RESUMEN
Although Janus kinase (JAK) inhibitors have demonstrated efficacy for treating autoimmune disorders and myeloproliferative neoplasms, their efficacy in treating other types of cancer has not been clearly demonstrated. We evaluated oral ruxolitinib (15 mg twice daily) with oral methylprednisolone (40 mg every other day) for multiple myeloma (MM) patients with progressive disease who had received a proteasome inhibitor, lenalidomide, glucocorticosteroids and three or more prior regimens. All of the planned 29 patients had been enrolled with follow-up until 28 April 2022. Median lines of prior therapy were 6 (range 3-12). Cytogenetics and fluorescent in situ hybridization were evaluable in 28 patients; 9 (32%) and 17 (70%) patients showed high-risk cytogenetics and/or 1q+, respectively. The overall response rate was 31%. The median duration of response was 13.1 (range 2.8-22.0) months. Median progression-free survival rate was 3.4 (range 0.5-24.6) months, Overall, the treatment was well tolerated. The combination of ruxolitinib and methylprednisolone demonstrated significant clinical activity among previously heavily-treated MM patients, and responses were achieved among patients who had high-risk cytogenetics. This is the first clinical study to show activity of JAK inhibitors in combination with steroids for MM patients and expands the potential use of these drugs to those with cancers other than myeloproliferative neoplasms.
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Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Metilprednisolona/uso terapéutico , Hibridación Fluorescente in Situ , Pirimidinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , DexametasonaRESUMEN
We hypothesized that ruxolitinib may inhibit the immune checkpoint protein, B7H3; and, thus, investigated its effects on this immune inhibitor using multiple myeloma (MM) cell lines, bone marrow (BM) mononuclear cells from MM patients and human MM LAGλ -1A xenografts. Ruxolitinib reduced B7H3 gene and protein expression and increased IL-2 and CD8 gene expression. These results suggest that ruxolitinib inhibition of B7H3 may restore exhausted T-cell activity in the MM BM tumor microenvironment.
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Mieloma Múltiple , Humanos , Mieloma Múltiple/patología , Proteínas de Punto de Control Inmunitario/farmacología , Janus Quinasa 1 , Transducción de Señal , Microambiente TumoralRESUMEN
OBJECTIVES: Isatuximab is approved for treatment of relapsed/refractory multiple myeloma (RRMM) with dexamethasone and carfilzomib or pomalidomide. Patients receiving these three-drug regimens have exhibited more Grade ≥ 3 adverse events (AEs) compared to the two-drug class combination of isatuximab and steroids alone. Thus, this single-center retrospective study investigated the efficacy of isatuximab with dexamethasone and methylprednisolone (ISAdm) for RRMM patients showing only biochemical progression (BP) of their disease. METHODS: Twenty-four RRMM patients exhibiting only BP were administered isatuximab at 10 mg/kg with dexamethasone once weekly for cycle 1 of a 28-day cycle, followed by every other week for each cycle thereafter. Starting in cycle 2, oral methylprednisolone was added every other day stopping 48 h before and starting 48 h after each dexamethasone infusion. RESULTS: Overall response rate and clinical benefit rate were 63% and 79%, respectively. Progression free survival was 12.9 months. There were only 5 AEs of Grade ≥ 3 which included lymphocytopenia (13%), leukopenia (4%), and neutropenia (4%). No Grade ≥ 3 AE related to respiratory infection, anemia, or thrombocytopenia were reported. CONCLUSION: This study shows that the two-drug class combination of ISAdm is an effective and well tolerated treatment option for RRMM patients exhibiting only BP.
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Mieloma Múltiple , Humanos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/etiología , Estudios Retrospectivos , Dexametasona , Recurrencia Local de Neoplasia/tratamiento farmacológico , Esteroides/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Previous retrospective studies have shown that serum B-cell maturation antigen (sBCMA) levels predict outcomes among patients with multiple myeloma (MM) undergoing new treatments. Specifically, baseline levels and changes during treatment of this protein predict both progression free survival (PFS) and overall survival. However, prospective studies are lacking evaluating sBCMA for determining outcomes among MM patients undergoing new treatments. Thus, we evaluated whether its baseline levels and changes during treatment in the amount of this serum marker predict outcomes among 38 relapsed/refractory MM patients treated with ruxolitinib, lenalidomide and methylprednisolone in a phase 1 trial. Patients with baseline sBCMA levels in the lowest three quartiles had longer PFS (median PFS 136 vs. 28 days; p < 0.0001). This was also shown for patients with baseline levels below the median (median PFS 140 vs. 77 days; p = 0.0225). PFS was shorter for patients whose sBCMA levels increased ≥25% through their first cycle (median PFS: 50 vs. 134 days, p = 0.0022), second cycle (median PFS: 50 vs. 141 days, p = 0.0273), and during the first three cycles of study treatment (median PFS: 50 vs. 220 days, p < 0.0001). No patient whose sBCMA increased ≥25% during cycle 1 responded whereas the majority (58%) of patients whose level increased <25% responded. This is the first prospective study to determine whether sBCMA levels predict outcomes for MM patients undergoing a non-BCMA directed treatment regimen and demonstrates that baseline levels and its changes during treatment predict PFS and the likelihood of responding to their treatment. These results add to the growing literature suggesting that this serum marker will be useful for determining outcomes for patients undergoing treatment for MM.
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Antígeno de Maduración de Linfocitos B , Mieloma Múltiple , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno de Maduración de Linfocitos B/uso terapéutico , Dexametasona/efectos adversos , Humanos , Lenalidomida/uso terapéutico , Metilprednisolona/uso terapéutico , Nitrilos , Estudios Prospectivos , Pirazoles , PirimidinasRESUMEN
Ruxolitinib with lenalidomide and dexamethasone shows anti-myeloma effects in vitro and in vivo. MUC1 leads to lenalidomide resistance in multiple myeloma (MM) cells, and ruxolitinib blocks its expression. Thus, ruxolitinib may restore sensitivity to lenalidomide. A phase I trial was conducted to determine the safety and efficacy of ruxolitinib with lenalidomide and methylprednisolone for patients with relapsed/refractory (RR)MM who had been treated with lenalidomide, steroids and a proteasome inhibitor and showed progressive disease at study entry. A traditional 3 + 3 dose escalation design was used to enroll subjects in four cohorts. Subjects received ruxolitinib twice daily, lenalidomide daily on days 1-21 of a 28 day cycle and methylprednisolone orally every other day. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Forty-nine patients were enrolled. The median age was 64 years and they had received a median of six prior treatments including lenalidomide and steroids to which 94% were refractory. No dose limiting toxicities occurred. The CBR and ORR were 49% and 36%, respectively. All responding patients were refractory to lenalidomide. Grade 3 or 4 adverse events (AEs) included anemia (17%), decreased lymphocyte count (15%), and hypophosphatemia (10%). Most common serious AEs included sepsis (9.8%) and pneumonia (7.8%). This Phase I trial demonstrates that a JAK inhibitor, ruxolitinib, can overcome refractoriness to lenalidomide and steroids for patients with RRMM. These results represent a promising novel therapeutic approach for treating MM. NCT03110822.
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Mieloma Múltiple , Humanos , Persona de Mediana Edad , Lenalidomida , Mieloma Múltiple/tratamiento farmacológicoRESUMEN
The serum B-cell maturation antigen (sBCMA) has been identified as a novel serum biomarker for patients with multiple myeloma. However, no study has yet established a reference range for sBCMA levels. Its levels were determined in 196 healthy subjects and showed a right-tailed distribution with a median value of 37·51 ng/ml with a standard deviation of 22·54 ng/ml (range 18·78-180·39 ng/ml). Partitioning of subgroup reference ranges was considered but determined to be irrelevant. A non-parametric method using the median ± 2 standard deviations suggests using a universal reference interval of <82·59 ng/ml.
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Antígeno de Maduración de Linfocitos B/sangre , Biomarcadores de Tumor/sangre , Mieloma Múltiple/sangre , Proteínas de Neoplasias/sangre , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Serum B-cell maturation antigen (sBCMA) is a novel biomarker for B-cell malignancies. A normal reference range (<82·59 ng/ml) has been recently established but the impact of achieving normal levels to outcomes for patients receiving treatment for B-cell malignancies has not been studied. We first found that among multiple myeloma (MM) patients starting a new treatment, those who begin treatment within normal sBCMA limits (<82·59 ng/ml) have improved progression-free survival (PFS; P = 0·0398) and overall survival (OS; P = 0·0217) than those who do not. Furthermore, among patients who begin treatment with elevated (≥82·59 ng/ml) sBCMA levels, we assessed the relationship of a decrease in sBCMA to the normal range to OS and found that those who normalize sBCMA demonstrated improved OS (P = 0·0078). Normalizing patients also experienced a markedly improved overall response rate (P < 0·0001). Moreover, all patients who achieved complete remission (CR) showed normalization of sBCMA, and time to normalization (median 0·9 months) was faster than time to CR (5·0 months; P = 0·0036) for these patients. These results suggest that normalization of sBCMA may be an accurate predictor of OS for MM patients during treatment and predict for a higher likelihood of response.
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Antígeno de Maduración de Linfocitos B/sangre , Mieloma Múltiple/sangre , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Pronóstico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Multiple myeloma (MM) tumour cells evade host immunity through a variety of mechanisms, which may potentially include the programmed cell death ligand-1 (PD-L1):programmed cell death protein-1 (PD-1) axis. This interaction contributes to the immunosuppressive bone marrow (BM) microenvironment, ultimately leading to reduced effector cell function. PD-L1 is overexpressed in MMBM and is associated with the resistance to immune-based approaches for treating MM. Ruxolitinib (RUX), an inhibitor of the Janus kinase (JAK) family of protein tyrosine kinases, is approved for myeloproliferative diseases. We investigated the effects of RUX alone or in combination with anti-MM agents on the expression of PD-L1 and T-cell cytotoxicity in MM. We showed that the expression of the PD-L1 gene was markedly increased in BM mononuclear cells from patients with MM with progressive disease versus those in complete remission. Furthermore, RUX treatment resulted in a concentration-dependent reduction of PD-L1 gene expression in the MM tumour cells cultured alone or co-cultured with stromal cells compared with untreated cells. The results also demonstrated that RUX increased MM cell apoptosis in the presence of interleukin-2-stimulated T cells to a similar degree as the treatment with anti-PD-1 or anti-PD-L1 antibodies. In summary, these results indicate that RUX can block PD-L1 expression resulting in augmentation of anti-MM effects of T cells.
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Antineoplásicos/uso terapéutico , Antígeno B7-H1/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Humanos , Quinasas Janus/antagonistas & inhibidores , Masculino , Ratones SCID , Mieloma Múltiple/genética , Nitrilos , Pirimidinas , Microambiente Tumoral/efectos de los fármacosRESUMEN
Venetoclax is a BCL-2 inhibitor currently indicated for use in treating hematologic malignancies with recommended doses ranging from 400 to 600 mg/day. Although currently not FDA-approved to treat multiple myeloma (MM) patients, there is a growing number of reports indicating its efficacy as a salvage therapy for these patients, especially for those with the t(11;14) chromosomal marker. These studies, however, have also indicated that venetoclax given at doses ≥ 400 mg/day can cause serious adverse events (SAEs) especially when administered with bortezomib, commonly related to infections. The purpose of this single-center retrospective study was to determine the efficacy of low dose venetoclax (defined as ≤ 250 mg/day) in combination with low dose bortezomib (defined as 1.0 mg/m2 per dose), daratumumab, and dexamethasone (Dvvd) as a salvage therapy for relapsed/refractory myeloma (RRMM) patients. Twenty-two RRMM patients were given venetoclax orally at doses ranging from 100 to 250 mg daily using this four-drug regimen. While the low doses resulted in reduced venetoclax efficacy among those lacking t(11;14) (overall response rate [ORR] = 31%), those harboring the t(11;14) marker exhibited an ORR of 80%. Notably, this response was without frequent infection-related SAEs as reported in previous studies. Together, the results of this study demonstrate that treatment of t(11;14) positive RRMM patients with Dvvd is both effective and well-tolerated.
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Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Dexametasona/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Anciano , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bortezomib/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Dexametasona/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estudios Retrospectivos , Sulfonamidas/administración & dosificación , Resultado del TratamientoRESUMEN
Multiple myeloma (MM) patients with smoldering (S) disease are defined by a lack of CRAB/SLiM criteria but may transform into disease requiring treatment. The International Myeloma Working Group risk stratification model for SMM uses serum M-protein, serum-free light chain ratio, and bone marrow plasma cell percentage. We investigated whether baseline serum B-cell maturation antigen (sBCMA) levels are predictive of disease progression among 65 patients with SMM. A receiver operating characteristic curve was used to establish a definition for high-risk baseline sBCMA. Mantel Byar analysis was used to examine whether high-risk sBCMA was correlated with shorter time to transformation, and a time-dependent cox proportional hazard was used to determine whether it is independent of other risk factors. A z test for proportions was used to compare the percentage of patients that progressed among high-risk versus low-risk sBCMA patients. A baseline sBCMA level ≥137.5 mg/ml was found to be the optimal cutoff between high- and low-risk SMM patients. Patients with high-risk sBCMA levels had a shorter time to transformation (P = .000332). sBCMA was also higher at the time of transformation than baseline levels (P = .0116). sBCMA was the only variable found to be significantly predictive of time to transformation and additionally was found to be independent of other risk factors. In this study, we have shown for the first time that sBCMA levels predict transformation of SMM to active disease and that these levels increase at the time of transformation. These results are consistent with other studies showing that active MM patients undergoing therapy with higher baseline sBCMA levels are more likely to progress early and its levels increase at the time of disease progression.
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Antígeno de Maduración de Linfocitos B/sangre , Biomarcadores de Tumor/sangre , Mieloma Múltiple Quiescente/sangre , Mieloma Múltiple Quiescente/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Antígeno de Maduración de Linfocitos B/inmunología , Biomarcadores de Tumor/inmunología , Progresión de la Enfermedad , Femenino , Glicoproteínas/sangre , Glicoproteínas/inmunología , Humanos , Cadenas kappa de Inmunoglobulina/sangre , Cadenas lambda de Inmunoglobulina/sangre , Masculino , Persona de Mediana Edad , Células Plasmáticas/inmunología , Células Plasmáticas/patología , Pronóstico , Modelos de Riesgos Proporcionales , Curva ROC , Factores de Riesgo , Mieloma Múltiple Quiescente/inmunología , Mieloma Múltiple Quiescente/mortalidadRESUMEN
Monocytes polarize into pro-inflammatory macrophage-1 (M1) or alternative macrophage-2 (M2) states with distinct phenotypes and physiological functions. M2 cells promote tumour growth and metastasis whereas M1 macrophages show anti-tumour effects. We found that M2 cells were increased whereas M1 cells were decreased in bone marrow (BM) from multiple myeloma (MM) patients with progressive disease (PD) compared to those in complete remission (CR). Gene expression of Tribbles homolog 1 (TRIB1) protein kinase, an inducer of M2 polarization, was increased in BM from MM patients with PD compared to those in CR. Ruxolitinib (RUX) is an inhibitor of the Janus kinase family of protein tyrosine kinases (JAKs) and is effective for treating patients with myeloproliferative disorders. RUX markedly reduces both M2 polarization and TRIB1 gene expression in MM both in vitro and in vivo in human MM xenografts in severe combined immunodeficient mice. RUX also downregulates the expression of CXCL12, CXCR4, MUC1, and CD44 in MM cells and monocytes co-cultured with MM tumour cells; overexpression of these genes is associated with resistance of MM cells to the immunomodulatory agent lenalidomide. These results provide the rationale for evaluation of JAK inhibitors, including MM BM in combination with lenalidomide, for the treatment of MM patients.
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Quimiocinas CXC/biosíntesis , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Quinasas Janus/metabolismo , Lenalidomida/farmacología , Mucina-1/biosíntesis , Mieloma Múltiple/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Estudios de Casos y Controles , Quimiocina CXCL12/biosíntesis , Quimiocina CXCL12/metabolismo , Quimiocinas CXC/metabolismo , Xenoinjertos , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Janus Quinasa 1/metabolismo , Janus Quinasa 2/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones SCID , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Mucina-1/metabolismo , Mieloma Múltiple/sangre , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores CXCR4/biosíntesis , Receptores CXCR4/metabolismo , Transducción de Señal , Células THP-1Asunto(s)
Antineoplásicos , Mieloma Múltiple , Humanos , ADP-Ribosil Ciclasa 1 , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genéticaRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of elotuzumab and dexamethasone (Ed) for relapsed or refractory multiple myeloma (RRMM) patients. METHOD: This retrospective study evaluated the efficacy and safety of Ed treatment for 21 RRMM patients, 11 of whom were considered lenalidomide-refractory, and all of whom had progressed on at least 1 prior steroid-containing regimen. We also evaluated the efficacy of adding lenalidomide to a subset of patients following progression from Ed. RESULTS: The overall response rate (ORR) and clinical benefit rate (CBR) of Ed were 10% and 19%, respectively. An additional 52% of patients demonstrated stable disease as their best response. The median PFS was 1.8 months on Ed for all patients. Fifteen patients received ERd following progression on Ed, and 60% of these patients were lenalidomide-refractory. The ORR and CBR were 20% and 33%, respectively, and the median PFS was 3.4 months. CONCLUSION: Our results suggest that some patients can benefit from Ed without an accompanying immunomodulatory agent and that efficacy can be achieved with the addition of lenalidomide at the time of progression. No new safety signals were detected, except for thrombocytopenia in 1 patient on Ed.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dexametasona/administración & dosificación , Resistencia a Antineoplásicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Recurrencia , Retratamiento , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVES: Data regarding bone marrow (BM) sampling and cytogenetic testing rates for identification of translocation (11q13;14q32) and their changes over time in a multiple myeloma (MM) population are limited. We analyzed these metrics at a clinic specializing in the treatment of MM. METHODS: A total of 760 BM aspirate samples from 351 patients were collected between August 2004 and October 2021. We analyzed BM sampling statistics, cytogenetic testing frequency, and the incidence rates for the t(11;14) translocation in a single clinic specializing in the treatment of MM. RESULTS: We report that most (54.4%) patients had only 1 aspirate collected; the main reason (64.6%) for BM collection was to confirm disease progression. Less than half (47.5%) of BM samples collected for evaluation of MM disease had cytogenetic testing, but the rates have markedly increased in recent years. Our data demonstrated an incidence rate of 19.3% for t(11;14). CONCLUSIONS: This report suggests that some patients may need to retest for this genetic aberration due to the possibility of false negatives and the potential benefit of identifying the t(11;14) marker for patients who may be candidates for a highly effective targeted therapy consisting of the BCL-2 inhibitor venetoclax.
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Mieloma Múltiple , Humanos , Mieloma Múltiple/genética , Incidencia , Translocación Genética , Médula Ósea , CitogenéticaRESUMEN
Introduction: Multiple myeloma (MM) is an incurable bone marrow (BM)-based cancer involving clonal plasma cells. Most patients show elevated levels of serum monoclonal protein (sMP) and kappa or lambda serum free light chains (sFLCs) at diagnosis. However, around 1-2% of patients, termed nonsecretory, do not produce these biomarkers. As the disease progresses, more patients may become unevaluable using conventional markers, requiring invasive and expensive procedures like BM biopsies and positron emission tomography-computed tomography (PET-CT) scans for assessment and highlighting the need for alternative methods to monitor disease progression. Case Presentation: We present a case report of an MM patient who developed nonsecretory disease during his second line of treatment when he complained of new rib pain; progressive disease was then confirmed on a PET-CT scan. The patient showed an increase in his serum B-cell maturation antigen (sBCMA) levels whereas his conventional myeloma markers did not detect disease activity (sMP remained undetectable and involved sFLC level was normal). After starting a new treatment regimen, his rib pain disappeared, PET-CT scan improved, and sBCMA levels decreased. Upon relapse, he developed increased rib pain with a rising sBCMA level; his conventional myeloma markers did not detect disease activity. After changing to a new regimen, his rib pain improved, and this was accompanied by a decrease in his sBCMA levels. Conclusion: Thus, this case exemplifies the potential for sBCMA to provide a non-invasive method for monitoring MM patients who develop nonsecretory disease.
RESUMEN
BACKGROUND: Ruxolitinib (RUX), an orally administered selective Janus kinase 1/2 inhibitor, has received approval for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. We have previously demonstrated the anti-multiple myeloma effects of RUX alone and in combination with the immunomodulatory agent lenalidomide (LEN) and glucocorticosteroids both pre-clinically and clinically. OBJECTIVE: This study aims to evaluate whether LEN can achieve clinical activity among patients with multiple myeloma progressing on the combination of RUX and methylprednisolone (MP). METHODS: In this part of a phase I, multicenter, open-label study, we evaluated the safety and efficacy of RUX and MP for patients with multiple myeloma with progressive disease who had previously received a proteasome inhibitor, LEN, glucocorticosteroids, and at least three prior regimens; we also determined the safety and efficacy of adding LEN at the time of disease progression from the initial doublet treatment. Initially, all subjects received oral RUX 15 mg twice daily and oral MP 40 mg every other day. Those patients who developed progressive disease according to the International Myeloma Working Group criteria then received LEN 10 mg once daily on days 1-21 within a 28-day cycle in addition to RUX and MP, which were administered at the same doses these patients were receiving at the time progressive disease developed. RESULTS: Twenty-nine subjects (median age 64 years; 18 [62%] male) were enrolled in this part of the study and initially received the two-drug combination of RUX and MP. The median number of prior therapies was six (range 3-12). The overall response rate from this two-drug combination was 31% and the clinical benefit rate was 34%. The best responses were 1 very good partial response, 8 partial responses, 1 minor response, 12 stable disease, and 7 progressive disease. The median progression-free survival was 3.5 months (range 0.5-36.2 months). The median time to response was 3.0 months. The median duration of response was 12.5 months (range 2.8-36.2 months). Twenty (69%) patients who showed progressive disease had LEN added to RUX and MP; all patients had prior exposure to LEN and all but one patient was refractory to their last LEN-containing regimen. After the addition of LEN, the overall response rate was 30% and the clinical benefit rate was 40%. The best responses of patients following the addition of LEN were 2 very good partial responses, 4 partial responses, 2 minor responses, 8 stable disease, and 4 progressive disease. The median time to response was 2.6 months (range 0.7-15.0 months). The median duration of response was not reached. The median progression-free survival following the addition of LEN was 3.5 months (range 0.3-25.9 months). CONCLUSIONS: For patients with multiple myeloma, treatment with RUX and MP is effective and well tolerated, and LEN can be used to extend the benefit of this RUX-based treatment. CLINICAL TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, NCT03110822, and is ongoing.
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Lenalidomida , Metilprednisolona , Mieloma Múltiple , Nitrilos , Pirazoles , Pirimidinas , Humanos , Mieloma Múltiple/tratamiento farmacológico , Masculino , Lenalidomida/uso terapéutico , Lenalidomida/farmacología , Femenino , Anciano , Pirazoles/uso terapéutico , Pirazoles/farmacología , Nitrilos/uso terapéutico , Pirimidinas/uso terapéutico , Pirimidinas/farmacología , Persona de Mediana Edad , Metilprednisolona/uso terapéutico , Metilprednisolona/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Anciano de 80 o más Años , Progresión de la Enfermedad , AdultoRESUMEN
BACKGROUND: Progression-free survival (PFS) and overall survival (OS) of newly diagnosed multiple myeloma (MM) patients have been widely published in the clinical trials setting, but data published from real-world settings are limited. OBJECTIVE: We determined the survival and factors that predict outcomes among 161 unselected, newly diagnosed MM patients whose frontline therapy was started at a single clinic specializing in the treatment of this B-cell malignancy. PATIENTS AND METHODS: None of these patients underwent an autologous stem cell transplantation as part of their initial therapy and the population had a high proportion (35%) of cytogenetic high-risk patients. RESULTS: With a median follow-up of 42.7 months, the cohort had a median PFS of 22.8 months and a median OS of 136.2 months. The 1-, 3-, and 5-year survival rates were 97.5%, 85.3%, and 76.2%, respectively. These results are considerably better than those reported from patients enrolled in clinical trials and those from countries with national registries. Age <65 years predicted for a longer OS (p = 0.0004). Baseline serum B-cell maturation antigen (sBCMA) levels were also assessed and showed median and mean levels of 320.3 ng/mL and 551.1 ng/mL, respectively. Furthermore, patients with baseline sBCMA levels in the lowest quartile (≤136.2 ng/mL) showed a longer PFS (p = 0.0262). CONCLUSION: These results provide clinicians with a real-world understanding of the survival of unselected, newly diagnosed patients initiating therapy in a clinic specializing in the care of MM patients.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Humanos , Anciano , Antígeno de Maduración de Linfocitos B , Trasplante Autólogo , Linfocitos BRESUMEN
We have reported that IgG antibody responses following two mRNA COVID-19 vaccinations are impaired among patients with multiple myeloma (MM). In the current study, sixty-seven patients with MM were tested for anti-spike IgG antibodies 0-60 days prior to their first vaccination, 14-28 days following the second dose, and both before and 14-28 days after their third dose of the mRNA-1273 or BNT162b2 vaccines. After the first two doses, most patients' (93 %) antibody levels declined to ineffective levels (<250 BAU/mL) prior to their third dose (D3). D3 elicited responses in 84 % of patients (61 % full response and 22 % partial response). The third vaccination increased antibody levels (average = 370.4 BAU/mL; range, 1.0-8977.3 BAU/mL) relative to just prior to D3 (average = 25.0 BAU/mL; range, 1.0-683.8 BAU/mL) and achieved higher levels than peak levels after the first two doses (average = 144.8 BAU/mL; range, 1.0-4,284.1 BAU/mL). D3 response positively correlated with mRNA-1273, a > 10-fold change from baseline for the two-dose series, switching from BNT162b2 to mRNA-1273 for D3, and treatment with elotuzumab and an immunomodulatory agent. Lower antibody levels prior to D3, poorer overall response to first two doses, and ruxolitinib or anti-CD38 monoclonal antibody treatment negatively correlated with D3 response. Our results show encouraging activity of the third vaccine, even among patients who failed to respond to the first two vaccinations. The finding of specific factors that predict COVID-19 antibody levels will help advise patients and healthcare professionals on the likelihood of responses to further vaccinations.
RESUMEN
BACKGROUND: Multiple myeloma (MM) patients have variable responses to mRNA vaccination to COVID-19. Little is known regarding their vaccine-induced antibody levels over time. METHODS: We monitored spike IgG antibody levels over 24 weeks among a subset of 18 MM patients who showed a full response after two mRNA vaccinations. RESULTS: MM patients had a more rapid decline in antibody levels as compared to eight healthy controls, with power law half-lives of 72 days (vs. 107 days) and exponential half-lives of 37 days (vs. 51 days). The patients with longer SARS-CoV-2 antibody half-lives were more likely to have undetectable monoclonal protein than those with shorter half-lives, suggesting better disease control may correlate with longer duration of vaccine-induced antibodies. Regardless, by 16 weeks post-second dose of mRNA vaccination, the majority of patients had antibody levels below 250 binding arbitrary units per milliliter, which would be unlikely to contribute to preventing COVID-19. CONCLUSIONS: Thus, even MM patients who respond adequately to vaccination are likely to require more frequent booster doses than the general population.
Asunto(s)
COVID-19 , Mieloma Múltiple , Humanos , COVID-19/prevención & control , SARS-CoV-2 , Vacunación , ARN MensajeroRESUMEN
BACKGROUND: Patients with multiple myeloma have unpredictable responses to vaccination for COVID-19. Anti-spike antibody levels can determine which patients develop antibodies at levels similar to healthy controls, and are a known correlate of protection. CASE REPORT: A multiple myeloma patient developed protective anti-spike antibodies after vaccination (608 IU/mL), but nonetheless developed severe breakthrough COVID-19 just 10 weeks following his second vaccination with mRNA-1273. RESULTS: Sequencing of the viral isolate revealed an extensively mutated variant with 10 spike protein mutations, including E484Q and N440K. Serology testing showed a dramatic decline in anti-spike antibodies immediately prior to virus exposure. CONCLUSIONS: Multiple myeloma patients who do develop detectable antibody responses to vaccination may be at increased risk for breakthrough infections due to rapid decline in antibody levels. Viral variants with immune escape mutations such as N440K, also seen independently in the SARS-CoV-2 Omicron variant (B.1.1.529) and in viral passaging experiments, likely require a higher level of anti-spike antibodies to prevent severe COVID-19.