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PURPOSE OF REVIEW: As the treatment landscape for multiple myeloma (MM) continues to expand at a rapid pace, management of older adults and frail patients becomes increasingly challenging. As these patients have traditionally been underrepresented on clinical trials, there is limited guidance on the optimal approach to frail patients with newly diagnosed multiple myeloma (NDMM) or relapsed and refractory multiple myeloma (RRMM). RECENT FINDINGS: Frailty is an independent predictor of tolerability and response to antineoplastic treatment. Stringent eligibility criteria have often excluded these patients, but recently some large trials have included frailty sub-analyses to help guide management. In general, triplet regimens are preferred to doublet regimens in this population and enrollment on a clinical trial should be prioritized when possible. In this review, we summarize the MM frailty scoring tools that have been developed to identify and assess this vulnerable population. We present the clinical trials over the past decade that have enrolled frail patients and/or have included subgroup analyses to help elucidate the response and tolerability of different regimens in this underrepresented group. We provide practical advice regarding assessment and management of frail patients NDMM and RRMM.
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Idoso Fragilizado , Mieloma Múltiplo , Medicina de Precisão , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/terapia , Medicina de Precisão/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fragilidade/complicações , IdosoRESUMO
INTRODUCTION: Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common toxicities associated with immunotherapies, including T cell redirecting bispecific antibodies. Although cooperative group guidelines recommend the use of tocilizumab or other IL-6/IL-6R inhibitors for the management of CRS and ICANS, reports on the use of siltuximab, an IL-6 inhibitor, for the treatment of CRS are limited. CASE REPORT: We present the case of a 77-year-old male who received T cell redirecting bispecific antibody therapy with talquetamab for relapsed/refractory multiple myeloma (RRMM) and developed CRS with concurrent ICANS after receiving a second dose of talquetamab. MANAGEMENT AND OUTCOME: The patient received an infusion of siltuximab. The patient recovered from CRS within 1â h of siltuximab administration and ICANS within 7â h of siltuximab administration. Patient tolerated the subsequent dose of talquetamab with no evidence of CRS and continued on study. DISCUSSION: This case describes the successful use of siltuximab for the management of CRS in a patient treated with a T cell redirecting bispecific antibody for RRMM.
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Anticorpos Biespecíficos , Mieloma Múltiplo , Masculino , Humanos , Idoso , Síndrome da Liberação de Citocina/tratamento farmacológico , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Mieloma Múltiplo/tratamento farmacológicoRESUMO
BACKGROUND: Proteasome inhibitors (PIs), including carfilzomib, potentiate the activity of selinexor, a novel, first-in-class, oral selective inhibitor of nuclear export (SINE) compound, in preclinical models of multiple myeloma (MM). METHODS: The safety, efficacy, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of selinexor (80 or 100 mg) + carfilzomib (56 or 70 mg/m2) + dexamethasone (40 mg) (XKd) once weekly (QW) was evaluated in patients with relapsed refractory MM (RRMM) not refractory to carfilzomib. RESULTS: Thirty-two patients, median prior therapies 4 (range, 1-8), were enrolled. MM was triple-class refractory in 38% of patients and 53% of patients had high-risk cytogenetics del(17p), t(4;14), t(14;16) and/or gain 1q. Common treatment-related adverse events (all/Grade 3) were thrombocytopenia 72%/47% (G3 and G4), nausea 72%/6%, anaemia 53%/19% and fatigue 53%/9%, all expected and manageable with supportive care and dose modifications. MTD and RP2D were identified as selinexor 80 mg, carfilzomib 56 mg/m2, and dexamethasone 40 mg, all QW. The overall response rate was 78% including 14 (44%) ≥ very good partial responses. Median progression-free survival was 15 months. CONCLUSIONS: Weekly XKd is highly effective and well-tolerated. These data support further investigation of XKd in patients with MM.
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Dexametasona/administração & dosagem , Hidrazinas/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Oligopeptídeos/administração & dosagem , Triazóis/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Hidrazinas/efeitos adversos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Oligopeptídeos/efeitos adversos , Análise de Sobrevida , Translocação Genética , Resultado do Tratamento , Triazóis/efeitos adversosRESUMO
Recent advances in the treatment of multiple myeloma have increased the need for accurate diagnosis of the disease. The detection of bone and bone marrow lesions is crucial in the investigation of multiple myeloma and often dictates the decision to start treatment. Furthermore, detection of minimal residual disease is important for prognosis determination and treatment planning, and it has underscored an unmet need for sensitive imaging methods that accurately assess patient response to multiple myeloma treatment. Low-dose whole-body CT has increased sensitivity compared with conventional skeletal survey in the detection of bone disease, which can reveal information leading to changes in therapy and disease management that could prevent or delay the onset of clinically significant morbidity and mortality as a result of skeletal-related events. Given the multiple options available for the detection of bone and bone marrow lesions, ranging from conventional skeletal survey to whole-body CT, PET/CT, and MRI, the International Myeloma Working Group decided to establish guidelines on optimal use of imaging methods at different disease stages. These recommendations on imaging within and outside of clinical trials will help standardise imaging for monoclonal plasma cell disorders worldwide to allow the comparison of results and the unification of treatment approaches for multiple myeloma.
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Diagnóstico por Imagem/métodos , Imagem Multimodal/métodos , Mieloma Múltiplo/diagnóstico , Paraproteinemias/diagnóstico , Plasmócitos/patologia , Guias de Prática Clínica como Assunto/normas , Consenso , Humanos , Agências Internacionais , Mieloma Múltiplo/diagnóstico por imagem , Paraproteinemias/diagnóstico por imagemRESUMO
Patients undergoing high-dose chemotherapy and autologous hematopoietic cell transplantation (auto-HCT) are at risk for multiple morbidities, including mucosal inflammation and neutropenic fever, both related to neutropenia. Evidence from our preclinical work in an umbilical cord blood (UCB) transplantation murine model suggests that treatment with hyperbaric oxygen (HBO) before UCB infusion improves UCB CD34+ cell engraftment by reducing erythropoietin levels. A pilot clinical trial using HBO in patients undergoing UCB transplantation showed improvement in kinetics of blood count recovery. In this study, we evaluated HBO in combination with auto-HCT. Our primary aim was to determine the safety of HBO in this setting and secondarily to determine its efficacy in reducing time to neutrophil and platelet engraftment compared with matched historic controls. Patients with multiple myeloma, non-Hodgkin lymphoma, and Hodgkin disease eligible for auto-HCT were included. On day 0, patients received HBO treatment consisting of exposure to 2.5 atmosphere absolutes for a total of 90 minutes, in a monoplace hyperbaric chamber, breathing 100% oxygen. Six hours after the start of HBO, peripherally mobilized stem/progenitor cells were infused and patients were followed daily for toxicity and blood count recovery. All patients received daily granulocyte colony-stimulating factor starting on day +5 and until absolute neutrophil count (ANC) of ≥1500 or ANC of 500 for 3 consecutive days. A matched historic cohort of 225 patients who received auto-HCT between January 2008 and December 2012 was chosen for comparison and matched on sex, age, conditioning regimen, and disease type. We screened 26 patients for this study; 20 were treated and included in the primary analysis, and 19 completed the HBO therapy and were included in the secondary analysis. Although the median time to neutrophil count recovery was 11 days in both the HBO and control cohorts, the Kaplan-Meier estimates of the full distributions indicate that the time to neutrophil recovery was generally about 1 day sooner for HBO versus historical controls (log-rank P = .005; range, 9 to 13 for HBO patients and 7 to 18 for controls). The median time to platelet count recovery was 16 days (range, 14 to 21) for HBO versus 18 days (range, 11 to 86) for controls (log-rank P < .0001). In the secondary analysis comparing the HBO cohort who completed HBO therapy (nâ¯=â¯19) with our historical cohort, we evaluated neutropenic fever, growth factor use, mucositis, day +100 disease responses, and blood product use. HBO was associated with less growth factor use (median 6 days in HBO cohort versus median 8 days in controls, P < .0001). Packed RBC and platelet transfusion requirements were not statistically different between the 2 cohorts. Mucositis incidence was significantly lower in the HBO cohort (26.3% in HBO cohort versus 64.2% in controls, Pâ¯=â¯.002). HBO therapy appears to be well tolerated in the setting of high-dose therapy and auto-HCT. Prospective studies are needed to confirm potential benefits of HBO with respect to earlier blood count recovery, reduced mucositis, and growth factor use, and a cost-benefit analysis is warranted. © 2019 American Society for Blood and Marrow Transplantation.
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Neoplasias Hematológicas/terapia , Oxigenoterapia Hiperbárica , Transplante de Células-Tronco de Sangue Periférico , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Taxa de SobrevidaRESUMO
Umbilical cord blood (UCB) engraftment is in part limited by graft cell dose, generally one log less than that of bone marrow (BM)/peripheral blood (PB) cell grafts. Strategies toward increasing hematopoietic stem/progenitor cell (HSPC) homing to BM have been assessed to improve UCB engraftment. Despite recent progress, a complete understanding of how HSPC homing and engraftment are regulated is still elusive. We provide evidence that blocking erythropoietin (EPO)-EPO receptor (R) signaling promotes homing to BM and early engraftment of UCB CD34+ cells. A significant population of UCB CD34+ HSPC expresses cell surface EPOR. Exposure of UCB CD34+ HSPC to EPO inhibits their migration and enhances erythroid differentiation. This migratory inhibitory effect was reversed by depleting EPOR expression on HSPC. Moreover, systemic reduction in EPO levels by hyperbaric oxygen (HBO) used in a preclinical mouse model and in a pilot clinical trial promoted homing of transplanted UCB CD34+ HSPC to BM. Such a systemic reduction of EPO in the host enhanced myeloid differentiation and improved BM homing of UCB CD34+ cells, an effect that was overcome with exogenous EPO administration. Of clinical relevance, HBO therapy before human UCB transplantation was well-tolerated and resulted in transient reduction in EPO with encouraging engraftment rates and kinetics. Our studies indicate that systemic reduction of EPO levels in the host or blocking EPO-EPOR signaling may be an effective strategy to improve BM homing and engraftment after allogeneic UCB transplantation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT02099266).
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Transplante de Células-Tronco de Sangue do Cordão Umbilical , Eritropoetina/metabolismo , ADP-Ribosil Ciclase 1/metabolismo , Adolescente , Adulto , Idoso , Animais , Antígenos CD34/metabolismo , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Quimiocina CXCL12/farmacologia , Quimerismo , Estudos de Coortes , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Oxigenoterapia Hiperbárica , Masculino , Camundongos , Pessoa de Meia-Idade , Células Mieloides/citologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Receptores da Eritropoetina/metabolismo , Análise de Sobrevida , Condicionamento Pré-Transplante , Resultado do Tratamento , Adulto JovemRESUMO
Renal impairment (RI) is a major complication of multiple myeloma (MM). This study aimed to characterize the single-dose pharmacokinetics (PK) of the oral proteasome inhibitor, ixazomib, in cancer patients with normal renal function [creatinine clearance (CrCl) ≥90 ml/min; n = 20), severe RI (CrCl <30 ml/min; n = 14), or end-stage renal disease requiring haemodialysis (ESRD; n = 7). PK and adverse events (AEs) were assessed after a single 3 mg dose of ixazomib. Ixazomib was highly bound to plasma proteins (~99%) in all renal function groups. Unbound and total systemic exposures of ixazomib were 38% and 39% higher, respectively, in severe RI/ESRD patients versus patients with normal renal function. Total ixazomib concentrations were similar in pre- and post-dialyser samples collected from ESRD patients; therefore, ixazomib can be administered without regard to haemodialysis timing. Except for anaemia, the incidence of the most common AEs was generally similar across groups, but grade 3 and 4 AEs were more frequent in the severe RI/ESRD groups versus the normal group (79%/57% vs. 45%), as were serious AEs (43%/43% vs. 15%). The PK and safety results support a reduced ixazomib dose of 3 mg in patients with severe RI/ESRD.
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Compostos de Boro/farmacocinética , Glicina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteases/farmacocinética , Insuficiência Renal/terapia , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/etiologia , Proteínas Sanguíneas/metabolismo , Compostos de Boro/administração & dosagem , Compostos de Boro/metabolismo , Cálculos da Dosagem de Medicamento , Feminino , Glicina/administração & dosagem , Glicina/metabolismo , Glicina/farmacocinética , Humanos , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Inibidores de Proteases/administração & dosagem , Diálise RenalRESUMO
BACKGROUND: Talquetamab is a bispecific antibody targeting the multiple myeloma-associated antigen G protein-coupled receptor family C group 5 member D (GPRC5D). In the phase 1/2 MonumenTAL-1 trial (NCT03399799/NCT04634552), overall responses rates were > 71% in patients with triple-class exposed relapsed/refractory multiple myeloma (RRMM). Due to the distribution of the target antigen, a unique pattern of GPRC5D-associated adverse events (AEs) was observed, together with T-cell redirection-associated AEs. Management strategies for talquetamab-associated AEs are described. DISCUSSION: GPRC5D-associated AEs included dermatologic (rash, nonrash, and nail toxicities) and oral AEs (dysgeusia, dysphagia, and dry mouth). The incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were consistent with other T-cell redirection therapies. The incidence of high-grade infections was lower than observed with B-cell maturation antigen-targeting bispecific antibodies, with less frequent use of intravenous immunoglobulin required. GPRC5D-associated AEs were mostly low grade and led to few discontinuations. Skin toxicities were managed with emollients, topical corticosteroids, and oral corticosteroids (for high-grade, persistent, or AEs that progress). Nail toxicities were commonly managed with emollients. Based on investigator experience, dose modification may be effective for controlling oral events. Observation for potential weight changes is required. Infections were managed per standard of care. CRS and ICANS were effectively managed, consistent with other trials of T-cell redirection therapies. CONCLUSION: Although talquetamab had a distinct safety profile, AEs were considered clinically manageable and mostly low grade. With appropriate education and support, health care practitioners can ensure patients with RRMM maintain quality of life and treatment adherence.
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Prior research establishing that bone interacts in coordination with the bone marrow microenvironment (BMME) to regulate hematopoietic homeostasis was largely based on analyses of individual bone-associated cell populations. Recent advances in intravital imaging has suggested that the expansion of hematopoietic stem cells (HSCs) and acute myeloid leukemia cells is restricted to bone marrow microdomains during a distinct stage of bone remodeling. These findings indicate that dynamic bone remodeling likely imposes additional heterogeneity within the BMME to yield differential clonal responses. A holistic understanding of the role of bone remodeling in regulating the stem cell niche and how these interactions are altered in age-related hematological malignancies will be critical to the development of novel interventions. To advance this understanding, herein, we provide a synopsis of the cellular and molecular constituents that participate in bone turnover and their known connections to the hematopoietic compartment. Specifically, we elaborate on the coupling between bone remodeling and the BMME in homeostasis and age-related hematological malignancies and after treatment with bone-targeting approaches. We then discuss unresolved questions and ambiguities that remain in the field.
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BACKGROUND: The increasing use of anti-CD38 monoclonal antibodies (αCD38 mAbs) for newly diagnosed or early relapsed multiple myeloma (MM), especially in non-transplant eligible patients, may lead to more patients developing αCD38 mAb-refractory disease earlier in the treatment course with fewer treatment options. PATIENTS AND METHODS: We analyzed the efficacy and safety of selinexor-based triplets (selinexor+dexamethasone [Sd] plus pomalidomide [SPd, n = 23], bortezomib [SVd, n = 16] or carfilzomib (SKd, n = 23]) in a subset of STOMP (NCT02343042) and BOSTON (NCT03110562) study patients treated previously with αCD38 mAbs. RESULTS: Sixty-two patients (median 4 prior therapies, range 1 to 11, 90.3% refractory to αCD38 mAb) were included. Overall response rates (ORR) in the SPd, SVd and SKd cohorts were 52.2%, 56.3%, and 65.2%, respectively. Overall response rate was 47.4% among patients who had MM refractory to the third drug reintroduced in the Sd-based triplet. Median progression-free survival in the SPd, SVd, and SKd cohorts was 8.7, 6.7, and 15.0 months, respectively, and median overall survival was 9.6, 16.9, and 33.0 months, respectively. Median time to discontinuation in the SPd, SVd, and SKd cohorts was 4.4, 5.9, and 10.6 months, respectively. The most common hematological adverse events were thrombocytopenia, anemia, and neutropenia. Nausea, fatigue, and diarrhea were primarily grade 1/2. Adverse events were generally manageable with standard supportive care and dose modifications. CONCLUSION: Selinexor-based regimens may offer effective and well-tolerated therapy to patients with relapsed and/or refractory MM who had disease previously exposed or refractory to αCD38 mAb therapy and could help address the unmet clinical need in these high-risk patients.
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Antineoplásicos , Mieloma Múltiplo , Humanos , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
PURPOSE: This study investigated the impact of prognostic variables, including the distance a patient lives from a transplant center, on the outcome of autologous hematopoietic stem cell transplantation (ASCT) for multiple myeloma. METHODS: This retrospective analysis included 77 myeloma patients who received an ASCT at Dartmouth Hitchcock Medical Center between 1996 and 2009, 70 of whom were treated between 2002 and 2009. Using linear regression and univariate analysis, we examined the impact of distance from the transplant center on survival. Kaplan-Meier curves identified overall and event-free survival. An association between distance from the transplant center and survival was examined using Cox regression analysis, while adjusting for patient-, disease-, and treatment-related variables. RESULTS: Increasing distance from the transplant center correlated with improved overall survival (P=.004), but had no impact on disease-free survival (P=.26). CONCLUSIONS: These results suggest that the distance from a transplant center should not be a barrier to ASCT for eligible patients with multiple myeloma.
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Transplante de Medula Óssea , Acessibilidade aos Serviços de Saúde , Mieloma Múltiplo/terapia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Prognóstico , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Multiple myeloma is primarily a disease of the elderly, and optimal treatments must weigh the risks of toxicity with the benefits of therapy. Frailty scales have been developed to aid treatment-decision making for older adults with MM. This review provides a framework for incorporating frailty scales into clinical care and highlights how patient-aligned priorities for care can influence the management of older or more vulnerable adults with newly diagnosed multiple myeloma newly diagnosed multiple myeloma. We review the currently available systemic therapies for managing older or more vulnerable adults with newly diagnosed multiple myeloma otherwise considered ineligible for autologous stem cell transplantation.
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Fragilidade , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Idoso , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/terapia , Transplante AutólogoRESUMO
CONTEXT.: The process for identifying patients with monoclonal gammopathies is complex. Initial detection of a monoclonal immunoglobulin protein (M protein) in the serum or urine often requires compilation of analytical data from several areas of the laboratory. The detection of M proteins depends on adequacy of the sample provided, available clinical information, and the laboratory tests used. OBJECTIVE.: To develop an evidence-based guideline for the initial laboratory detection of M proteins. DESIGN.: To develop evidence-based recommendations, the College of American Pathologists convened a panel of experts in the diagnosis and treatment of monoclonal gammopathies and the laboratory procedures used for the initial detection of M proteins. The panel conducted a systematic literature review to address key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation approach, recommendations were created based on the available evidence, strength of that evidence, and key judgements as defined in the Grading of Recommendations Assessment, Development, and Evaluation Evidence to Decision framework. RESULTS.: Nine guideline statements were established to optimize sample selection and testing for the initial detection and quantitative measurement of M proteins used to diagnose monoclonal gammopathies. CONCLUSIONS.: This guideline was constructed to harmonize and strengthen the initial detection of an M protein in patients displaying symptoms or laboratory features of a monoclonal gammopathy. It endorses more comprehensive initial testing when there is suspicion of amyloid light chain amyloidosis or neuropathies, such as POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome, associated with an M protein.
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Paraproteinemias , Humanos , Laboratórios , Paraproteinemias/diagnóstico , Revisões Sistemáticas como AssuntoRESUMO
Interrogation of cell-free DNA (cfDNA) represents an emerging approach to non-invasively estimate disease burden in multiple myeloma (MM). Here, we examined low-pass whole genome sequencing (LPWGS) of cfDNA for its predictive value in relapsed/ refractory MM (RRMM). We observed that cfDNA positivity, defined as ≥10% tumor fraction by LPWGS, was associated with significantly shorter progression-free survival (PFS) in an exploratory test cohort of 16 patients who were actively treated on diverse regimens. We prospectively determined the predictive value of cfDNA in 86 samples from 45 RRMM patients treated with elotuzumab, pomalidomide, bortezomib, and dexamethasone in a phase II clinical trial (NCT02718833). PFS in patients with tumor-positive and -negative cfDNA after two cycles of treatment was 1.6 and 17.6 months, respectively (HR 7.6, P < 0.0001). Multivariate hazard modelling confirmed cfDNA as independent risk factor (HR 96.6, P = 6.92e-05). While correlating with serum-free light chains and bone marrow, cfDNA additionally discriminated patients with poor PFS among those with the same response by IMWG criteria. In summary, detectability of MM-derived cfDNA, as a measure of substantial tumor burden with therapy, independently predicts poor PFS and may provide refinement for standard-of-care response parameters to identify patients with poor response to treatment earlier than is currently feasible.
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Ácidos Nucleicos Livres , Mieloma Múltiplo , Ácidos Nucleicos Livres/genética , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Falha de TratamentoRESUMO
Infection remains the leading cause of morbidity and mortality in patients with multiple myeloma because of the cumulative effect of disease, treatment, and host-related factors. Given that infectious risk is cumulative through the course of the disease, preventing infections is paramount. Optimal preventive strategies include vaccination against common pathogens, antimicrobial prophylaxis, infection control measures, and immunoglobulin replacement in a small subset of patients; however, there are no universally accepted guidelines for infection prevention. This Review provides a consensus statement from a panel of 36 experts with global representation, which was convened by The International Myeloma Society to review existing literature and current guidelines, address issues associated with the risk of infection and prevention of infectious complications in multiple myeloma in the context of emerging therapies, and offer recommendations for preventing these complications.
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Infecções , Mieloma Múltiplo , Consenso , Humanos , Infecções/complicações , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológicoRESUMO
There is a lack of consensus on therapy sequencing in previously treated multiple myeloma, particularly after anti-B-cell maturation antigen (BCMA) therapy. Earlier reports on selinexor (X) regimens demonstrated considerable efficacy in early treatment, and after anti-BCMA-targeted chimeric antigen receptor-T cell therapy. Here, we present data from 11 heavily pretreated patients who predominantly received BCMA-antibody-drug conjugate therapy. We observe that X-containing regimens are potent and achieve durable responses with numerically higher overall response and clinical benefit rates, as well as median progression free survival compared to patients' prior anti-BCMA therapies, despite being used later in the treatment course. In an area of evolving unmet need, these data reaffirm the efficacy of X-based regimens following broader anti-BCMA therapy.
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Advances in the design of potential bone-selective drugs for the treatment of various bone-related diseases are creating exciting new directions for multiple unmet medical needs. For bone-related cancers, off-target/non-bone toxicities with current drugs represent a significant barrier to the quality of life of affected patients. For bone infections and osteomyelitis, bacterial biofilms on infected bones limit the efficacy of antibiotics because it is hard to access the bacteria with current approaches. Promising new experimental approaches to therapy, based on bone-targeting of drugs, have been used in animal models of these conditions and demonstrate improved efficacy and safety. The success of these drug-design strategies bodes well for the development of therapies with improved efficacy for the treatment of diseases affecting the skeleton. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.
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Difosfonatos , Preparações Farmacêuticas , Animais , Bactérias , Biofilmes , Humanos , Qualidade de VidaRESUMO
BACKGROUND: The introduction of immunomodulatory agents, proteasome inhibitors, and autologous haematopoietic stem-cell transplantation has improved outcomes for patients with multiple myeloma, but patients with high-risk multiple myeloma have a poor long-term prognosis. We aimed to address optimal treatment for these patients. METHODS: SWOG-1211 is a randomised phase 2 trial comparing eight cycles of lenalidomide (25 mg orally on days 1-14 every 21 days), bortezomib (1·3 mg/m2 subcutaneously on days 1, 4, 8, and 11 every 21 days), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days; RVd) induction followed by dose-attenuated RVd maintenance (bortezomib 1 mg/m2 subcutaneously on days 1, 8, and 15; lenalidomide 15 mg orally on days 1-21; dexamethasone 12 mg orally on days 1, 18, and 15 every 28 days) until disease progression with or without elotuzumab (10 mg/kg intravenously on days 1, 8, and 15 for cycles 1-2, on days 1 and 11 for cycles 3-8, and on days 1 and 15 during maintenance). Patients were randomly assigned (1:1) to either RVd or RVd-elotuzumab. High-risk multiple myeloma was defined by one of the following: gene expression profiling high risk (GEPhi), t(14;16), t(14;20), del(17p) or amp1q21, primary plasma cell leukaemia and elevated serum lactate dehydrogenase (two times the upper limit of normal or more). The primary endpoint was progression-free survival, and all analyses were done on intention-to-treat basis among eligible patients who were evaluable for response. This study is registered with ClinicalTrials.gov, NCT01668719. FINDINGS: 100 (RVd n=52, RVd-elotuzumab n=48) patients were enrolled between Oct 27, 2013, and May 15, 2016, across 26 cooperative group institutions in the USA. Median age was 64 years (IQR 57-70, range 36-85). 74 (75%) of 99 had International Staging System stage II or stage III disease, 47 (47%) of 99 had amp1q21, 37 (37%) of 100 had del17p, 11 (11%) of 100 had t(14;16), eight (9%) of 90 were GEPhi, seven (7%) of 100 had primary plasma cell leukaemia, five (5%) of 100 had t(14;20), four (4%) of 100 had elevated serum lactate dehydrogenase, and 17 (17%) had two or more features. With a median follow-up of 53 months (IQR 46-59), no difference in median progression-free survival was observed (RVd 33·64 months [95% CI 19·55-not reached], RVd-elotuzumab 31·47 months [18·56-53·98]; hazard ratio 0·968 [80% CI 0·697-1·344]; one-sided p=0·45]. 37 (71%) of 52 patients in the RVd group and 37 (77%) of 48 in the RVd-elotuzumab group had grade 3 or worse adverse events. No significant differences in the safety profile were observed, although some notable results included grade 3-5 infections (four [8%] of 52 in the RVd group, eight [17%] of 48 in the RVd-elotuzumab group), sensory neuropathy (four [8%] of 52 in the RVd group, six [13%] of 48 in the RVd-elotuzumab group), and motor neuropathy (one [2%] of 52 in the RVd group, four [8%] of 48 in the RVd-elotuzumab group). There were no treatment-related deaths in the RVd group and one death in the RVd-elotuzumab group for which study treatment was listed as possibly contributing by the investigator. INTERPRETATION: In the first randomised study of high-risk multiple myeloma reported to date, the addition of elotuzumab to RVd induction and maintenance did not improve patient outcomes. However, progression-free survival in both study groups exceeded the original statistical assumptions and supports the role for continuous proteasome inhibitors and immunomodulatory drug combination maintenance therapy for this patient population. FUNDING: National Institutes of Health, National Cancer Institute, Bristol Myers Squibb, Celgene, Leukemia and Lymphoma Society.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Taxa de SobrevidaRESUMO
We assessed the safety, efficacy, maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D) of selinexor, a first in class oral selective inhibitor of nuclear export (100 mg once weekly [QW] or 60 mg twice weekly), in combination with daratumumab (16 mg/kg per label) and dexamethasone (40 mg QW) (SDd) in patients with relapsed refractory multiple myeloma (RRMM). Thirty-four patients (median prior therapies, 3 [range, 2-10]) were enrolled; MM was refractory to proteasome inhibitor (PI) in 85%, immunomodulatory agent (IMiD) in 76%, both in 74%, and daratumumab in 6% of patients. Two dose-limiting toxicities (DLTs) were reported in the selinexor 60 mg twice-weekly cohort with no DLTs in the 100 mg QW cohort, making 100 mg QW the MTD and RP2D. Common treatment-related adverse events included thrombocytopenia (70.6%), nausea (70.6%), fatigue (61.8%), anemia (61.8%), and neutropenia (50.0%). Overall response rate was 73% and median progression-free survival 12.5 months in daratumumab-naïve patients. SDd was well tolerated and its promising efficacy suggests that further study of this PI- and IMiD-free regimen in RRMM patients who had at least one prior line of therapy including a PI and an IMiD but whose disease is naïve to daratumumab is warranted.
RESUMO
CASE VIGNETTE: A 75-year-old male undergoes an evaluation for progressively worsening fatigue with associated shortness of breath. He also reports back pain worse at night, which does not resolve with acetaminophen. He is retired, but over the past 2 months he is unable to garden or perform household chores. Due to his pain and fatigue, he has limited his activity. He currently takes 9 prescription medications for chronic medical conditions, which include diabetes mellitus with neuropathy, hypertension, hyperlipidemia, and COPD. Initial evaluation reveals anemia (Hgb 9.0 g/dl last known normal was 2 years ago, Hgb 13.5 g/dl), renal impairment (serum creatinine 2.5 mg/dL), hypercalcemia (11.5 g/dl). Plain X-rays reveal compression fractures involving T3 and T4. Multiple myeloma is suspected, further labs confirm the diagnosis of IgG kappa multiple myeloma. LDH is elevated, beta-2-microglobulin is elevated at 6.1 mg/L and albumin < 3.5 mg/dl. Bone marrow aspiration and biopsy reveal plasmacytosis of 55% and on fluorescence in situ hybridization testing, del 17p/TP53 mutation in 85% of cells is detected. PET/CT confirms diffuse bone disease involving the axial and appendicular skeleton. His Karnofsky performance status (KPS) is 70%. He is widowed and lives alone but has 2 adult children who currently live out of state. This abstract will discuss how assessments of fitness/frailty may be used to develop personalized care tailored to the unique needs of older frail adults with multiple myeloma.