RESUMEN
The authors report the case of a multiple myeloma recurrence isolated to the lacrimal gland. The patient is a 54-year-old man with a medical history of IgA kappa multiple myeloma status post multiple lines of chemotherapy and stem cell transplantation (×2) who was presumed to be without evidence of disease. Six years following the transplant, he presented with a lacrimal gland tumor with a biopsy consistent with multiple myeloma. Systemic disease evaluation at that time, including positron emission tomography scan, bone marrow biopsy, and serum analysis, were negative. To the best of the authors' knowledge, no prior reports exist describing an isolated lacrimal gland recurrence of multiple myeloma with ultrasound and MRI imaging.
Asunto(s)
Neoplasias del Ojo , Trasplante de Células Madre Hematopoyéticas , Aparato Lagrimal , Mieloma Múltiple , Masculino , Humanos , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Aparato Lagrimal/diagnóstico por imagen , Aparato Lagrimal/patología , Recurrencia Local de Neoplasia/diagnóstico , Neoplasias del Ojo/diagnóstico , Neoplasias del Ojo/patología , RecurrenciaRESUMEN
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.
Asunto(s)
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
The primary cause of morbidity and mortality in patients with multiple myeloma (MM) is an infection. Therefore, there is great concern about susceptibility to the outcome of COVID-19-infected patients with MM. This retrospective study describes the baseline characteristics and outcome data of COVID-19 infection in 650 patients with plasma cell disorders, collected by the International Myeloma Society to understand the initial challenges faced by myeloma patients during the COVID-19 pandemic. Analyses were performed for hospitalized MM patients. Among hospitalized patients, the median age was 69 years, and nearly all patients (96%) had MM. Approximately 36% were recently diagnosed (2019-2020), and 54% of patients were receiving first-line therapy. Thirty-three percent of patients have died, with significant geographic variability, ranging from 27% to 57% of hospitalized patients. Univariate analysis identified age, International Staging System stage 3 (ISS3), high-risk disease, renal disease, suboptimal myeloma control (active or progressive disease), and 1 or more comorbidities as risk factors for higher rates of death. Neither history of transplant, including within a year of COVID-19 diagnosis, nor other anti-MM treatments were associated with outcomes. Multivariate analysis found that only age, high-risk MM, renal disease, and suboptimal MM control remained independent predictors of adverse outcome with COVID-19 infection. The management of MM in the era of COVID-19 requires careful consideration of patient- and disease-related factors to decrease the risk of acquiring COVID-19 infection, while not compromising disease control through appropriate MM treatment. This study provides initial data to develop recommendations for the management of MM patients with COVID-19 infection.
Asunto(s)
COVID-19/complicaciones , Internacionalidad , Mieloma Múltiple/complicaciones , Mieloma Múltiple/virología , SARS-CoV-2/fisiología , Sociedades Médicas , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Factores de RiesgoRESUMEN
BACKGROUND: Isatuximab (Isa), an anti-CD38 monoclonal antibody, and carfilzomib (K), a next-generation proteasome inhibitor (PI), both have potent single-agent activity in relapsed and refractory multiple myeloma (RRMM). METHODS: This phase 1b study evaluated the combination of Isa and K in 33 patients with RRMM. Isa was administered by intravenous infusion in 3 dosing cohorts: dose level 1 (Isa at 10 mg/kg biweekly), dose level 2 (DL2; Isa at 10 mg/kg weekly for 4 doses and then biweekly), and dose level 3 (Isa at 20 mg/kg weekly for 4 doses and then biweekly) and all patients received K (20 mg/m2 intravenously for cycle 1, days 1 and 2, and then 27 mg/m2 for all subsequent doses). A standard 3+3 dose-escalation design was used, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. An expansion cohort of 18 patients was enrolled at DL2 to further evaluate safety and efficacy. Responses were assessed with the International Myeloma Working Group response criteria, and patients continued treatment until disease progression or unacceptable toxicity. RESULTS: With a median follow-up of 26.7 months, in this heavily pretreated population with a median of 3 prior lines (refractory to PIs and immunomodulatory drugs, 76%; refractory to K, 27%), the overall response rate was 70% (stringent complete response/complete response, 4; very good partial response, 8; partial response, 11). The median progression-free survival was 10.1 months, and the 2-year survival probability was 76%. The most common treatment-related adverse events (grade 2 or higher) were anemia, leukopenia, neutropenia, thrombocytopenia, hypertension, and infection. Infusion reactions were common (55%) but did not limit dosing. CONCLUSIONS: Treatment with Isa plus K was well tolerated with no unexpected toxicity. The combination was effective despite the enrollment of heavily pretreated patients with RRMM. LAY SUMMARY: This phase 1b study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of isatuximab and carfilzomib in patients with relapsed and refractory multiple myeloma. Thirty-three patients were treated: 15 in dose escalation and 18 in dose expansion. Patients received an average of 10 cycles. The treatment was safe and effective. No unexpected toxicity or drug-drug interactions were noted. Seventy percent of the subjects responded to therapy, and the progression-free survival was 10.1 months.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Mieloma Múltiple , Oligopéptidos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Humanos , Mieloma Múltiple/tratamiento farmacológico , Oligopéptidos/efectos adversos , RecurrenciaRESUMEN
BACKGROUND: Selinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM). This study examines impact of selinexor treatment on HRQoL of patients treated in STORM and reports two approaches to calculate minimal clinically important differences for the FACT-MM. METHODS: FACT-MM data were collected at baseline, on day 1 of each 4-week treatment cycle, and at end of treatment (EOT). Changes from baseline were analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain using mixed-effects regression models. Two approaches for evaluating minimal clinically important differences were explored: the first defined as 10% of the instrument range, and the second based on estimated mean baseline differences between Eastern Cooperative Oncology Group performance status (ECOG PS) scores. Post-hoc difference analysis compared change in scores from baseline to EOT for treatment responders and non-responders. RESULTS: Eighty patients were included in the analysis; the mean number of prior therapies was 7.9 (standard deviation [SD] 3.1), and mean duration of myeloma was 7.6 years (SD 3.4). Each exploratory minimal clinically important difference threshold yielded consistent results whereby most patients did not experience HRQoL decline during the first six cycles of treatment (range: 53.9 to 75.7% for the first approach; range: 52.6 to 72.9% for the second). Treatment responders experienced less decline in HRQoL from baseline to EOT than non-responders, which was significant for the FACT-G, but not for other scores. CONCLUSION: The majority of patients did not experience decline in HRQoL based on minimal clinically important differences during early cycles of treatment with selinexor and dexamethasone in the STORM trial. An anchor-based approach utilizing patient-level data (ECOG PS score) to define minimal clinically important differences for the FACT-MM gave consistent results with a distribution-based approach. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov under the trial-ID NCT02336815 on January 8, 2015.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Calidad de Vida , Adulto , Anciano , Anciano de 80 o más Años , Dexametasona/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Hidrazinas/administración & dosificación , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia/patología , Pronóstico , Tasa de Supervivencia , Triazoles/administración & dosificaciónRESUMEN
Twice-weekly carfilzomib (27 mg/m2 ) with lenalidomide-dexamethasone (KRd) is a standard-of-care in relapsed or refractory multiple myeloma (RRMM). This phase 1b study evaluated KRd with once-weekly carfilzomib in RRMM. Patients received carfilzomib (30-minute infusion; 56 or 70mg/m2 ) on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on days 1, 8, 15, and 22 (day 22 omitted for cycles 9+) of 28-day cycles. Primary objective was safety/tolerability; efficacy was a secondary objective. Fifty-six RRMM patients enrolled: 22 during dose evaluation (56-mg/m2 , n = 10; 70-mg/m2 , n = 12) and 34 during dose expansion (all initiated dosing at 70 mg/m2 ). After 2 fatal adverse events (AEs) during 70-mg/m2 dose expansion, dosage reduction to 56 mg/m2 was permitted. Results are presented for carfilzomib 56-mg/m2 (n = 10) and 70-mg/m2 groups (dose evaluation/expansion; n = 46). Median carfilzomib dose was 53.2 mg/m2 (56-mg/m2 group) and 62.4 mg/m2 (70-mg/m2 group). Grade ≥3 AE rates were 70.0% (56 mg/m2 ) and 69.6% (70 mg/m2 ). Overall response rates were 90.0% (56 mg/m2 ) and 89.1% (70 mg/m2 ); ≥very good partial response rates were 50.0% (56 mg/m2 ) and 73.9% (70 mg/m2 ). Once-weekly KRd was active with acceptable toxicity in RRMM, supporting further evaluation of this regimen.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Femenino , Humanos , Lenalidomida/administración & dosificación , Lenalidomida/efectos adversos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Oligopéptidos/administración & dosificación , Oligopéptidos/efectos adversos , RecurrenciaRESUMEN
Clinical trials of vorinostat, a Class I/II histone deacetylase inhibitor, in combination with proteasome inhibitors and immunomodulatory agents have shown activity in relapsed/refractory multiple myeloma. This phase IIb, open-label, single-institution study evaluated the efficacy of vorinostat in combination with lenalidomide and dexamethasone in lenalidomide-refractory patients. Patients were considered lenalidomide-refractory if they had no clinical response (Asunto(s)
Dexametasona/administración & dosificación
, Ácidos Hidroxámicos/administración & dosificación
, Mieloma Múltiple/tratamiento farmacológico
, Terapia Recuperativa/métodos
, Talidomida/análogos & derivados
, Anciano
, Anciano de 80 o más Años
, Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
, Supervivencia sin Enfermedad
, Femenino
, Humanos
, Lenalidomida
, Masculino
, Persona de Mediana Edad
, Mieloma Múltiple/complicaciones
, Inducción de Remisión
, Terapia Recuperativa/efectos adversos
, Talidomida/administración & dosificación
, Resultado del Tratamiento
, Vorinostat
RESUMEN
Renal dysfunction negatively impacts outcomes in patients with multiple myeloma (MM). Few treatment options are currently available for patients with MM and comorbid renal dysfunction, and as they are generally excluded from clinical trials, data on the use of immunomodulatory drugs in this population are scarce. In this paper, we describe a case series of five women with MM and severe renal dysfunction or dialysis dependency who were refractory to both bortezomib and either lenalidomide or thalidomide and were treated with full-dose (4 mg) pomalidomide. As part of their treatment regimen, these patients also received carfilzomib and dexamethasone with or without cyclophosphamide. All five patients achieved at least a partial response to pomalidomide-based therapy, which was relatively well tolerated. Our findings suggest that pomalidomide may represent a valuable and tolerable treatment option for MM patients with severe renal impairment. The fact that pomalidomide is extensively metabolized prior to urinary excretion may explain the improved tolerability of pomalidomide versus lenalidomide in such patients. Copyright © 2016 John Wiley & Sons, Ltd.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Femenino , Humanos , Enfermedades Renales/etiología , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Oligopéptidos/administración & dosificación , Recurrencia , Talidomida/administración & dosificación , Talidomida/efectos adversos , Talidomida/análogos & derivadosRESUMEN
Escalating doses of bortezomib with high-dose melphalan was evaluated as as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory multiple myeloma (MM). MM patients with less than a partial remission (PR) (or 50% reduction) compared to their pretransplantation paraprotein parameters after a prior ASCT with melphalan conditioning, or who were in relapse after a prior autologous transplantation, were eligible for study. Bortezomib was dose escalated in steps of 1, 1.3, and 1.6 mg/m2 (3 × 3 design) on days -4 and -1 before transplantation with melphalan 200 mg/m2 given on day -2. Thirty-two patients were enrolled: 12 in the phase I dose escalation phase and an additional 20 in phase II to gain additional experience with the regimen. Twenty-four (75%) patients were Durie Salmon stage III, and 12 (37.5%) had >2 prior lines of therapy. The overall response rate (≥PR) was 44% with 22% complete remission. Two-year overall survival and progression-free survival were 76% and 39%, respectively, with a median follow-up of 31.7 months. The most common grade 3 and 4 nonhematologic adverse events were neutropenic fever (25%), nausea (18.8%), and mucositis (9.4%). Serious adverse events included intensive care unit admission (9.4%), seizure (3.1%), prolonged diarrhea (3.1%), and Guillain-Barre syndrome (3.1%). Two patients (6%) died of sepsis. There was no emergent peripheral neuropathy nor increase in any pre-existing peripheral neuropathy. The addition of bortezomib to melphalan as conditioning for salvage ASCT was well tolerated. More importantly, it can provide durable remission for patients who have a suboptimal response to prior single-agent melphalan conditioning for ASCT, without requiring a reduction in the dose of melphalan. Larger randomized prospective studies to determine the effect of combination conditioning are being conducted.
Asunto(s)
Bortezomib/administración & dosificación , Melfalán/administración & dosificación , Mieloma Múltiple/terapia , Terapia Recuperativa/métodos , Acondicionamiento Pretrasplante/métodos , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nivel sin Efectos Adversos Observados , Trasplante de Células Madre de Sangre Periférica , Análisis de Supervivencia , Trasplante AutólogoAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dexametasona/uso terapéutico , Lenalidomida/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dexametasona/efectos adversos , Estudios de Seguimiento , Humanos , Lenalidomida/efectos adversos , Mieloma Múltiple/terapia , Trasplante de Células Madre , Trasplante AutólogoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bases de Datos Factuales , Mieloma Múltiple , Anciano , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Hidrazinas/administración & dosificación , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Tasa de Supervivencia , Triazoles/administración & dosificaciónRESUMEN
BACKGROUND: The mechanisms allowing residual multiple myeloma (MM) cells to persist after bortezomib (Bz) treatment remain unclear. We hypothesized that studying the biology of bortezomib-surviving cells may reveal markers to identify these cells and survival signals to target and kill residual MM cells. METHODS: We used H2B-GFP label retention, biochemical tools and in vitro and in vivo experiments to characterize growth arrest and the unfolded protein responses in quiescent Bz-surviving cells. We also tested the effect of a demethylating agent, 5-Azacytidine, on Bz-induced quiescence and whether inhibiting the chaperone GRP78/BiP (henceforth GRP78) with a specific toxin induced apoptosis in Bz-surviving cells. Finally, we used MM patient samples to test whether GRP78 levels might associate with disease progression. Statistical analysis employed t-test and Mann-Whitney tests at a 95% confidence. RESULTS: We report that Bz-surviving MM cells in vitro and in vivo enter quiescence characterized by p21(CIP1) upregulation. Bz-surviving MM cells also downregulated CDK6, Ki67 and P-Rb. H2B-GFP label retention showed that Bz-surviving MM cells are either slow-cycling or deeply quiescent. The Bz-induced quiescence was stabilized by low dose (500nM) of 5-azacytidine (Aza) pre-treatment, which also potentiated the initial Bz-induced apoptosis. We also found that expression of GRP78, an unfolded protein response (UPR) survival factor, persisted in MM quiescent cells. Importantly, GRP78 downregulation using a specific SubAB bacterial toxin killed Bz-surviving MM cells. Finally, quantification of Grp78(high)/CD138+ MM cells from patients suggested that high levels correlated with progressive disease. CONCLUSIONS: We conclude that Bz-surviving MM cells display a GRP78(HIGH)/p21(HIGH)/CDK6(LOW)/P-Rb(LOW) profile, and these markers may identify quiescent MM cells capable of fueling recurrences. We further conclude that Aza + Bz treatment of MM may represent a novel strategy to delay recurrences by enhancing Bz-induced apoptosis and quiescence stability.
Asunto(s)
Bortezomib/administración & dosificación , Quinasa 6 Dependiente de la Ciclina/biosíntesis , Proteínas de Choque Térmico/biosíntesis , Mieloma Múltiple/tratamiento farmacológico , Quinasas p21 Activadas/biosíntesis , Adulto , Anciano , Animales , Apoptosis/efectos de los fármacos , Azacitidina/administración & dosificación , Supervivencia Celular/efectos de los fármacos , Quinasa 6 Dependiente de la Ciclina/genética , Chaperón BiP del Retículo Endoplásmico , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas de Choque Térmico/genética , Humanos , Masculino , Ratones , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasas p21 Activadas/genéticaRESUMEN
The prognostic impact of amplification of chromosome 1(C1A) in newly diagnosed multiple myeloma (nMM) patients treated with the most commonly used bortezomib-based triplet regimens is unclear. In this study, we analyzed the outcome of novel triplet therapies in a series of unselected patients with C1A detected by FISH. We identified 28 unselected nMM patients with C1A who had a gain of 1q21 locus. Despite 50% of patients being diagnosed at ISS stage 1 or 2 and 93% having no other high-risk molecular findings, the median overall survival of all patients was only 37 months, with 8 deaths (29%) occurring 8-37 months after diagnosis. Those who died had a median of four lines (range was 1-8) of therapy. Moreover, 71% of patients were non-Caucasian. Extra-osseous and CNS involvement occurred in 36 and 11% of patients respectively. Gain of the long arm of chromosome 1 detected by FISH remains a high-risk prognostic marker even in the setting of novel triplet therapies.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cromosomas Humanos Par 1 , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Anciano , Aberraciones Cromosómicas , Supervivencia sin Enfermedad , Femenino , Amplificación de Genes , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Ploidias , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the neoplastic proliferation of plasma cells, which produce monoclonal immunoglobulin that can cause vital organ damage, subsequently leading to significant morbidity and mortality. Autologous hematopoietic stem cell transplant (ASCT) is the standard-of-care management of eligible patients with newly diagnosed MM. Experts recommend collecting enough stem cells upfront to support a possible tandem transplant, salvage ASCT, or a stem cell "boost" to allow for the administration of multiagent cytotoxic chemotherapy in patients with relapsed/refractory disease. OBJECTIVE: There is currently a paucity of data on the response rates and outcomes of patients with relapsed MM who undergo cytotoxic chemotherapy followed by a stem cell boost; this study examines the outcomes of patients treated with this approach. METHODS: We conducted a retrospective chart review from two oncologic treatment centers in the United States of adult patients who underwent a first ASCT between 1999 and 2021 and subsequently received cytotoxic chemotherapy followed by stem cell boost further on in their disease course. Survival analysis was carried out using the Kaplan-Meier method, and the log-rank test was used to compare survival curves. RESULTS: We found that the majority (56.6%) of these patients responded to therapy and that 60.6% of these patients were able to receive at least one subsequent line of therapy post-boost. Furthermore, patients who responded to therapy had significantly longer median overall survival compared to those who did not respond (323 days vs 93 days, p=0.0045), and age did not affect response to therapy. CONCLUSION: This data allow clinicians to appropriately implement and inform patients of the therapeutic uses and clinical outcomes of stem cell boost in patients with multiply relapsed/refractory MM.
RESUMEN
Patients with high-risk multiple-myeloma (HRMM) and ultra-high-risk multiple-myeloma (UHRMM) show rapid disease progression and shorter survival compared to those with standard-risk multiple-myeloma (SRMM). Lenalidomide maintenance after autologous stem cell transplant (ASCT) has shown inferior outcomes in this subgroup compared to SRMM, and there is an unmet need for improved post-ASCT therapy. This retrospective study, from September 2016 to March 2023, assesses elotuzumab combined with lenalidomide or pomalidomide and dexamethasone (ERd or EPd) as consolidation therapy post-ASCT for HRMM and UHRMM patients. HRMM (1 cytogenetic abnormality) and UHRMM (≥2 cytogenetic abnormalities) were defined using IMWG and mSMART criteria. Among 75 patients (median age: 64 years), 59 received ERd and 16 EPd. Median progression-free survival was 29.3 months for all patients, 32.7 months for HRMM, and 21.9 months for UHRMM. Elotuzumab plus an IMiD consolidation therapy post-ASCT demonstrated promising efficacy compared to other studies, with a fixed duration and reduced lenalidomide-related toxicity.
RESUMEN
Persons with myeloma were randomized to receive an anti-TIGIT (T cell immunoreceptor) or anti-LAG3 (lymphocyte activation gene) antibody followed by combination with pomalidomide and dexamethasone ( NCT04150965 ). Primary and secondary endpoints were safety and efficacy, respectively. Therapy was well tolerated without dose-limiting toxicity. Durable clinical responses were observed in both the anti-TIGIT(three of six participants) and the anti-LAG3 (two of six participants) arms. Anti-LAG3 responders had higher naive cluster of differentiation 4 (CD4)-positive T cells and lower programmed cell death protein 1-positive effector T cells. Anti-TIGIT responders had higher CD226 expression, natural killer cell activation and lower CD112 expression. These data demonstrate the clinical activity of TIGIT-LAG3 blockade and identify pathway-specific response correlates in myeloma.
RESUMEN
Survival in multiple myeloma (MM) is variable, ranging from several months to more than 15 years. While survival has recently improved with the use of novel therapy, approximately 25% of patients have a median survival of 2 years or less. Accurate identification of high-risk patients, and risk stratification, are crucial in improving outcomes for all patients. In the first part of this two part series, we review the currently identified prognostic factors characterized by disease burden (Durie-Salmon staging system, International Staging System, magnetic resonance imaging, (18F) fluorodeoxyglucose positron emission tomography, presence of extramedullary disease or plasma-cell leukemia), host factors (age, performance status, and renal function), tumor biology (proliferation rate, conventional cytogenetics, interphase fluorescence in situ hybridization, and gene expression profiling), and depth of response to therapy. Efforts have been made to identify ultra-high-risk patients by combining all the identified variables into a unifying comprehensive model. In the second part of this series, we will discuss the significance of these factors in the context of currently available therapies for MM, distinguishing between treatments that only improve outcomes of high-risk patients when compared with previous therapies, versus those that overcome high-risk status, thereby reclassifying these patients as standard risk.
Asunto(s)
Mieloma Múltiple , Estadificación de Neoplasias/métodos , Supervivencia sin Enfermedad , Humanos , Mieloma Múltiple/diagnóstico por imagen , Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Radiografía , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Multiple myeloma (MM) is a heterogeneous disease, and a variety of risk factors at the time of initial diagnosis can be used to stratify patients. In the first part of this 2-part series, we reviewed the currently identified prognostic factors, characterized by disease burden, host factors, tumor biology, and depth of response to therapy. However, these risk factors cannot be interpreted independently of therapies. Novel therapies have the potential to worsen or improve outcomes compared with conventional therapy in high-risk patients, or actually overcome the high-risk status, thereby resulting in reclassification as standard risk. For example, thalidomide (Thalomid, Celgene) is associated with worse outcomes in patients with high-risk cytogenetic abnormalities, such as deletion of chromosomes 13 and 17p, whereas proteasome inhibitors appear to overcome t(4;14). The second part of this series reviews the significance of various genetic risks in the era of novel therapies for MM.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Deleción Cromosómica , Trastornos de los Cromosomas , Inhibidores de Proteasoma/uso terapéutico , Talidomida/uso terapéutico , Inhibidores de la Angiogénesis/efectos adversos , Cromosomas Humanos Par 13 , Cromosomas Humanos Par 17 , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Inhibidores de Proteasoma/efectos adversos , Factores de Riesgo , Síndrome de Smith-Magenis , Talidomida/efectos adversosRESUMEN
BACKGROUND: The increasing use of anti-CD38 monoclonal antibodies (αCD38 mAbs) for newly diagnosed or early relapsed multiple myeloma (MM), especially in non-transplant eligible patients, may lead to more patients developing αCD38 mAb-refractory disease earlier in the treatment course with fewer treatment options. PATIENTS AND METHODS: We analyzed the efficacy and safety of selinexor-based triplets (selinexor+dexamethasone [Sd] plus pomalidomide [SPd, n = 23], bortezomib [SVd, n = 16] or carfilzomib (SKd, n = 23]) in a subset of STOMP (NCT02343042) and BOSTON (NCT03110562) study patients treated previously with αCD38 mAbs. RESULTS: Sixty-two patients (median 4 prior therapies, range 1 to 11, 90.3% refractory to αCD38 mAb) were included. Overall response rates (ORR) in the SPd, SVd and SKd cohorts were 52.2%, 56.3%, and 65.2%, respectively. Overall response rate was 47.4% among patients who had MM refractory to the third drug reintroduced in the Sd-based triplet. Median progression-free survival in the SPd, SVd, and SKd cohorts was 8.7, 6.7, and 15.0 months, respectively, and median overall survival was 9.6, 16.9, and 33.0 months, respectively. Median time to discontinuation in the SPd, SVd, and SKd cohorts was 4.4, 5.9, and 10.6 months, respectively. The most common hematological adverse events were thrombocytopenia, anemia, and neutropenia. Nausea, fatigue, and diarrhea were primarily grade 1/2. Adverse events were generally manageable with standard supportive care and dose modifications. CONCLUSION: Selinexor-based regimens may offer effective and well-tolerated therapy to patients with relapsed and/or refractory MM who had disease previously exposed or refractory to αCD38 mAb therapy and could help address the unmet clinical need in these high-risk patients.
Asunto(s)
Antineoplásicos , Mieloma Múltiple , Humanos , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: Extramedullary multiple myeloma (MM) (EMM) is a rare and aggressive subentity of MM that can be present at diagnosis or develop anytime during the disease course. There is a paucity of data on the clinical characteristics and overall epidemiology of EMM. Furthermore, there is a scarcity of data on how the interaction of age and gender influences the survival of EMM. AIM: To evaluate the clinical characteristics of patients with EMM over the past 2 decades and to identify epidemiologic characteristics that may impact overall prognosis. METHODS: A total of 858 patients diagnosed with EMM, between 2000 and 2017, were ultimately enrolled in our study by retrieving the Surveillance, Epidemiology, and End Results database. We analyzed demographics, clinical characteristics, and overall mortality (OM) as well as cancer-specific mortality (CSM) of EMM. Variables with a P value < 0.1 in the univariate Cox regression were incorporated into the multivariate Cox model to determine the independent prognostic factors, with a hazard ratio (HR) of greater than 1 representing adverse prognostic factors. RESULTS: From a sample of 858 EMM, the male gender (63.25%), age range 60-79 years (51.05%), and non-Hispanic whites (66.78%) were the most represented. Central Nervous System and the vertebral column was the most affected site (33.10%). Crude analysis revealed higher OM in the age group 80+ [HR = 6.951, 95% confidence interval (95%CI): 3.299-14.647, P = 0], Non-Hispanic Black population (HR = 1.339, 95%CI: 1.02-1.759, P = 0.036), Bones not otherwise specified (NOS) (HR = 1.74, 95%CI: 1.043-2.902, P = 0.034), and widowed individuals (HR = 2.107, 95%CI: 1.511-2.938, P = 0). Skin involvement (HR = 0.241, 95%CI: 0.06-0.974, P = 0.046) and a yearly income of $75000+ (HR = 0.259, 95%CI: 0.125-0.538, P = 0) had the lowest OM in the crude analysis. Crude analysis revealed higher CSM in the age group 80+, Non-Hispanic Black, Bones NOS, and widowed. Multivariate cox proportional hazard regression analyses only revealed higher OM in the age group 80+ (HR = 9.792, 95%CI: 4.403-21.774, P = 0) and widowed individuals (HR = 1.609, 95%CI: 1.101-2.35, P = 0.014). Multivariate cox proportional hazard regression analyses of CSM also revealed higher mortality of the same groups. Eyes, mouth, and ENT involvement had the lowest CSM in the multivariate analysis. There was no interaction between age and gender in the adjusted analysis for OM and CSM. CONCLUSION: EMM is a rare entity. To our knowledge, there is a scarcity of data on the clinical characteristics and prognosis factors of patients with extramedullary multiple myeloma. In this retrospective cohort, using a United States-based population, we found that age, marital status, and tumor site were independent prognostic factors. Furthermore, we found that age and gender did not interact to influence the mortality of patients with EMM.