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1.
Eur J Haematol ; 109(6): 749-754, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36066204

RESUMO

OBJECTIVES: Despite the effectiveness of newer drugs for the treatment of multiple myeloma (MM), the outcomes are further improved by subsequent autologous stem cell transplantation (ASCT). Data on effectiveness in older patients are limited. We compared outcomes in patients aged 65-75 years depending on whether they were treated with ASCT or not and compared those to outcomes in patients <65 years. METHODS: This was a retrospective, single-center study. We compared progression-free survival (PFS) and overall survival (OS) for all MM patients below and above the age of 65 years treated ± ASCT at the Karolinska University Hospital between 2010 and 2020. PFS and OS were calculated by the Kaplan-Meier method. Variables affecting PFS and OS were evaluated using Cox regression model. RESULTS: Both PFS and OS were improved in the group 65-75 years treated +ASCT compared to those treated pharmacologically (p = 0.008 and p < 0.001, respectively). There were no significant differences between patients <65 years and those 65-75 years treated with ASCT. CONCLUSION: The findings indicate that even patients >65 years should be evaluated as candidates for ASCT. An individualized approach supported by a frailty/geriatric assessment score could assist clinicians to select the appropriate treatment for each patient.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Idoso , Humanos , Melfalan/uso terapêutico , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Transplante Autólogo , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Intervalo Livre de Doença , Estudos Retrospectivos , Padrão de Cuidado , Resultado do Tratamento
2.
Eur J Haematol ; 106(4): 546-554, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33471414

RESUMO

INTRODUCTION: Novel drugs and drug combinations have improved outcomes for multiple myeloma patients. However, subgroups of patients still have a poor progression-free survival (PFS) and overall survival (OS). In an attempt to identify how the novel drugs affect the outcome in standard-risk and high-risk patients, respectively, we have investigated 715 multiple myeloma (MM) patients who have undergone high dose treatment followed by autologous stem cell transplantation at our center during 1995 - 2020. Outcomes during three time periods, 1995-1999 (period I), 2000-2009 (period II), and 2010-2020 (period III), were compared separately for standard-risk and high-risk patients. Risk stratification was based on chromosome analysis for periods II and III. RESULTS: The whole cohort of patients showed significantly improved OS with time during the three periods being at a median of 5.8, 7.0, and 10.0 years, respectively. There is also a weak tendency for improved PFS, that is, a median of 2.4, 2.6, and 2.9 years, respectively, during the same periods. However, the separate analysis of standard-risk and high-risk patients showed that the overall improvement with time was due to improved standard-risk patients (median OS 8.4 years for the period I and not reached for period II and III). In contrast, no significant improvement was seen in high-risk patients. For patients with del17p, PFS was even worse during period III as compared to period II (median 1.6 vs 3.2 years respectively). CONCLUSION: Our results show that the dramatic improvement in outcome for MM patients during the last 20 years only applies for standard-risk patients, while high-risk MM patients still are doing poorly, indicating that the novel drugs developed during this time are preferentially effective in standard-risk patients. New treatment modalities like CAR-T cells, CAR-NK cells, and/or bispecific antibodies should be tried in clinical studies early in the course of the disease, especially in patients with high-risk cytogenetics.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Adulto , Idoso , Aberrações Cromossômicas , Terapia Combinada , Análise Citogenética , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/etiologia , Prognóstico , Retratamento , Análise de Sobrevida , Transplante Autólogo , Resultado do Tratamento
3.
Am J Hematol ; 96(8): 925-933, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33901326

RESUMO

Approximately 20% of newly diagnosed multiple myeloma (NDMM) patients harbor t(11;14), a marker of inferior prognosis, resulting in up-regulation of CCND1. These patients respond to BCL2 inhibitor experimental drug venetoclax. Furthermore, t(11;14) is reported to be associated with increased BCL2/MCL1 ratio. We investigated the use of venetoclax (400 mg daily) in a cohort of 25 multiple myeloma (MM) and AL-amyloidosis patients harboring t(11;14) and assessed safety and efficacy. Efficacy was assessed by response rate (RR) and time on treatment. Furthermore, immunohistochemistry (IHC), for BCL2 family member expression was assessed at diagnosis and relapse in the venetoclax-treated group and analyzed for correlation with clinical RR. Additionally, patient material from venetoclax non-treated group including non-t(11;14) diagnosis (n = 27), t(11;14) diagnosis (n = 17), t(11;14) relapse (n = 7), hyperdiploidy (n = 6) and hyperdiploidy + t(11;14) (n = 6) was used for RNA sequencing (RNASeq) and validation by qPCR. Venetoclax treatment in t(11;14) patients demonstrated manageable safety and promising efficacy. Partial responses or better were observed in eleven patients (44%). Responding patients had significantly higher BCL2/MCL1 (p = 0.031) as well as BCL2/BCL-XL (p = 0.021) ratio, regardless of time of measurement before venetoclax treatment. Furthermore, an IRF5 motif was enriched (p < .001) in the downregulated genes in t(11;14) relapses vs diagnoses. The RR with single agent venetoclax was 71% in AL-amyloidosis and 33% in MM, and IHC proved useful in prediction of treatment outcome. We could also demonstrate possible resistance mechanisms of t(11;14), downregulation of IRF5 targeted genes, which can be exploited for therapeutic advantages.


Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Humanos , Pessoa de Meia-Idade , Neoplasias de Plasmócitos , Estudos Retrospectivos , Sulfonamidas/farmacologia
4.
Eur J Haematol ; 103(6): 588-596, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31487754

RESUMO

OBJECTIVES: The most common translocation in multiple myeloma (MM) is t(11;14)(q13;q32), and its importance as prognostic factor has been controversial. The aim was to analyze its prognostic value. METHOD: In this retrospective study of 469 newly diagnosed myeloma patients, outcomes in patients with (11;14) and standard risk (t(11;14)SR) or high risk (t(11;14)HR) cytogenetics were compared to outcomes of patients without t(11;14) and SR (non-t(11;14)SR) or HR (non-t(11;14)HR), respectively. RESULTS: Overall progression-free survival (PFS) was shorter in t(11;14)SR than non-t(11;14)SR (median 28.9 vs 35.3 months); however, the difference was not significant (P = .2). Overall survival (OS) did not differ significantly between the groups. In the subgroup of patients that did not receive high-dose treatment, PFS was shorter for t(11;14)SR compared to non-t(11;14)SR, 10.6 vs 24.6 months (P = .01). Although OS were shorter for t(11,14)SR compared to non-t(11;14)SR (5-year OS 41.7% vs 63.8%), the difference was not significant (P = .1). In HDT patients, no significant difference was observed for OS or PFS between those with or without t(11;14). CONCLUSION: This study shows that t(11;14) is associated with poorer outcome in MM, particularly in non-high-dose-treated SR patients. It should be considered an intermediate or high-risk marker in these patients.


Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Translocação Genética , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Estudos Retrospectivos , Taxa de Sobrevida
5.
Eur J Haematol ; 103(3): 247-254, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31231833

RESUMO

OBJECTIVES: At our center, patients with multiple myeloma (MM) were treated upfront with bortezomib, cyclophosphamide, and dexamethasone (VCD) until cyclophosphamide was replaced with lenalidomide in the combination (VRD). These treatments have never been compared head-to-head in large real-life patient material. METHOD: A retrospective analysis of patients treated with VRD and VCD in the first line, both with and without subsequent high-dose treatment (HDT) and autologous stem cell transplantation. A total of 681 patients were included, 117 receiving VRD (71 with, 46 without HDT) and 564 receiving VCD (351 with, 213 without HDT). RESULTS: Overall response rate (≥partial response) was higher with VRD compared to VCD in the entire VRD group (98% vs 88%, P < 0.001) and in the non-HDT group (98% vs 79%, P < 0.001). Progression-free survival (PFS) at 18 months was longer with VRD compared to VCD in the entire VRD group, the non-HDT group and the HDT group (88% vs 63%, 82% vs 32% and 91% vs 73%, respectively). Overall survival at 18 months was better for VRD-treated patients in the entire VRD group (95% vs 89%, P = 0.048). CONCLUSION: Upfront VRD gives better responses and longer PFS compared to VCD in MM patients with or without subsequent HDT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Feminino , Humanos , Lenalidomida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sobrevida , Teniposídeo/efeitos adversos , Teniposídeo/uso terapêutico , Resultado do Tratamento
7.
Eur J Haematol ; 99(3): 216-222, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28544116

RESUMO

Solitary plasmacytoma (SP) and plasma cell leukemia (PCL) are uncommon (3-6%) types of plasma cell disease. The risk of progression to symptomatic multiple myeloma (MM) is probably important for the outcome of SP. PCL is rare and has a dismal outcome. In this study, we report on incidence and survival in PCL/SP, and progression to MM in SP, using the prospective observational Swedish Multiple Myeloma Register designed to document all newly diagnosed plasma cell diseases in Sweden since 2008. Both solitary bone plasmacytoma (SBP) (n=124) and extramedullary plasmacytoma (EMP) (n=67) have better overall survival (OS) than MM (n=3549). Progression to MM was higher in SBP than in EMP (35% and 7% at 2 years, respectively), but this did not translate into better survival in EMP. In spite of treatment developments, the OS of primary PCL is still dismal (median of 11 months, 0% at 5 years). Hence, there is a great need for diagnostic and treatment guidelines as well as prospective studies addressing the role for alternative treatment options, such as allogeneic stem cell transplantation and monoclonal antibodies in the treatment of PCL.


Assuntos
Leucemia Plasmocitária/epidemiologia , Plasmocitoma/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Humanos , Incidência , Leucemia Plasmocitária/diagnóstico , Leucemia Plasmocitária/mortalidade , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados da Assistência ao Paciente , Plasmocitoma/diagnóstico , Plasmocitoma/mortalidade , Vigilância da População , Sistema de Registros , Análise de Sobrevida , Suécia/epidemiologia
9.
Br J Haematol ; 164(5): 684-93, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24313224

RESUMO

The outcome for multiple myeloma patients has improved since the introduction of bortezomib, thalidomide and lenalidomide. However, studies comparing new and conventional treatment include selected patient groups. We investigated consecutive patients (n = 1638) diagnosed in a defined period and compared survival with a gender- and age-matched cohort Swedish population (n = 9 340 682). Median overall survival for non-high-dose treated patients was 2·8 years. The use of bortezomib, thalidomide or lenalidomide in first line therapy predicted a significantly longer overall survival (median 4·9 years) compared to conventional treatment (2·3 years). Among non-high-dose treated patients receiving at least 2 lines with bortezomib, thalidomide or lenalidomide, 69% and 63% have survived at 3 and 5 years as compared to 48% and 22% with conventional drugs and 88% and 79% in the matched cohort populations, respectively. The median overall survival in high-dose treated patients was 6·9 years. Of these patients, 84% survived at 3 years and 70% at 5 years as compared to 98% and 95% in the matched cohort population. Overall survival in the best non-high-dose treated outcome group is closing the gap with the matched cohort. Upfront use of new drugs is clearly better than waiting until later lines of treatment.


Assuntos
Mieloma Múltiplo/mortalidade , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/uso terapêutico , Bortezomib , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Pirazinas/administração & dosagem , Pirazinas/uso terapêutico , Sistema de Registros , Análise de Sobrevida , Suécia/epidemiologia , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Resultado do Tratamento
10.
Eur J Haematol ; 92(1): 19-25, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24118547

RESUMO

The combination of melphalan and prednisone (MP) has been the standard treatment of multiple myeloma (MM). Since the introduction of novel agents, the clinical outcome in MM has improved. Six randomized prospective studies with thalidomide combined with melphalan and prednisone (MPT) compared to MP have been performed, most of them showing that MPT gives a better response rate and median overall survival (OS). Amongst 1843 MM patients admitted to 15 Swedish centres, we selected all patients treated with MP and MPT in first, second, third or fourth line of therapy, in total 888 patients treated with MP and 274 with MPT. Patients were evaluated for response rate, OS and Time to Next Treatment. Multivariate Cox model analysis was made to adjust for different criteria at time for MM-diagnosis. The median OS from beginning of first line of treatment was 2.2/4.2 yrs after MP/MPT respectively, and in second, third and fourth line of treatment 1.8/2.9, 1.4/1.6 and 1.1/1.9 yrs (P < 0.0001, 0.003, 0.74 and 0.235). The relative risk for death in the MPT group vs. the MP group was 0.61 (95% CI: 0.45-0.84) in first and 0.55 (0.38-0.83), P < 0.01) in second line. Treatment with MPT gave a significantly better OS rate after both first and second line of therapy when compared with treatment with MP only.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Prednisona/uso terapêutico , Retratamento , Estudos Retrospectivos , Talidomida/administração & dosagem , Fatores de Tempo , Resultado do Tratamento
11.
Cancer Med ; 13(8): e7048, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38651177

RESUMO

BACKGROUND: Multiple myeloma (MM), an incurable disease characterized by frequent relapses and a need for multiple treatments, often progresses to a relapse/refractory status resistant to all available drugs and drug classes. Bispecific antibodies, specifically BCMA T-cell engagers, have emerged as effective treatments for MM, demonstrating impressive efficacy. However, these treatments can adversely affect the immune system, increasing vulnerability to infections. METHODS/RESULTS: This study evaluated the efficacy and safety of BCMA T-cell engagers in 58 Swedish patients with poor MM prognosis. The patients exhibited a 69% overall response rate, with 69% survival and 60% progression-free survival at 15 months. CONCLUSIONS: Despite the risk of infectious complications, the prognosis of MM patients can be significantly improved with vigilant monitoring and proactive management of infections. This real-world data highlight the potential of BCMA T-cell engagers in treating MM, emphasizing the need for careful patient monitoring to mitigate infection risks.


Assuntos
Anticorpos Biespecíficos , Antígeno de Maturação de Linfócitos B , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Suécia/epidemiologia , Masculino , Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Antígeno de Maturação de Linfócitos B/imunologia , Pessoa de Meia-Idade , Feminino , Idoso , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/efeitos adversos , Idoso de 80 Anos ou mais , Adulto , Linfócitos T/imunologia , Resultado do Tratamento , Intervalo Livre de Progressão , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos
12.
Cancers (Basel) ; 16(5)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38473382

RESUMO

Scarce data exist on double maintenance in transplant-eligible high-risk (HR) newly diagnosed multiple myeloma (NDMM) patients. This prospective phase 2 study enrolled 120 transplant-eligible NDMM patients. The treatment consisted of four cycles of ixazomib-lenalidomide-dexamethasone (IRD) induction plus autologous stem cell transplantation followed by IRD consolidation and cytogenetic risk-based maintenance therapy with lenalidomide + ixazomib (IR) for HR patients and lenalidomide (R) alone for NHR patients. The main endpoint of the study was undetectable minimal residual disease (MRD) with sensitivity of <10-5 by flow cytometry at any time, and other endpoints were progression-free survival (PFS) and overall survival (OS). We present the preplanned analysis after the last patient has been two years on maintenance. At any time during protocol treatment, 28% (34/120) had MRD < 10-5 at least once. At two years on maintenance, 66% of the patients in the HR group and 76% in the NHR group were progression-free (p = 0.395) and 36% (43/120) were CR or better, of which 42% (18/43) had undetectable flow MRD <10-5. Altogether 95% of the patients with sustained MRD <10-5, 82% of the patients who turned MRD-positive, and 61% of those with positive MRD had no disease progression at two years on maintenance (p < 0.001). To conclude, prolonged maintenance with all-oral ixazomib plus lenalidomide might improve PFS in HR patients.

13.
Acta Haematol ; 130(1): 7-15, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23363691

RESUMO

BACKGROUND: Induction therapy for multiple myeloma (MM) and remission status before high-dose treatment (HDT) have been shown to be prognostic factors for survival outcome, although the optimal induction therapy is yet to be defined. METHODS: We conducted a retrospective analysis of the impact of induction therapy on survival outcome before and after HDT in MM patients. The study included 236 consecutive patients who underwent HDT. RESULTS: One hundred and forty-two patients (62%) were treated with vincristine, doxorubicin and dexamethasone (VAD) or cyclophosphamide and betamethasone (CyBet) and 94 (38%) were treated with bortezomib, cyclophosphamide and betamethasone (VCB) as induction. Time to first and time to best response was faster in the VCB group than in the VAD/CyBet group, with 42 versus 75 (p < 0.001) and 54 versus 88 days (p < 0.001), respectively. After induction therapy, 49% of the patients in the VCB group and 38% in the VAD/CyBet group achieved a very good partial response or better. Multivariate analysis revealed younger age, lower International Staging System stage and induction treatment with VCB as variables associated with favourable time to progression. CONCLUSIONS: Outcome measured as response and time to progression before and after HDT in MM differs depending on type of induction treatment and suggests that VCB is a highly effective induction regimen that confers a post-HDT advantage.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Betametasona/administração & dosagem , Ácidos Borônicos/administração & dosagem , Ciclofosfamida/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Pirazinas/administração & dosagem , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Bortezomib , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Quimioterapia Combinada , Feminino , Glucocorticoides/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Análise Multivariada , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Suécia , Resultado do Tratamento , Vincristina/administração & dosagem
14.
Cancer Med ; 12(22): 20736-20744, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37921243

RESUMO

BACKGROUND: The presence of minimal residual disease (MRD+) following autologous stem cell transplantation (ASCT) in multiple myeloma represents a poor prognostic factor for progression-free survival (PFS) and overall survival (OS). METHODS: At our department, we recommend lenalidomide maintenance for patients who are MRD+ after ASCT, while MRD-negative (MRD-) patients, after information about the national guidelines, were not advised to follow this regimen. RESULTS: Out of the total 228 patients, 175 received ASCT following first-line induction (MRD- 92 (53%), MRD+ 83 (47%), at 2 months post-ASCT), while 53 underwent ASCT after second-line treatment (MRD- 27 (51%), MRD+ 26 (49%), at the same time point). Comparatively, MRD- patients who did not receive maintenance demonstrated better OS than MRD+ patients who received upfront ASCT and maintenance treatment (96% vs. 86%, p = 0.030, at 3 years). However, nonsignificant difference was found in PFS (76% vs. 62%, at 3 years). Furthermore, second-line ASCT, MRD- non-maintained patients exhibited significantly better PFS than MRD+ (71% vs. 27%, p > 0.001, at 3 years). However, OS was better but nonsignificant (96% vs. 76%, at 3 years). Fluorescence in situ hybridization (FISH) analysis was performed on 141 out of the 228 patients. Of these, 85 (60%) patients were deemed standard risk (SR), and 56 (40%) were classified as high risk (HR). In the SR cohort, MRD- patients exhibited better PFS and OS than MRD+ patients (71% vs. 59% and 100% vs. 85%, respectively). In the HR cohort, the MRD- patients showed superior PFS but similar OS compared to MRD+ patients (66% vs. 42% and 81% vs. 80%, respectively). CONCLUSIONS: Our results indicate that being MRD- is a more crucial prognostic factor for the 3-year PFS and OS than the presence of high-risk cytogenetic markers or undergoing maintenance treatment. The latter appears insufficient, particularly for MRD+ patients following ASCT in the second-line setting, suggesting that these patients may require a more intensive treatment approach.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/métodos , Prognóstico , Neoplasia Residual , Hibridização in Situ Fluorescente , Transplante Autólogo , Resultado do Tratamento
15.
PLoS One ; 10(9): e0138248, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26378933

RESUMO

Loss of the chromosomal region 8p21 negatively effects survival in patients with multiple myeloma (MM) that undergo autologous stem cell transplantation (ASCT). In this study, we aimed to identify the immunological and molecular consequences of del(8)(p21) with regards to treatment response and bortezomib resistance. In patients receiving bortezomib as a single first line agent without any high-dose therapy, we have observed that patients with del(8)(p21) responded poorly to bortezomib with 50% showing no response while patients without the deletion had a response rate of 90%. In vitro analysis revealed a higher resistance to bortezomib possibly due to an altered gene expression profile caused by del(8)(p21) including genes such as TRAIL-R4, CCDC25, RHOBTB2, PTK2B, SCARA3, MYC, BCL2 and TP53. Furthermore, while bortezomib sensitized MM cells without del(8)(p21) to TRAIL/APO2L mediated apoptosis, in cells with del(8)(p21) bortezomib failed to upregulate the pro-apoptotic death receptors TRAIL-R1 and TRAIL-R2 which are located on the 8p21 region. Also expressing higher levels of the decoy death receptor TRAIL-R4, these cells were largely resistant to TRAIL/APO2L mediated apoptosis. Corroborating the clinical outcome of the patients, our data provides a potential explanation regarding the poor response of MM patients with del(8)(p21) to bortezomib treatment. Furthermore, our clinical analysis suggests that including immunomodulatory agents such as Lenalidomide in the treatment regimen may help to overcome this negative effect, providing an alternative consideration in treatment planning of MM patients with del(8)(p21).


Assuntos
Bortezomib/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Mieloma Múltiplo/genética , Receptores Chamariz do Fator de Necrose Tumoral/biossíntese , Antineoplásicos/uso terapêutico , Apoptose/genética , Deleção Cromossômica , Cromossomos Humanos Par 8/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Prognóstico , RNA Mensageiro/genética , Receptores Chamariz do Fator de Necrose Tumoral/genética
16.
PLoS One ; 9(7): e101819, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25003848

RESUMO

BACKGROUND: Renal impairment is a common feature in multiple myeloma and is considered a poor prognostic factor. AIM: To determine the impact of novel drugs (i.e. bortezomib, lenalidomide and thalidomide) in the treatment of myeloma patients with renal impairment. The primary endpoint was overall survival and secondary endpoints were time to next treatment and response. METHODS: The study population included all patients diagnosed with treatment-demanding multiple myeloma January 2000 to June 2011 at 15 Swedish hospitals. Renal impairment was defined as an estimated glomerular filtration rate under 60 mL/min/1.73 m2. RESULT: The study population consisted of 1538 patients, of which 680 had renal impairment at diagnosis. The median overall survival in patients with renal impairment was 33 months, which was significantly shorter than 52 months in patients with normal renal function (P<0.001). Novel agents in first line improved overall survival (median 60 months) in non-high-dose treated patients with renal impairment (n = 143) as compared to those treated with conventional cytotoxic drugs (n = 411) (median 27 months) (P<0.001). In the multivariate analysis up front treatment with bortezomib was an independent factor for better overall survival in non-high-dose treated renally impaired patients. High-dose treated renally impaired patients had significantly better median overall survival than non-high-dose ones (74 versus 26 months) and novel drugs did not significantly improve survival further in these patients. Patients with renal impairment had both a shorter median time to next treatment and a lower response rate than those with normal renal function. However, novel drugs and high dose treatment lead to a significantly longer time to next treatment and the use of novel agents significantly improved the response rate of these patients. CONCLUSION: High dose treatment and novel drugs, especially bortezomib, can effectively overcome the negative impact of renal impairment in patients with multiple myeloma.


Assuntos
Mieloma Múltiplo/complicações , Mieloma Múltiplo/epidemiologia , Insuficiência Renal/etiologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Recidiva Local de Neoplasia , Sistema de Registros , Insuficiência Renal/fisiopatologia , Retratamento , Suécia/epidemiologia , Resultado do Tratamento
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