoV-2 booster vaccination. Vaccination improves the breadth of binding antibodies but not neutralization activity against current variants. Hybrid immunity and immune imprinting impact vaccine-elicited immunity.
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We characterized virus-neutralization and spike-binding antibody profiles in myeloma patients following monovalent or bivalent-SARS-CoV-2 booster vaccination. Vaccination improves the breadth of binding antibodies but not neutralization activity against current variants. Hybrid immunity and immune imprinting impact vaccine-elicited immunity.
RESUMEN
Entry of antigen-specific T cells into human tumors is critical for immunotherapy, but the underlying mechanisms are poorly understood. Here, we combined high-dimensional spatial analyses with in vitro and in vivo modeling to study the mechanisms underlying immune infiltration in human multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS). Clustered tumor growth was a feature of MM but not MGUS biopsies, and this growth pattern was reproduced in humanized mouse models. MM biopsies exhibited intralesional as well as spatial heterogeneity, with coexistence of T cell-rich and T cell-sparse regions and the presence of areas of T cell exclusion. In vitro studies demonstrated that T cell entry into MM clusters was regulated by agonistic signals and CD2-CD58 interactions. Upon adoptive transfer, antigen-specific T cells localized to the tumor site but required in situ DC-mediated antigen presentation for tumor entry. C-type lectin domain family 9 member A-positive (CLEC9A+) DCs appeared to mark portals of entry for gradients of T cell infiltration in MM biopsies, and their proximity to T cell factor 1-positive (TCF1+) T cells correlated with disease state and risk status. These data illustrate a role for tumor-associated DCs and in situ activation in promoting the infiltration of antigen-specific T cells in MM and provide insights into spatial alterations in tumor/immune cells with malignant evolution.
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Mieloma Múltiple , Lesiones Precancerosas , Animales , Ratones , Humanos , Mieloma Múltiple/patología , Linfocitos T , Lesiones Precancerosas/patología , Inmunoterapia/métodos , Presentación de Antígeno , Células DendríticasRESUMEN
Patients with multiple myeloma (MM) mount suboptimal neutralizing antibodies (nAb) following 2 doses of SARS-CoV-2 mRNA vaccines. Currently, circulating SARS-CoV-2 variants of concern (VOC) carry the risk of breakthrough infections. We evaluated immune recognition of current VOC including BA.1, BA.2, and BA.5 in 331 racially representative patients with MM following 2 or 3 doses of mRNA vaccines. The third dose increased nAbs against WA1 in 82%, but against BA variants in only 33% to 44% of patients. Vaccine-induced nAbs correlated with receptor-binding domain (RBD)-specific class-switched memory B cells. Vaccine-induced spike-specific T cells were detected in patients without seroconversion and cross-recognized variant-specific peptides but were predominantly CD4+ T cells. Detailed clinical/immunophenotypic analysis identified features correlating with nAb/B/T-cell responses. Patients who developed breakthrough infections following 3 vaccine doses had lower live-virus nAbs, including against VOC. Patients with MM remain susceptible to SARS-CoV-2 variants following 3 vaccine doses and should be prioritized for emerging approaches to elicit variant-nAb and CD8+ T cells. SIGNIFICANCE: Three doses of SARS-CoV-2 mRNA vaccines fail to yield detectable VOC nAbs in nearly 60% and spike-specific CD8+ T cells in >80% of myeloma patients. Patients who develop breakthrough infections following vaccination have low levels of live-virus nAb. This article is highlighted in the In This Issue feature, p. 101.
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COVID-19 , Mieloma Múltiple , Humanos , SARS-CoV-2 , Infección Irruptiva , COVID-19/prevención & control , Linfocitos T CD8-positivos , Vacunas de ARNm , Anticuerpos NeutralizantesRESUMEN
BACKGROUND: Melphalan is an alkylating agent used in both autologous (ASCT) and allogeneic stem cell transplantation. It is a substrate of L-type amino acid transporter-1 (LAT-1) and LAT-2, which are involved in its tissue penetration and elimination. Gabapentin and pregabalin, common concomitant medications in patients with multiple myeloma undergoing ASCT, are also substrates of LAT transporters, raising concern for potential competitive inhibition of melphalan transport. We evaluated whether concurrent use of gabapentin or pregabalin in patients receiving high-dose melphalan (≥140 mg/m2 ) prior to ASCT impacted frequency and severity of melphalan-related adverse events. OBJECTIVE: We aimed to determine if concurrent administration of gabapentin or pregabalin and melphalan increased melphalan toxicity. METHODS: This was a single-center, retrospective evaluation including patients ≥18 years of age who received high-dose melphalan as part of a conditioning regimen at the Winship Cancer Institute of Emory University between August 1, 2010 and April 1, 2020 and were followed through their transplant admission. After identification and inclusion of patients who received melphalan in combination with gabapentin or pregabalin, patient matching based on age (±5 years), sex, and melphalan dose (140 mg/m2 or 200 mg/m2 ) was utilized to generate a comparable cohort of patients who received melphalan alone. The primary outcome was hospital length of stay (LOS); secondary outcomes included supportive care requirements between days +4 and day +14 and time to neutrophil and platelet-20 engraftment. RESULTS: Among 176 patients evaluated in each group, median hospital LOS was 16 days, median time to neutrophil engraftment was 14 days, and median time to platelet-20 engraftment was 16 days in both groups. In addition, there were no significant differences in supportive care requirements between groups. CONCLUSION: In this study, use of gabapentin or pregabalin in combination with melphalan did not impact safety of the conditioning regimen in patients undergoing ASCT.
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Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Gabapentina/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Melfalán/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Pregabalina/uso terapéutico , Estudios Retrospectivos , Acondicionamiento Pretrasplante/efectos adversosRESUMEN
Although survival outcomes have improved dramatically over the last few decades in newly diagnosed myeloma patients, elderly patients have not yielded the same magnitude of benefit as evidenced by higher rates of reported myeloma-related deaths in patients over the age of 75. This is of particular importance given this cohort comprises a large proportion of myeloma patients with the median age of diagnosis being 70 years. One contributor to this discrepancy is reduced use of high-dose therapy and autologous stem cell transplantation (HDT/ASCT) in this population because of concerns for increased toxicity and safety. The objective of this retrospective analysis is to evaluate survival and safety outcomes in 53 newly diagnosed patients ≥74 years of age who underwent HDT/ASCT at our institution in comparison to 122 control patients in the same age bracket who did not undergo stem cell transplantation during this same time period. Patients treated at our institution were identified in our institutional myeloma database by age. They were all treated between November 2006 and October 2016 at the Winship Cancer Institute of Emory University. Fifty-three patients were identified who had undergone HDT/ASCT, and, to assess the relative benefit of ASCT, 122 control patients in the same age range were also identified who did not undergo HDT/ASCT during the same time period. The median age for the entire cohort was 77 years (74 years in the ASCT group versus 78 in the non-ASCT group). Median time to ASCT was 6 months (range 2-57 months). There were no gender or race differences between the 2 groups, although a higher proportion of high-risk patients underwent HDT/ASCT. Ninety-three percent of ASCT patients received triplet induction therapy with a proteasome inhibitor and immunomodulatory agent backbone in comparison to only 55% of patients the non-ASCT group. The median progression-free survival (PFS) for the ASCT group was 50 months versus 30 months in the non-ASCT group. The median overall survival (OS) was 80 months versus 40 months, respectively. In high-risk patients, the median PFS was 60.8 months, and the median OS was 77.8 months in the ASCT group compared to 26 months and 38 months in the non-ASCT group, respectively. There were no transplant-related deaths within the first 100 days in the ASCT group. This study offers real-world perspective and data on the safety and survival benefit of ASCT in the elderly population with a near doubling of OS when compared to those treated with similar regimens and modern agents without ASCT. These data provide a rationale for offering ASCT in elderly patients pending a thorough pretransplantation evaluation.
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Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Anciano , Humanos , Mieloma Múltiple/terapia , Estudios Retrospectivos , Trasplante de Células Madre/efectos adversos , Trasplante AutólogoRESUMEN
PURPOSE: Vaccine-induced neutralizing antibodies (nAbs) play a critical role in protection from SARS CoV-2. Patients with B-cell malignancies including myeloma are at increased risk of COVID-19-related mortality and exhibit variable serologic response to the vaccine. The capacity of vaccine-induced antibodies in these patients to neutralize SARS CoV-2 or its variants is not known. METHODS: Sera from 238 patients with multiple myeloma (MM) undergoing SARS CoV-2 vaccination were analyzed. Antibodies against the SARS CoV-2 spike receptor-binding domain (RBD) and viral nucleocapsid were measured to detect serologic response to vaccine and environmental exposure to the virus. The capacity of antibodies to neutralize virus was quantified using pseudovirus neutralization assay and live virus neutralization against the initial SARS CoV-2 strain and the B1.617.2 (Delta) variant. RESULTS: Vaccine-induced nAbs are detectable at much lower rates (54%) than estimated in previous seroconversion studies in MM, which did not monitor viral neutralization. In 33% of patients, vaccine-induced antispike RBD antibodies lack detectable neutralizing capacity, including against the B1.617.2 variant. Induction of nAbs is affected by race, disease, and treatment-related factors. Patients receiving mRNA1273 vaccine (Moderna) achieved significantly greater induction of nAbs compared with those receiving BNT162b2 (Pfizer; 67% v 48%, P = .006). CONCLUSION: These data show that vaccine-induced antibodies in several patients with MM lack detectable virus-neutralizing activity. Vaccine-mediated induction of nAbs is affected by race, disease, vaccine, and treatment characteristics. These data have several implications for the emerging application of booster vaccines in immunocompromised hosts.
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Vacunas contra la COVID-19 , COVID-19 , Mieloma Múltiple , Vacuna nCoV-2019 mRNA-1273 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacuna BNT162 , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Humanos , Pruebas de Neutralización , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , VacunaciónRESUMEN
ABSTRACT: Over the last decade, several very important prospective randomized controlled trials have confirmed the significant survival benefit conferred by maintenance therapies. Owing to these developments, the role of continued maintenance in the optimal management strategies of newly diagnosed myeloma patients (both transplant-eligible and transplant-ineligible) has been strongly cemented. In dealing with an incurable disease such as myeloma, whether to offer maintenance is no longer as relevant a question as it was before, but which antimyeloma agent or agents to use, as maintenance remains more pertinent today. More importantly, a personalized risk-stratified maintenance approach for an individual patient to yield the best benefit for that specific patient is yet to be uniformly adapted. In this article, we review the available and evolving clinical data leading to our current-day practices, and we make an effort to describe what lies ahead.
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Mieloma Múltiple , Humanos , Quimioterapia de Mantención , Mieloma Múltiple/tratamiento farmacológico , Estudios ProspectivosRESUMEN
Though survival outcomes in multiple myeloma patients have improved drastically over the past few decades, there still remains an ongoing need for effective and tolerable treatment options in the relapsed and refractory space. Encouragingly, there have been three recent FDA approvals for triple-class refractory multiple myeloma, and there is promising ongoing development of additional agents with varying novel mechanisms of action. Here, we will review the most recent data on both belantamab mafodotin, an antibody drug conjugate (ADC) targeting BCMA, and selinexor, a first-in-class selective inhibitor of XPO1, as well as touch on some of the recently published data for other immunotherapies in development, namely bispecific T cell engagers, ADCs, and CAR-T cell therapies.
RESUMEN
Waldenstrom macroglobulinemia (WM) and its precursor IgM gammopathy are distinct disorders characterized by clonal mature IgM-expressing B-cell outgrowth in the bone marrow. Here, we show by high-dimensional single-cell immunogenomic profiling of patient samples that these disorders originate in the setting of global B-cell compartment alterations, characterized by expansion of genomically aberrant extrafollicular B cells of the nonmalignant clonotype. Alterations in the immune microenvironment preceding malignant clonal expansion include myeloid inflammation and naïve B- and T-cell depletion. Host response to these early lesions involves clone-specific T-cell immunity that may include MYD88 mutation-specific responses. Hematopoietic progenitors carry the oncogenic MYD88 mutations characteristic of the malignant WM clone. These data support a model for WM pathogenesis wherein oncogenic alterations and signaling in progenitors, myeloid inflammation, and global alterations in extrafollicular B cells create the milieu promoting extranodal pattern of growth in differentiated malignant cells. SIGNIFICANCE: These data provide evidence that growth of the malignant clone in WM is preceded by expansion of extrafollicular B cells, myeloid inflammation, and immune dysfunction in the preneoplastic phase. These changes may be related in part to MYD88 oncogenic signaling in pre-B progenitor cells and suggest a novel model for WM pathogenesis. This article is highlighted in the In This Issue feature, p. 549.
Asunto(s)
Factor 88 de Diferenciación Mieloide , Macroglobulinemia de Waldenström , Linfocitos B/patología , Humanos , Inflamación/genética , Factor 88 de Diferenciación Mieloide/genética , Oncogenes , Microambiente Tumoral , Macroglobulinemia de Waldenström/genéticaRESUMEN
Smoldering multiple myeloma (SMM) is a precursor disease state that precedes the development of symptomatic myeloma. As we have learned more about the disease biology of SMM and risk factors for progression, updated risk stratification models, such as the Mayo 2018 model, or 20/2/20, have been developed. More accurate risk stratification and the development of effective and well-tolerated therapeutic agents have led to the investigation of early treatment of select patients with high-risk SMM with the aim of delaying time to progression to multiple myeloma. Ongoing debate surrounds which subset of patients with SMM to target, as well as the best treatment approach: preventative versus curative. Phase III data from the Spanish Myeloma Group/PETHEMA as well as the Eastern Cooperative Oncology Group (ECOG) E3A06 trial have shown the efficacy of lenalidomide with and without dexamethasone in high-risk SMM in delaying progression to symptomatic disease. Conversely, there exists an alternate strategy attempting to cure the disease prior to progression utilizing more intensive regimens similar to what is used for patients with newly diagnosed myeloma. However, our understanding of the disease biology of SMM and the role of immune regulation in preventing malignant transformation provides a strong rationale for an interventional strategy. Here, we review the definition of SMM, the current models for risk stratification, and the current data available supporting the early treatment of patients with high-risk SMM.