Clinical characterization and outcomes of a cohort of colombian patients with AL Amyloidosis

Background: Amyloid light chain (AL) amyloidosis is characterized by amyloid fibril deposition derived from monoclonal immunoglobulin light chains, resulting in multiorgan dysfunction. Limited data exist on the clinical features of AL amyloidosis. Objective: This study aims to describe the clinical characteristics, treatments, and outcomes in Colombian patients with AL amyloidosis. Methods: A retrospective descriptive study was conducted at three high-complexity centers in Medellín, Colombia. Adults with AL amyloidosis diagnosed between 2012 and 2022 were included. Clinical, laboratory, histological, treatment, and survival data were analyzed. Results: The study included 63 patients. Renal involvement was most prevalent (66%), followed by cardiac involvement (61%). Multiorgan involvement occurred in 61% of patients. Amyloid deposition was most commonly detected in renal biopsy (40%). Bortezomib-based therapy was used in 68%, and 23.8% received high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT-ASCT). Hematological response was observed in 95% of patients with available data. Cardiac and renal organ responses were 15% and 14%, respectively. Median overall survival was 45.1 months (95% CI: 22.2-63.8). In multivariate analysis, cardiac involvement was significantly associated with inferior overall survival (HR 3.27; 95% CI: 1.23-8.73; p=0.018), HDCT-ASCT had a non-significant trend towards improved overall survival (HR 0.25; 95% CI: 0.06-1.09; p=0.065). Conclusions: In this study of Colombian patients with AL amyloidosis, renal involvement was more frequent than cardiac involvement. Overall survival and multiorgan involvement were consistent with data from other regions of the world. Multivariate analysis identified cardiac involvement and HDCT-AHCT as possible prognostic factors.

Antecedentes: La amiloidosis por amiloide de cadenas ligeras (AL) se caracteriza por el depósito de fibrillas amiloides derivadas de cadenas ligeras de inmunoglobulinas monoclonales, lo que resulta en disfunción multiorgánica. Existen datos limitados sobre las características clínicas de la amiloidosis AL. Objetivo: Este estudio tiene como objetivo describir las características clínicas, tratamientos y desenlaces en pacientes colombianos con amiloidosis AL. Métodos: Se llevó a cabo un estudio descriptivo retrospectivo en tres centros de alta complejidad en Medellín, Colombia. Se incluyeron adultos con diagnóstico de amiloidosis AL entre 2012 y 2022. Se analizaron datos clínicos, de laboratorio, histológicos, de tratamiento y de supervivencia. Resultados: El estudio incluyó 63 pacientes. La afectación renal fue más prevalente (66%), seguida de la afectación cardíaca (61%). El 61% de los pacientes presentaron afectación multiorgánica. El depósito amiloide se detectó con mayor frecuencia en la biopsia renal (40%). El tratamiento basado en bortezomib se utilizó en el 68%, y el 23.8% recibió altas dosis de quimioterapia con trasplante autólogo de progenitores hematopoyéticos (ADQT-TAPH). Se observó respuesta hematológica en el 95% de los pacientes con datos disponibles. La respuesta de órgano cardíaca y renal fue del 15% y 14%, respectivamente. La mediana de la supervivencia global fue de 45.1 meses (IC del 95%: 22.2-63.8). En el análisis multivariado, la afectación cardíaca se asoció significativamente con una supervivencia global inferior (HR 3.27; IC del 95%: 1.23-8.73; p=0.018), ADQT-TAPH mostró una tendencia no significativa hacia una mejora en la supervivencia global (HR 0.25; IC 95%: 0.06-1.09; p=0.065). Conclusiones: En este estudio de pacientes colombianos con amiloidosis AL, la afectación renal fue más frecuente que la afectación cardíaca. La supervivencia global y la afectación multiorgánica fueron consistentes con datos de otras regiones del mundo. El análisis multivariado identificó la afectación cardíaca y ADQT-TAPH como posibles factores pronósticos.

The Efficacy and Safety of Daratumumab-Based Regimen in Treatment of Multiple Myeloma Patients with Renal Impairment / 中国实验血液学杂志

OBJECTIVE@#To investigate the efficacy and safety of daratumumab in treatment of multiple myeloma (MM) patients with renal impairment (RI).@*METHODS@#The clinical data of 15 MM patients with RI who received daratumumab-based regimen from January 2021 to March 2022 in three centers were retrospectively analyzed. Patients were treated with daratumumab or daratumumab combined with dexamethasone or daratumumab combined with bortezomib and dexamethasone and the curative effect and survival were analyzed.@*RESULTS@#The median age of 15 patients was 64 (ranged 54-82) years old. Six patients were IgG-MM, 2 were IgA-MM,1 was IgD-MM and 6 were light chain MM. Median estinated glomerular filtration rate (eGFR) was 22.48 ml/(min·1.73 M2). Overall response rate of 11 patients with MM was 91% (≥MR), including 1 case of stringent complete response (sCR), 2 cases of very good partial response (VGPR), 3 cases of partial response (PR) and 4 cases of minor response (MR). The rate of renal response was 60%(9/15), including 4 cases of complete response (CR), 1 case of PR and 4 cases of MR. A median time of optimal renal response was 21 (ranged 7-56) days. With a median follow-up of 3 months, the median progression-free survival and overall survival of all patients were not reached. After treatment with daratumumab-based regimen, grade 1-2 neutropenia was the most common hematological adverse reaction. Non-hematological adverse reactions were mainly infusion-related adverse reactions and infections.@*CONCLUSION@#Daratumumab-based regimens have good short-term efficacy and safety in the treatment of multiple myeloma patients with renal impairment.

IgD multiple myeloma: report of 1 case and review of literature / 白血病·淋巴瘤

Objective:To investigate the clinical features of IgD multiple myeloma (MM) and the effect and prognosis of daratumumab-based combination therapy.Methods:The clinicopathological data of a IgD MM patient with disease progression and extramedullary infiltration treated with daratumumab in the Affiliated Hospital of Qingdao University in December 2019 were retrospectively analyzed.Results:The 74-year-old woman was diagnosed as IgD MM by bone marrow aspiration and immunofixation electrophoresis. The patient was given VD (bortezomib, dexamethasone), RD (lenalidomide, dexamethasone) and ID (ixazomib, dexamethasone) regimens. In June 2020, the patient developed multiple subcutaneous nodules, and she was assessed as progressive disease with extensive extramedullary infiltration. After treated with daratumumab-PAD (liposomal doxorubicin, bortezomib, dexamethasone) regimen, the patient's subcutaneous nodules were significantly reduced and partially disappeared, and the general condition was significantly improved. But the patient was in a cachexia state and finally died of the irregular treatment and disease progression.Conclusions:IgD MM has a low incidence and a short survival period, and there is no uniform standard treatment. The early application of daratumumab combined with proteasome inhibitors, immunomodulators, cytotoxic drugs and hematopoietic stem cell transplantation may improve the overall survival of patients.

Efficacy and safety of daratumumab in the treatment of advanced light chain amyloidosis / 中华血液学杂志

Objective: The study investigated the efficacy and safety of daratumumab in the treatment of cardiac light chain (AL) amyloidosis. Methods: We retrospectively analyzed the clinical characteristics, hematologic response, organ response, long-term survival, and adverse events of 20 patients with newly diagnosed or relapsed/refractory cardiac AL amyloidosis treated with daratumumab in Peking Union Medical College Hospitalo from January 2017 to March 2021. Results: The overall median age of 20 patients was 62 (range, 45-73) yeas, with a male to female ratio of 2.3:1. Nine patients were newly diagnosed, while 11 patients had relapsed or refractory disease. Based on Mayo 2004 cardiac AL staging system, stages Ⅱ and Ⅲ diseases were present in 20 patients respectively. Four patients died during the first cycle of daratumumab, and the remaining 16 patients completed a median of 3 (range, 1-10) cycles of treatment. Overall hematologic response rates were 80% each at 1, 3, and 6 months after treatment initiation, and 45% , 60% , and 60% of the patients achieved at least a very good partial response at 1, 3, and 6 months respectively. The median duration to hematologic response was 13 (range, 6-28) days. At 3, 6, and 12 months, 20% , 30% , and 40% of the patients respectively achieved a cardiac response, and the median days to response was 91 (range, 30-216) days. As of the last follow-up, 9 (45% ) patients died. The 1-month mortality rate of all the patients and stage IIIb patients was 25% and 40% , respectively. The 1-year overall survival rate was 48.4% . Lymphocytopenia was the most common hematological adverse event (above grade 3) . Non-hematological adverse events were mainly infusion-related reactions and infections. Conclusion: Daratumumab could induce deep and rapid hematologic response in newly diagnosed and previously treated cardiac AL amyloidosis patients. However, daratumumab was not effective in preventing the high and early mortality rate in stage Ⅲb patients.

Pharmacoeconomic evaluation of additional use of daratumumab in the treatment of transplant-ineligible newly diagnosed multiple myeloma / 中国药房

OBJECTIVE To evaluate the econ omical efficiency of daratumumab combined with lenalidomide and dexamethasone （D-Rd） regimen versus lenalidomide and dexamethasone （Rd） regimen alone in the treatment of transplant- ineligible newly diagnosed multiple myeloma （TNE-NDMM）. METHODS From the perspective of China ’s health system ，a partitioned survival model with three health states of progression free survival ，disease progression and death was established by using the published MAIA test data and relevant literature data. The model cycle was 28 days and the simulation time limit was 20 years. The incremental cost-effectiveness ratio （ICER）was calculated using quality-adjusted life years （QALY）as the output index. Sensitivity analysis was performed for key parameters. RESULTS The results of basic analysis showed that the ICER of D-Rd regimen versus Rd regimen was 2 719 038.08 yuan/QALY，far exceeding 3 times of GDP per capita in 2021（242 928 yuan）. The results of single factor sensitivity analysis showed that cost discount rate ，progression-free survival utility value ，utility discount rate，the cost of daratumumab and lenalidomide had a greater impact on ICER. Probabilistic sensitivity analysis suggested that the probability of economic advantage of D-Rd regimen was always 0 within the WTP range of 0-1 200 000 yuan. CONCLUSIONS Compared with Rd regimen ，D-Rd regimen has no cost-effectiveness advantage for the treatment of TNE-NDMM under the WTP of 3 times GDP per capita of China .

Gestão do cuidado ao paciente com doença hemato-oncológica sob a perspectiva do SUS: análise de hospitalizações e avaliação econômica do daratumumabe no tratamento do mieloma múltiplo / Health care manegement for patients with hematologic malignances from the perspective of the Brazilian Public Health System: analysis of hospitalizations and economic evaluation of daratumumab in the treatment of multiple myeloma

Com o objetivo de contribuir para a gestão do Sistema único de Saúde (SUS) no que se refere às neoplasias hematológicas (NH), este trabalho apresenta a elaboração de dois estudos: (a) analise de custos por hospitalização por NH, e (b) avaliação de custo-efetividade da adição de daratumumabe ao esquema de tratamento do Mieloma Múltiplo (MM) em pacientes não elegíveis para transplante autológico de células tronco hematopoiéticas (TCTH). Por meio da extração de dados do sistema de internações hospitalares do SUS, desenvolveu-se uma análise retrospectiva descritiva de frequências e custos das internações por NH de acordo com sua distribuição temporal, espacial (por estados e regiões), e por patologia, na década compreendida entre os anos de 2010 e 2019. Foram também calculados custo médio pro procedimento e taxa de acesso. Foi observado que houve uma tendência de crescimento estável das frequências e dos custos ao longo do período analisado. Além disso, contatou-se uma significativa discrepância na frequência dos procedimentos entre as regiões Norte e Sudeste, que registraram o menor e o maior número de procedimentos, respectivamente. Observou-se também eu a frequência das internações por patologia não refletiu a incidência estimada pela literatura no país para cada uma das patologias avaliadas. Para o estudo de custo-efetividade, foi desenvolvido um modelo de simulação de sobrevida particionado para a adição do daratumumabe ao esquema de tratamento composto por bortezomibe, melfalano e prednisona (VMP). O horizonte temporal de 30 anos e a perspectiva de análise do SUS, foram usados. Com base nos dados da literatura foi possível observar que a adição deste medicamento ao VMP no tratamento desses pacientes pode aumentar a sobrevida global e a sobrevida livre de progressão. Considerados os custos relacionados a esta tecnologia e ao manejo do paciente no cenário brasileiro, no entanto, a inclusão do daratumumabe está aparentemente acima do limiar de aceitabilidade adotado pelo SUS. Para que esta estratégia seja custo-efetiva no cenário observado, a tecnologia precisaria sofrer uma redução de quase 50% no custo. O estudo, portanto, não recomenda a adição do daratumumabe ao VMP no tratamento do MM em pacientes não elegíveis para TCTH.

Aiming to contribute to the management of the Brazilian Public Health System (SUS) regarding hematologic malignances (NH), this work presents the development of two studies: (a) cost analysis per hospitalization for NH, and (b) cost-effectiveness evaluation of adding daratumumab to the treatment scheme for Multiple Myeloma (MM) in patients not eligible for autologous hematopoietic stem cell transplantation (TCTH). By extracting data from the SUS hospital admissions system, we developed a retrospective descriptive analysis of frequencies and costs of NH admissions according to their temporal, spatial distribution (by states and regions), and by pathology, in the decade between the years 2010 and 2019. Average cost per procedure and access rate were also estimated. It was observed that there was a stable growth trend in frequencies and costs over the analyzed period. Furthermore, a significant discrepancy in the procedure frequency was found between the North and Southeast regions, which recorded the lowest and highest number of procedures, respectively. It was also observed that the frequency of hospitalizations per pathology did not reflect the incidence estimated by the literature in the country for each of the pathologies evaluated. For the cost-effectiveness study, a partitioned survival simulation model was developed for the inclusion of daratumumab in the treatment scheme consisting of bortezomib, melphalan, and prednisone (VMP). A 30-year time horizon and the perspective of the SUS were used for the analysis. Based on literature data, it was possible to observe that the inclusion of this drug to VMP in the treatment of these patients can increase overall survival and progression-free survival. Considering the costs related to this technology and patient management in the Brazilian scenario, however, the inclusion of daratumumab is seemingly above the threshold of acceptability adopted by SUS. For this strategy to be cost-effective in the observed scenario, the technology would require a cost reduction of almost 50%. The study, therefore, does not recommend the inclusion of daratumumab to VMP in the treatment of MM in patients not eligible for TCTH.

Efficacy and safety of daratumumab-based combined regimens for treatment of multiple myeloma / 白血病·淋巴瘤

Objective:To evaluate the safety and efficacy of daratumumab in the treatment of multiple myeloma (MM).Methods:The clinical data of 19 MM patients treated with daratumumab alone or in combination with chemotherapy regimens from June 2021 to December 2021 in the Affiliated Hospital of Jining Medical College were retrospectively analyzed, of which 2 patients received daratumumab alone, 6 cases received daratumumab combined with lenalidomide+dexamethasone (DRD) regimen, 1 case received daratumumab combined with liposomal doxorubicin+dexamethasone (DVD) regimen, 2 case received daratumumab combined with dexamethasone+cyclophosphamide+etoposide+cisplatin (DECP) regimen, 3 cases received daratumumab combined with isazomib+dexamethasone (ID) regimen, 2 cases received daratumumab combined with bortezomib+dexamethasone (BD) regimen, and 3 cases received daratumumab combined with dexamethasone (DD) regimen. The efficacy and incidence of adverse effects were analyzed.Results:Among the 19 patients, 8 had complete remission (CR), 1 had very good partial remission (VGPR), 5 had partial remission (PR), 1 had stable disease (SD), and 4 had progressive disease (PD). The overall response rate (ORR) was 73.7% (14/19). The median progression-free survival (PFS) time was 10.42 months (95% CI 8.04-12.79 months) and the median overall survival (OS) time was 52.06 months (95% CI 37.85-66.27 months). The main adverse reactions during treatment were grade 3 neutropenia in 3 cases, grade 3 lymphopenia in 3 cases, grade 2 anemia in 5 cases, grade 2 nausea and vomiting in 7 cases, and infusion-related adverse reactions in 7 cases. Conclusions:Daratumumab-based chemotherapy regimens for the treatment of MM patients can achieve great efficacy with good safety and tolerability.

Results of the daratumumab monotherapy early access treatment protocol in patients from Brazil with relapsed or refractory multiple myeloma

ABSTRACT Introduction: Daratumumab is a CD38-targeting monoclonal antibody with established efficacy and safety in patients with relapsed or refractory multiple myeloma (RRMM). We report results of an early access protocol (EAP) of daratumumab monotherapy for RRMM in a cohort of Brazilian patients. Methods: Patients with RRMM and ≥3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or who were double refractory to both a PI and IMiD received daratumumab, 16 mg/kg, intravenously weekly for 8 weeks, biweekly for 16 weeks, and every 4 weeks thereafter until disease progression, unacceptable toxicity, loss of clinical benefit, or study conclusion or if daratumumab became available with reimbursement. Results: Forty-nine patients received ≥1 dose of daratumumab. The median (range) duration of treatment was 6.4 (0.3-11.8) months, with a median (range) of 8 (1-13) treatment cycles. Grade 3/4 treatment-emergent adverse events (TEAEs) were reported in 38.8% of patients, most frequently neutropenia and pneumonia (10.2% each). Seven (14.3%) patients discontinued treatment due to TEAEs; 3 patients discontinued due to daratumumab-related TEAEs. Serious TEAEs occurred in 38.8% of patients. Infusion-related reactions were reported in 25 (51.0%) patients, were primarily grade 1/2, and the majority (23 patients) occurred during the first infusion. Twenty (40.8%) patients achieved a partial response or better; median progression-free survival was 8.25 (95% confidence interval, 5.55-17.54) months. Conclusion: In this EAP, daratumumab monotherapy in Brazilian patients showed a safety and efficacy profile consistent with clinical studies of daratumumab monotherapy in patients with heavily pretreated RRMM. ClinicalTrials.gov identifier: NCT02477891.

Daratumumab for the treatment of primary systemic amyloidosis: a multicenter retrospective analysis / 中华内科杂志

Objective:To analyze the efficacy and safety of Daratumumab for the treatment of primary AL light chain systemic amyloidosis.Methods:Twenty one patients who were diagnosed as primary AL light chain systemic amyloidosis and treated with Daratumumab from 7 centers were retrospectively analyzed. Daratumumab was administrated as first line therapy in seven patients and 14 patients with relapsed settings. Hematological response, safety and survival were analyzed.Results:All 7 patients achieved very good partial response (VGPR) or better with first-line application of daratumumab. Three patients died, and the other four achieved organ remission. Among 14 relapsed patients, 2 patients had a difference of free light chain (dFLC) less than 20 mg/L before treatment, and 9 with a dFLC of more than 50 mg/L. All patients reached partial response (PR) or better, including 4 patients with complete response (CR), 3 with VGPR and 2 with PR. The response rate was 100% in 3 patients with dFLC 20-50 mg/L at baseline. The organ remission rate was 50% in patients with heart involvement and 58.3% in patients with kidney impairment. The overall median follow-up period was 5.3 months, and 11 months in surviving patients. One patient died of severe infection and disseminated intravascular coagulation (DIC) with stable amyloidosis. One patient switched to other regimens because dFLC elevated but did not fulfill progressive disease after 2 year application. As to safety, no grade 3/4 infusion reaction developed, and grade 1 infusion reaction occurred in 3 cases during the first infusion. Lymphocytopenia was seen in 75% patients including grade 3 or more in 30% patients.Conclusion:Daratumumab is effective to eliminate serum free light chain in both newly diagnosed and relapsed patients with systemic amyloidosis.

Tumor lysis syndrome in multiple myeloma treated by daratumumab combined with chemotherapy: report of two cases and review of literature / 白血病·淋巴瘤

Objective:To investigate the clinical safety of daratumumab (DARA) in patients with relapsed/refractory multiple myeloma (MM).Methods:The diagnosis and treatment process of 2 cases of relapsed/refractory MM treated in Huadong Hospital of Fudan University in 2020 were retrospectively analyzed, the related laboratory indicators indexes after using DARA were analyzed, and the related literature was reviewed.Results:After using DARA, the 2 patients rapidly developed tumor lysis syndrome (TLS) such as high potassium, high phosphorus, high uric acid, low calcium and kidney damage, which eventually led to the death of patients.Conclusions:Patients with high tumor load treated by DARA are prone to TLS, which is often life-threatening. Clinicians should be alert to the occurrence of such events.

Daratumumab combined with chemotherapy bridging to allogeneic hematopoietic stem cell transplantation followed by daratumumab and lenalidomide maintenance therapy for primary plasma cell leukemia: report of one case and review of literature / 白血病·淋巴瘤

Objective:To observe the therapeutic efficacy and prognosis of daratumumab combined with chemotherapy bridging to allogeneic hematopoietic stem cell transplantation (allo-HSCT) followed by daratumumab and lenalidomide maintenance treatment for primary plasma cell leukemia (PCL).Methods:The clinical data of a patient with primary PCL admitted to the First People's Hospital of Yunnan Province in January 2020 were retrospectively analyzed, and relevant literatures were reviewed.Results:The patient was diagnosed with primary PCL and treated with daratumumab combined with BD (bortezomib + dexamethasone) for 1 course and BCDD (bortezomib + cyclophosphamide + liposomaldoxorubicin + dexamethasone) for two courses. The patient was treated with daratumumab combined with allo-HSCT after complete remission. The donor cells were successfully implanted and the chimerism rate of donor cells was 94.36% without acute graft-versus-host disease reaction. And then the patient received intermittent maintenance therapy of daratumumab combined with low dose lenalidomide after transplantation, and the current remission period after transplantation reached 4 months.Conclusions:Daratumumab combined with chemotherapy bridging to allo-HSCT followed by daratumumab and lenalidomide may improve the prognosis of primary PCL and prolong survival time.

Análise de custo por desfecho das novas terapias de combinação tripla com lenalidomida para o mieloma múltiplo recidivado/refratário no Brasil / Cost by outcomes analysis of novel triplecombination therapies with lenalidomide for relapsed/refractory multiple myeloma in Brazil

Objetivo: Estimar o custo de tratamento das novas terapias de combinação tripla com lenalidomida no manejo dos pacientes com mieloma múltiplo recidivado/refratário (MMRR) sob a perspectiva do sistema de saúde privado brasileiro. Métodos: Os custos associados da combinação de lenalidomida + dexametasona com carfilzomibe (KRd), daratumumabe (DRd), elotuzumabe (ERd) e ixazomibe (IRd) foram comparados. Para cada terapia, a duração de tratamento foi estimada pela média do tempo de sobrevida livre de progressão (SLP) restrita a três anos a partir de dados de SLP dos estudos pivotais das respectivas terapias. Os custos de tratamento foram estimados para a duração de tratamento, considerando a posologia específica dos regimes terapêuticos. Os preços dos medicamentos foram baseados no preço fábrica de abril de 2020. Não foi considerado o compartilhamento de doses. O custo total do tratamento, o custo médio por ciclo e o custo por taxa de resposta objetiva (TRO) em três anos foram comparados. Resultados: A duração de tratamento no período de três anos foi de 23,3, 27,6, 20,3 e 20,9 meses para KRd, DRd, ERd e IRd, respectivamente. O custo médio total de tratamento foi estimado em 975.557 reais (BRL) para KRd, 1.507.544 BRL para DRd (+55% versus KRd), 1.207.899 BRL para ERd (+24% versus KRd) e 983.917 para IRd (+1% versus KRd). KRd teve o menor custo médio por mês de SLP (horizonte de três anos) entre as terapias, 41.957 BRL versus 54.709 BRL para DRd (+30% versus KRd), 59.635 BRL para ERd (+42% versus KRd) e 47.147 para IRd (+12% versus KRd). Similarmente, o custo por TRO foi 31% menor para KRd (1.119.770 BRL), comparado ao DRd (1.621.015 BRL), 27% menor, comparado ao ERd (1.528.986 BRL), e 11% menor, comparado ao IRd (1.256.064). Conclusões: Resultados da presente análise indicam que KRd está associado a um menor custo médio de tratamento, acompanhado de maior previsibilidade, menor custo por TRO e por mês de SLP, comparado ao DRd, ERd e IRd no horizonte de três anos sob a perspectiva do sistema de saúde privado brasileiro. Os resultados estão associados com alguma incerteza em razão das diferenças nas populações dos estudos, desenho dos estudos (duração fixa de carfilzomibe vs. tratamento até a progressão para daratumumabe, elotuzumabe e ixazomibe) e porque a duração de tratamento é tipicamente menor do que a SLP.

Objective: To estimate treatment costs for novel triple-combination therapies with lenalidomide in the management of relapsed/refractory multiple myeloma (RRMM) patients from the Brazilian private healthcare perspective. Methods: Treatment costs associated with lenalidomide + dexamethasone combinations with carfilzomib (KRd), daratumumab (DRd), elotuzumab (ERd) and ixazomib (IRd) were compared. For each therapy, treatment duration was estimated as the mean progression-free survival (PFS) time restricted to three years using published PFS data from pivotal trials available for these treatments. Treatment costs were estimated for the modeled treatment duration considering therapy-specific dosing schedules. Drug prices were based on April 2020 Brazilian list prices. No vial sharing was assumed. Total treatment costs, average cost per cycle, and cost per overall response rate (ORR) over the three-year period were compared. Results: Modeled treatment duration over the three-year period was 23.3, 27.6, 20.3 and 20.9 months for KRd, DRd, ERd and IRd respectively. Corresponding average total treatment costs were estimated to be 975,557 Brazilian Real (BRL) for KRd; 1,507,544 BRL for DRd (+55% versus KRd); 1,207,899 BRL for ERd (+24% versus KRd) and 983,917 for IRd (+1% versus KRd). KRd had the lowest average cost per month of restricted PFS (3-year time frame) among the therapies, 41,957 BRL versus 54,709 BRL for DRd (+30% versus KRd); 59,635 BRL for ERd (+42% versus KRd); and 47,147 for IRd (+12% versus KRd). Similarly, the cost per achieved ORR was lower for KRd (1,119,770 BRL) than that for DRd (1,621,015 BRL); ERd (1,528,986 BRL); and IRd (1,256,064) by 31%, 27% and 11%, respectively. Conclusions: Results of the present analysis indicate that KRd is associated with lower mean treatment costs and more predictable costs, lower cost per ORR and per month in PFS than DRd, ERd and IRd over a relevant three-year time horizon from the Brazilian private healthcare perspective. The results are associated with some uncertainty due to differences in trial populations, trial design (fixed duration for carfilzomib vs treatment till progression for daratumumab, elotuzumab and ixazomib) and because treatment duration is typically shorter than PFS.

Custo-efetividade do esquema com daratumumabe, bortezomibe e dexametasona em comparação com terapias à base de carfilzomibe, elotuzumabe e ixazomibe para o tratamento de mieloma múltiplo recidivado e refratário na perspectiva de um pagador do sistema de saúde suplementar brasileiro / Cost-effectiveness analysis of daratumumab, bortezomib, and dexamethasone combination in comparison to carfilzomib, elotuzumab and ixazomib-based therapies for the treatment of patients with relapsed and refractory multiple myeloma from a Brazilian private payer perspective

Objetivo: O objetivo deste estudo é estimar a razão de custo-efetividade incremental da combinação de daratumumabe, bortezomibe e dexametasona (DVd) em comparação com carfilzomibe com dexametasona (Kd); carfilzomibe, lenalidomida e dexametasona (KRd); elotuzumabe, lenalidomida e dexametasona (ERd); e ixazomibe, lenalidomida e dexametasona (IRd) no tratamento do mieloma múltiplo refratário ou recidivado (MMRR) sob a perspectiva de um pagador privado no Brasil. Métodos: Foi utilizado um modelo de transição com três estados, baseado no método de área sob a curva, para simular a trajetória de uma coorte com MMRR: pré-progressão, pós-progressão e morte. Parâmetros clínicos foram obtidos por meio de uma metanálise e os custos incluídos foram aquisição e administração de medicamentos e serviços médicos. O horizonte de tempo adotado foi de 30 anos e descontos de 5% foram aplicados tanto a custos quanto a desfechos de efetividade. Análise de sensibilidade probabilística foi realizada. Resultados: Demonstrou-se que o esquema terapêutico DVd é dominante sobre Kd, KRd, ERd e IRd. DVd gerou 1,09 ano de vida incremental versus Kd com economia de R$ 174.227; 0,15 ano de vida incremental com redução de R$ 238.324 em comparação com KRd; incremento de 0,06 ano de vida com redução de R$ 641.021 comparado com ERd; e 0,59 ano de vida incremental com economia de R$ 254.367 comparado com IRd. A análise de sensibilidade probabilística confirmou a consistência e a robustez do modelo e demonstrou que DVd tem probabilidades de 92,9%, 89,1%, 99,9% e 94,2% de ser custo-efetivo em comparação com Kd, KRd, ERd e IRd, respectivamente, assumindo um limiar de disposição a pagar de 3 PIB per capita. Conclusão: DVd demonstrou ser superior aos comparadores tanto em desfechos clínicos quanto econômicos no tratamento do MMRR, dados a maior sobrevida e os menores custos.

Objective: To estimate the incremental cost-effectiveness ratio of daratumumab, bortezomib, and dexamethasone (DVd) combination in comparison to carfilzomib and dexamethasone (Kd); carfilzomib, lenalidomide and dexamethasone (KRd); elotuzumab, lenalidomide and dexamethasone (ERd); and ixazomib, lenalidomide and dexamethasone (IRd) for the treatment of patients with relapsed and refractory multiple myeloma (RRMM) from a Brazilian private payer perspective. Methods: It was used a three-health state transition model based on the area under the curve method to simulate the cohort trajectory: pre-progression, post-progression, and death. Clinical parameters were obtained in a meta-analysis and considered costs were: drugs acquisition and administration, and medical services. Time-horizon was 30 years, and discount rates applied to costs and outcomes were 5%. A probabilistic sensitivity analysis was performed to evaluate the impact of the uncertainty of the input values. Results: The analysis demonstrated that DVd treatment is dominant over Kd, KRd, ERd, and IRd, providing an increment of 1.09 life year with cost reduction of R$174.227 when compared to Kd, an increment of 0,15 life year with cost reduction of R$238.324 when compared to KRd, an increment of 0,06 life year with cost reduction of R$641.021 when compared to ERd, and an increment of 0,59 life year with cost reduction of R$254.367 when compared to IRd. The probabilistic sensitivity analysis confirms the robustness of the model and results consistency, demonstrating that DVd has 92.9%, 89.1%, 99.9%, and 94,2% probability of being cost-effective versus Kd, KRd, Erd, and IRd, respectively, when an ICER of 3 per-capita GDP is assumed. Conclusion: DVd combination demonstrated superior clinical and economic outcomes in RRMM patients when compared to Kd, KRd, Erd, and IRd, since the therapy provides longer survival to patients at a lower cost to payers.

A Case of Panagglutination on Antibody Identification in a Multiple Myeloma Patient Receiving Daratumumab / 대한수혈학회지

Herein, we report a patient showing panagglutination in the unexpected antibody identification test after the administration of daratumumab. The patient was a 66-year-old woman who had undergone multiple cycles of chemotherapy and autologous peripheral blood stem cell transplantation for treating multiple myeloma; however, despite treatment, she had relapsed. Therefore, daratumumab, on clinical trials in Korea, started to be administered. After administration of daratumumab, the result of antibody screening test was positive, on the contrary to the result prior to the administration. Moreover, all positive reactions were shown in the antibody identification to the panel cells. After destroying CD38 antigens on the surface of RBCs using DTT, negative results were obtained. Daratumumab—a novel therapeutic human CD38 monoclonal antibody that can be used as targeted immunotherapy—is an FDA-approved drug for treating multiple myeloma. Because CD38 is expressed not only on myeloma cells, but also on red blood cells (RBCs), the use of daratumumab might lead to RBC agglutinations, and thereby resulting in false-positive results on the pre-transfusion tests. Therefore, caution is needed in case of a patient receiving daratumumab. Furthermore, additional test using DTT is required, especially when panagglutination was shown in the antibody identification test, as in this case.