The efficacy and tolerability of bortezomib, thalidomide, and dexamethasone induction therapy with a thalidomide dose step-up strategy in patients with newly diagnosed multiple myeloma: A prospective observational study.

BACKGROUND: Thalidomide-containing regimens cause adverse events (AEs) that may require a reduction in treatment intensity or even treatment discontinuation in patients with multiple myeloma. As thalidomide toxicity is dose-dependent, identifying the most appropriate dose for each patient is essential. AIMS: This study aimed to investigate the effects of a thalidomide dose step-up strategy on treatment response and progression-free survival (PFS). METHODS AND RESULTS: This prospective observational study included 93 patients with newly diagnosed multiple myeloma (NDMM) who received bortezomib, thalidomide, and dexamethasone (VTD). The present study assessed the incidence of thalidomide dose reduction and discontinuation, the overall dose intensity, and their effects on therapeutic efficacy. Furthermore, this study used Cox proportional hazard models to analyze the factors contributing to thalidomide intolerability. The results showed the overall response rates in all patients and the evaluable patients were 78.5% and 98.7%, respectively. The median PFS in the study cohort was not reached. The most common thalidomide-related AEs were constipation (32.3%) and skin rash (23.7%), resulting in dose reduction and discontinuation rates of 22.6% and 21.5%, respectively. The responders had a significantly higher average thalidomide dose intensity than the nonresponders (88.6% vs. 42.9%, p < .001). CONCLUSION: The thalidomide dose step-up approach is a viable option for patients with NDMM receiving VTD induction therapy with satisfactory efficacy and tolerability. However, thalidomide intolerance may lead to dose reduction or discontinuation due to unpredictable AEs, leading to lower dose intensity and potentially inferior treatment outcomes. In addition to a dose step-up strategy, optimal supportive care is critical for patients with multiple myeloma receiving VTD induction therapy.

Efficacy Analysis of Bortezomib Combined with Lenalidomide in Newly Diagnosed Multiple Myeloma with 1q21 Gain/Amp.

OBJECTIVE: 1q21 gain/Amp is one of the most common cytogenetic abnormalities. There are controversies about its effects on prognosis and may be associated with inferior outcomes in patients with newly diagnosed multiple myeloma (NDMM). To explore the optimal induction treatment, we analyzed and compared the efficacy of combinations of bortezomib-lenalidomide-dexamethasone (VRD) and only bortezomib-based triplet regimens without lenalidomide (only bortezomib-based) as induction therapy in patients with NDMM with 1q21 gain/Amp. METHODS: Seventy-six NDMM patients with 1q21 gain/Amp who were admitted to our center from 2016 to 2022 were retrospectively analyzed in this study. The progression and efficacy of the patients were observed. RESULTS: Within our study group, the overall survival rate stood at 75.0%, and the progression-free survival (PFS) rate reached 40.8% in NDMM patients with 1q21 gain/Amp. The best outcome assessment was that 17.1% achieved complete response (CR) and 44.7% achieved very good partial response (VGPR). Patients in the VRD group had a deeper response (VGPR: 63.6% vs 37.0%, P = 0.034), lower disease progression rate (31.8% vs 70.3%, P = 0.002), longer sustained remission (median 49.7 months vs 18.3 months, P = 0.030), and longer PFS (median 61.9 months vs 22.9 months, P = 0.032) than those treated with only bortezomib-based induction therapy. No significant differences were found among patients with partial response or better (86.4% vs 77.8%, P = 0.532) or CR (27.3% vs 13.0%, P = 0.180). Multivariate analysis showed that only bortezomib-based induction therapy (P = 0.003, HR 0.246, 95% CI 0.097-0.620), International Staging System stage III (P = 0.003, HR 3.844, 95% CI 1.588-9.308) and LMR <3.6 (P = 0.032, HR 0.491, 95% CI 0.257-0.940) were significantly associated with adverse PFS. CONCLUSIONS: When compared with the sequential administration of bortezomib and lenalidomide or only bortezomib-based protocols, NDMM patients with 1q21 gain/Amp may benefit more from VRD as initial treatments.

When Waldenström macroglobulinemia hits the kidney: Description of a case series and management of a "rare in rare" scenario.

BACKGROUND: Renal injury related to Waldenström macroglobulinemia (WM) occurs in approximately 3% of patients. Kidney biopsy is crucial to discriminate between distinct histopathological entities such as glomerular (amyloidotic and non-amyloidotic), tubulo-interstitial and non-paraprotein mediated renal damage. In this context, disease characterization, management, relationship between renal, and hematological response have been poorly explored. We collected clinical, genetic and laboratory data of seven cases of biopsy-proven renal involvement by WM managed at our academic center and focused on three cases we judged paradigmatic discussing their histopathological patterns, clinical features, and therapeutic options. CASE: In this illustrative case series, we confirm that serum creatinine levels and 24 h proteinuria are parameters that when altered should prompt the clinical suspicion of WM-related renal involvement, even if at present there are not precise cut-off levels recommending the execution of a renal biopsy. In our series AL Amyloidosis (n = 3/7) and tubulo-interstitial infiltration by lymphoma cells (n = 3/7) were the two more represented entities. BTKi did not seem to improve renal function (Case 1), while bortezomib-based regimens demonstrated a beneficial activity on the hematological and organ response, even when used as second-line therapy after chemoimmunotherapy (Case 3) and also with coexistence of anti-MAG neuropathy (Case 2). In case of poor response to bortezomib, standard chemoimmunotherapy (CIT), such as rituximab-bendamustine, represents an effective option (Case 1, 6, and 7). In our series, CIT generates durable responses more frequently in cases with amyloidogenic renal damage (Case 1, 5, and 7). CONCLUSION: In this illustrative case series, we confirm that serum creatinine levels and 24 h proteinuria are parameters that when altered should prompt the clinical suspicion of WM-related renal involvement, even if at present there are not precise cut-off levels recommending the execution of a renal biopsy. Studies with higher numerosity are needed to better clarify the pathological and clinical features of renal involvement during WM and to determine the potential benefit of different therapeutic regimens according to the histopathological subtypes.

Assessment of prolonged proteasome inhibition through ixazomib-based oral regimen on newly diagnosed and first-relapsed multiple myeloma: A real-world Chinese cohort study.

OBJECTIVE: To evaluate the effectiveness, safety, and convenience of in-class transition (iCT) from intravenous bortezomib-based induction to ixazomib-based oral regimens. METHODS: This retrospective real-world study was conducted in 16 Chinese hospitals between October 2017 and April 2023 and analyzed newly diagnosed (NDMM) and first-line relapsed multiple myeloma (FRMM) patients who attained at least a partial response from bortezomib-based induction therapy, followed by an ixazomib-based oral regimen for 2 year or until disease progression or intolerable toxicity. RESULTS: The study enrolled 199 patients, median age: 63 years old, male 55.4%, 53% as high risk (HR), and 47% as standard risk. Cytogenetic risk stratification by metaphase fluorescence in situ hybridization (M-FISH), based on the Mayo Clinic risk stratification system. The median duration of total PI therapy was 11 months, with ixazomib-based treatment spanning 6 months. At the 20-month median follow-up, 53% of patients remained on therapy. The 24-month PFS rate was 84.3% from the initiation of bortezomib-based induction and 83.4% from the start of ixazomib-based treatment. Overall response rate (ORR) was 100% post-bortezomib induction and 90% following 6 cycles of the ixazomib-based regimen. Based on the Sankey diagrams, 89.51% of patients maintained or improved their disease response after 2 cycles of iCT, 6 cycles (90.14%), and 12 cycles (80%). The HR level of Mayo was found to be a significant independent factor in a worse remission (hazard ratio (HR) 2.55; p = 0.033). Ixazomib's safety profile aligned with previous clinical trial data, with 49% of patients experiencing at least one AE of any grade. The most common AEs included peripheral neuropathy, nausea and vomiting, diarrhea, thrombocytopenia, and granulocytopenia. CONCLUSION: In the real-world Chinese MM population, NDMM and FRMM patients responded favorably to PI-based continuous therapy, demonstrating substantial response rates. The ixazomib-based iCT allows for sustained PI-based treatment, offering promising efficacy and tolerable AEs.

MRD at the end of induction and EFS in T-cell lymphoblastic lymphoma: Children's Oncology Group trial AALL1231.

ABSTRACT: Defining prognostic variables in T-lymphoblastic lymphoma (T-LL) remains a challenge. AALL1231 was a Children's Oncology Group phase 3 clinical trial for newly diagnosed patients with T acute lymphoblastic leukemia or T-LL, randomizing children and young adults to a modified augmented Berlin-Frankfurt-Münster backbone to receive standard therapy (arm A) or with addition of bortezomib (arm B). Optional bone marrow samples to assess minimal residual disease (MRD) at the end of induction (EOI) were collected in T-LL analyzed to assess the correlation of MRD at the EOI to event-free survival (EFS). Eighty-six (41%) of the 209 patients with T-LL accrued to this trial submitted samples for MRD assessment. Patients with MRD <0.1% (n = 75) at EOI had a superior 4-year EFS vs those with MRD ≥0.1% (n = 11) (89.0% ± 4.4% vs 63.6% ± 17.2%; P = .025). Overall survival did not significantly differ between the 2 groups. Cox regression for EFS using arm A as a reference demonstrated that MRD EOI ≥0.1% was associated with a greater risk of inferior outcome (hazard ratio, 3.73; 95% confidence interval, 1.12-12.40; P = .032), which was independent of treatment arm assignment. Consideration to incorporate MRD at EOI into future trials will help establish its value in defining risk groups. CT# NCT02112916.

Thromboembolic risk of carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for newly diagnosed multiple myeloma: A comparative systematic review and meta-analysis.

Thrombosis represents a frequent and potentially severe complication in individuals diagnosed with multiple myeloma (MM). These events can be driven by both the disease as well as the therapies themselves. Overall, available evidence is inconclusive about the differential thrombogenicity of carfilzomib/lenalidomide/dexamethasone (KRd) and bortezomib/lenalidomide/dexamethasone (VRd). This meta-analysis compares the risk for venous thromboembolism (VTE; including deep venous thrombosis and pulmonary embolism) and arterial thromboembolism (ATE; including myocardial infarction and ischemic stroke) with KRd versus VRd as primary therapy for newly diagnosed MM (NDMM). Out of 510 studies identified after deduplication, one randomized controlled trial and five retrospective cohort studies were included. We analyzed 2304 patients (VRd: 1380; KRd: 924) for VTE events and 2179 patients (VRd: 1316; KRd: 863) for ATE events. Lower rates of VTE were observed in the VRd group when compared with the KRd group (6.16% vs. 8.87%; odds ratio [OR], 0.53; 95% confidence interval [CI], 0.32-0.88; p = .01). Both treatment groups exhibited minimal ATE incidence, with no significant difference between them (0.91% vs. 1.16%; OR, 1.01; 95% CI, 0.24-4.20; p = .99). In view of potential biases from retrospective studies, heterogeneity of baseline population characteristics, and limited access to patient-level data (e.g., VTE risk stratification and type of thromboprophylaxis regimen used) inherent to this meta-analysis, additional research is warranted to further validate our findings and refine strategies for thrombosis prevention in MM.

An Open-Label Phase I Study of Metformin and Nelfinavir in Combination With Bortezomib in Patients With Relapsed and Refractory Multiple Myeloma.

BACKGROUND: In preclinical models, combining a GLUT4 inhibitor with an oxidative phosphorylation inhibitor shows synergistic therapeutic potential against multiple myeloma (MM). Thus, this study evaluated the safety and tolerability of repurposing metformin, a complex I inhibitor, and nelfinavir, a GLUT4 inhibitor, in combination with bortezomib for the treatment of relapsed/refractory MM that had progressed on all standard of care therapies. MATERIALS AND METHODS: This trial utilized a 3 + 3 dose escalation design with 3 dose levels planned for up to a maximum of 6 (21-day) cycles. Metformin and nelfinavir were administered for 14 of 21 days, and subQ bortezomib was administered to a portion of patients on days 1, 8, and 15. The primary objective was to determine the maximal tolerated dose, and the secondary objective was to evaluate the safety and overall response rate (ORR) of this combination. RESULTS: Nine patients were accrued with a median age of 65 (range: 42-81) and received a median of 7 prior lines of therapy (Range: 5-12). The first 3 patients received only metformin (500 mg BID) and nelfinavir (1250 mg BID) at the first dose level, with 1 patient experiencing an unconfirmed minimal response (MR) in the first cycle, 1 experiencing progressive disease after 1 cycle of treatment and 1 patient going off treatment prior to assessing response but with signs of progressive disease. Given the limited therapeutic activity, the upfront addition of bortezomib (1.3 mg/m2) was utilized for the subsequent 6 patients accrued. Three of these 6 patients went off study due to progressive disease, 1 patient achieved an unconfirmed partial response after 1 cycle of treatment but reported progressive disease in the subsequent cycle, 1 patient went off study to enter hospice, and the remaining patient experienced stable disease (SD) after receiving 6 cycles of clinical trial treatment. The study was closed before accrual to the next dose level was started. CONCLUSION: This is the first study to evaluate the safety and efficacy of this repurposed drug combination in this very difficult-to-treat population of relapsed and refractory MM. This was an overall negative study with no ORR observed. Fortunately, 1 patient experienced an SD response, allowing this combination to stabilize their disease until another novel therapy on a clinical trial was available.

Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma.

BACKGROUND: Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed. METHODS: In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)-negative status. RESULTS: At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P = 0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group. CONCLUSIONS: The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.).

Carfilzomibe no tratamento de pacientes com mieloma múltiplo recidivado ou refratário, que receberam terapia prévia / Carfilzomib in the treatment of patients with relapsed or refractory multiple myeloma who have received prior therapy

INTRODUÇÃO: O mieloma múltiplo (MM) é uma neoplasia hematológica maligna caracterizada pela proliferação descontrolada de plasmócitos alterados na medula óssea, resultando na produção aumentada de imunoglobulinas não funcional (proteína monoclonal). O acúmulo destas imunoglobulinas e a interação dos plasmócitos com outras células da medula óssea resultam em anemia, lesões ósseas, infecções, hipercalcemia, injúria renal, fadiga e dor. A incidência mundial informada pelo Globocan é de 2,2 novos casos por 100.000 habitantes em homens e 1,5/100.000 em mulheres, com ocorrência, a nível mundial, de 176 mil novos casos e 117 mil mortes em 2020. Carfilzomibe é um agente antineoplásico, inibidor de proteassoma que se liga seletiva e irreversivelmente nos sítios ativos. Tem atividade antiproliferativa e pró-apoptóticas. PERGUNTA DE PESQUISA: Kyprolis® (carfilzomibe) em combinação com dexametasona é eficaz e seguro no tratamento de pacientes com mieloma múltiplo recidivado ou refratário que receberam uma terapia prévia quando em comparação a bortezomibe, ciclofosfamida, dexametasona, cisplatina, doxorrubicina, doxorrubicina lipossomal, etoposídeo, melfalana, vincristina ou talidomida? EVIDÊNCIAS CLÍNICAS: O demandante realizou as buscas na literatura utilizando as seguintes bases de dados: The Cochrane Library, Medline via PubMed, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Centre for Reviews and Dissemination (CRD), o que resultou na inclusão de 14 publicações. Na análise conduzida pela Secretaria Executiva foram consideradas 12 publicações referentes a um ensaio clínico randomizado e uma publicação de revisão sistemática. O estudo ENDEAVOR foi um ensaio clínico de fase III, multicêntrico, aberto, que incluiu 929 participantes randomizados para receber carfilzomibe+dexametasona ou bortezomibe+dexametasona. A mediana de SLP foi 18,7 meses (IC 95%, 15,6 a não estimável) no grupo que recebeu carfilzomibe comparado a 9,4 meses (IC 95%, 8,4 a 10,4) no grupo que recebeu bortezomibe, resultando em uma magnitude de benefício absoluto de 9,3 meses (HR 0,53 [IC95% 0,44 a 0,65]; p< 0,0001). A duração mediana de resposta foi 21,3 meses (IC95% 21,3 a não estimável) no grupo carfilzomibe e 10,4 meses (IC95% 9,3 a 13,8) no grupo bortezomibe. Em ambos os grupos, 98% dos participantes apresentaram eventos adversos (qualquer grau), sendo a anemia (43% versus 28%), diarreia (36,7% versus 40,6%) e febre (32,6% versus 15,4%) os eventos mais frequentes nos grupos carfilzomibe e bortezomibe, respectivamente. Os eventos adversos mais comuns grau 3 ou maior foram reportados em 81,9% dos participantes do grupo carfilzomibe (n=379) e 71,1% no grupo bortezomibe (n=324), sendo a anemia (17,3% no grupo carfilzomibe e 10,1% no grupo bortezomibe), hipertensão (14,9% versus 3,3%), trombocitopenia (12,5% versus 14,7%),os três eventos mais frequentes. Insuficiência cardíaca grau 3 ou superior, foi mais frequente no grupo carfilzomibe (6%) que no grupo bortezomibe (2%.). AVALIAÇÃO ECONÔMICA: O demandante apresentou uma análise de custo-efetividade. Na análise do cenário base, em um horizonte temporal de 30 anos, carfilzomibe acrescentou ganhos incrementais de 1,19 QALY, resultando em uma razão de custo utilidade incremental (RCEI) de R$ 195.310,00 por QALY. No cenário proposto pela Secretária-Executiva (horizonte temporal de 10 anos e valor de utilidade derivada do estudo ENDEAVOR), carfilzomibe gerou benefício de 0,63 QALY, com RCEI de R$ 365.830,00 por QALY. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Com o desconto apresentado pelo demandante, a incorporação de carfilzomibe ao SUS implica em custos adicionais ao sistema de saúde no montante de aproximadamente R$ 365 milhões em cinco anos. A principal limitação da análise foi a estimativa da população. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram identificadas 10 tecnologias potenciais para compor o esquema terapêutico de pacientes adultos com mieloma múltiplo recidivado ou refratário: Belantamabe mafodotin, Ciltacabtageno autoleucel, Elranatamab, Iberdomida, Idecabtagene vicleucel, Isatuximabe, nivolumabe, selinexor, teclistamab, venetoclax. Tais medicamentos são anticorpo monoclonal ligado a um antineoplásico, anticorpo biespecífico, anticorpo monoclonal, imumodulador, terapias baseadas em células T autólogas geneticamente modificadas (CAR-T), inibidor SINE, ou inibidor de Bcl-2. A maioria não possui registro na FDA, EMA ou Anvisa. CONSIDERAÇÕES FINAIS: Os resultados sugerem eficácia e segurança do carfilzomibe na população elegível, porém, no horizonte temporal de 10 anos, com QALY < 1, RCEI de R$ 365.830,00 por QALY e impacto orçamentário de aproximadamente R$ 17 milhões no primeiro ano de incorporação e R$ 131 milhões no 5º ano da incorporação, totalizando R$ 365 milhões em cinco anos. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Plenário presentes na 109ª Reunião Ordinária da Conitec, realizada no dia 08 de junho de 2022, sem nenhuma declaração de conflito de interesse, deliberaram por unanimidade, encaminhar o tema para consulta pública com recomendação preliminar desfavorável à incorporação de carfilzomibe para o tratamento de mieloma múltiplo recidivado ou refratário no SUS. Os membros consideraram a evidência científica boa e favorável ao carfilzomibe, porém, a RCEI e o impacto orçamentário foram considerados muito altos para o tratamento de uma doença que já tem outras opções terapêuticas disponíveis no SUS. CONSULTA PÚBLICA: Entre os dias 08/07/2022 e 27/07/2022 foram recebidas 421 contribuições, sendo 152 pelo formulário para contribuições técnico-científicas e 269 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. A maioria foi a favor da incorporação de carfilzomibe no SUS (97% via formulário técnico-científico e 100%). O principal benefício apontado nas contribuições técnico-científicas foi sobre a eficácia, aumento da sobrevida e qualidade de vida, além da disponibilidade de mais uma opção terapêutica e promoção da igualdade no tratamento nos sistemas público e privado de saúde. A empresa detentora do registro do medicamento atualizou o preço do medicamento, e consequentemente os valores do impacto orçamentário e avaliação econômica. No impacto orçamentário o valor ficou em R$ 95,3 milhões em cinco anos. Nas contribuições de experiência e opinião, a totalidade dos respondentes discordou da recomendação preliminar da Conitec. No âmbito das opiniões e experiências positivas, foi mencionada a necessidade de garantir o acesso ao carfilzomibe, especialmente por representar uma alternativa para pacientes recidivados e refratários. Também foi citada a eficácia da tecnologia. Como dificuldades, destacou-se a falta de acesso pelo SUS. Em relação a outros medicamentos, foram mencionados benefícios, mas, também, a eficácia limitada no caso de pacientes recidivados. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do Plenário da Conitec, em sua 112ª Reunião Ordinária, realizada no dia 31 de agosto de 2022, deliberaram por maioria simples, recomendar a não incorporação no SUS de carfilzomibe para o tratamento de pacientes com mieloma múltiplo recidivado ou refratário, que receberam terapia prévia, no SUS. Não houve apresentação de dados clínicos adicionais. Com o preço do medicamento atualizado, ainda assim não se mostrou custo-efetivo. Foi assinado o Registro de Deliberação nº 765/2022. DECISÃO: Não incorporar, no âmbito do Sistema Único de Saúde - SUS, o carfilzomibe para o tratamento de pacientes com mieloma múltiplo recidivado ou refratário, conforme a Portaria nº 107, publicada no Diário Oficial da União nº 184, seção 1, página 75, em 27 de setembro de 2022.

Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma.

BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown. METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival. RESULTS: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P = 0.55); 42.0% and 46.8%, respectively, had a complete response or better (P = 0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65). CONCLUSIONS: Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION ClinicalTrials.gov number, NCT01208662.).

Effect of Autologous Stem Cell Transplantation Combined with Modified VTD Regimen on Elderly Patients with Multiple Myeloma and Its Influence on miRNA Cytokines.

OBJECTIVE: To explore the effect of autologous stem cell transplantation combined with modified VTD regimen on elderly patients with multiple myeloma and its influence on miRNA cytokines. METHODS: The data of 42 elderly patients with multiple myeloma who were treated in our hospital from May 2010 to June 2018 were retrospectively analyzed, and they were divided into the combined group (autologous stem cell transplantation combined with improved VTD scheme, n = 25) and the control group (improved VTD scheme, n = 17) according to different treatment schemes, and the clinical efficacy of the two groups was compared. The levels of CD3+, CD4+, CD4+/CD8+, and Treg were measured in the two groups. The expression levels of miRNA-15a, miRNA-16, and miRNA-21 in the bone marrow fluid of the two groups were measured before and after treatment. The levels of M protein and myeloma cells in the two groups were detected. Comparing the incidence of adverse reactions between the two groups, the Kaplan-Meier method was used for survival analysis. RESULTS: The total effective rate of the combined group (84.00%) was higher than that of the control group (52.94%), and the difference was statistically significant (P < 0.05). After treatment, the levels of CD3+, CD4+, CD4+/CD8+, Treg, miRNA-15a, and miRNA-16 in the combined group were higher than those in the control group, and the levels of miRNA-21, M protein, and myeloma cells were lower than those in the control group, with statistical significance (P < 0.05). There was no significant difference in adverse reactions between the two groups (P > 0.05). The first, second, and third year survival rates of group A (96.00%, 88.00%, and 80.00%) were significantly higher than those of the control group (70.59%, 58.82%, and 47.06%), and the difference was statistically significant (P < 0.05). CONCLUSION: Autologous stem cell transplantation combined with a modified VTD regimen can effectively improve the immune function and survival rate of elderly patients with multiple myeloma, which is safe and effective.

Bortezomib-cyclophosphamide-dexamethasone induction/consolidation and bortezomib maintenance for transplant-eligible newly diagnosed multiple myeloma: phase 2 multicenter trial.

OBJECTIVES: We conducted a phase II trial to prospectively evaluate the efficacy and safety of bortezomib-cyclophosphamide-dexamethasone (VCD) induction, autologous stem cell transplantation (ASCT), VCD consolidation, and bortezomib maintenance in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients in Japan (UMIN000010542). METHODS: From 2013 to 2016, 42 patients with a median age of 58 (range 42-65) years with NDMM were enrolled in 15 centers. The primary endpoint was the complete response (CR) /stringent CR (sCR) rate after transplantation, and overall/progression-free survival rates were also evaluated. RESULTS: Following induction therapy, the overall response rate was obtained in 71% of patients, including a CR/sCR of 10% and a very good partial response (VGPR) of 26%. Twenty-six of the 42 patients completed ASCT following the protocol and CR/sCR and VGPR rate 100 days after ASCT was 26% and 17%, respectively. During consolidation therapy, 3 of the 24 patients achieved deeper responses. Eight of the 18 patients completed 2-year bortezomib maintenance without disease progression and grade 3/4 toxicities. Five patients were VGPR or partial response after ASCT but maintained response with 2-year bortezomib maintenance. Two-year overall and progression-free survival rates were 92.5% (95% confidence interval [CI]: 78.5%-97.5%) and 62.6% (95% CI: 45.8%-75.5%), respectively. Grade 3/4 toxicities (≥ 10%) included neutropenia (19%) and anemia (17%) in induction, and thrombocytopenia (29%) in consolidation. CONCLUSION: VCD induction/consolidation and bortezomib maintenance with ASCT for NDMM resulted in a high CR/sCR rate and provided good overall/progression-free survival in Japan.

Evaluation of the frailty characteristics and clinical outcomes according to the new frailty-based outcome prediction model (Myeloma Risk Profile-MRP) in a UK real-world cohort of elderly newly diagnosed Myeloma patients.

The management of myeloma in the elderly is shifting its focus towards reducing the risk of under-treating fit patients and the risk of over-treating frail patients. Frailty assessment is required in this patient group in order to individualise treatment decisions. In addition to the proven prognostic values of the International Myeloma Working Group (IMWG) frailty score and the revised Myeloma Co-morbidity Index (R-MCI), a new easy-to-use frailty-based risk profile score (high-risk (i.e. frail), medium risk (i.e. intermediate-fitness) and low-risk (i.e. fit)) named Myeloma Risk Profile (MRP) was shown to be predictive of survival in the clinical trial setting. In this retrospective real-world study, we set out to evaluate the frailty characteristics and clinical outcomes according to the different MRP scoring algorithm categories (frail vs. intermediate vs fit), in a high risk cohort of elderly newly diagnosed myeloma patients treated with the fixed-duration triplet therapy VCD (bortezomib with cyclophosphamide and dexamethasone). Clinical outcomes included: reason for treatment discontinuation, overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Out of 100 patients, 62 were frail, 27 were intermediate and 11 were fit, according to MRP scores. To enable meaningful comparisons between comparable numbers, subgroups analyses for ORR, OS, PFS, and AEs focused on frail (n = 62) versus intermediate or fit (n = 38) patients. The proportion of patients in each subgroup who were able to complete the planned course of treatment was (frail: 43.5% vs. intermediate or fit: 55.3%). A higher proportion in the frail subgroup discontinued therapy due to progressive disease (19.4% vs. 2.6%). Discontinuation due to toxicity was comparable across subgroups (14.5% vs. 15.8%), ORR in the total cohort was 75%, and this was comparable between subgroups (frail: 74.2% vs. intermediate or fit: 76.3%). There was a trend for a shorter median OS in the frail subgroup but without a statistical significance: (frail vs. intermediate or fit): (46 months vs. not reached, HR: 1.94, 95% CI 0.89-4.2, p = 0.094). There was no difference in median PFS between subgroups: (frail vs. intermediate or fit): (11.8 vs. 9.9 months, HR: 0.99, 95% CI: 0.61-1.61, P = 0.982). This cohort demonstrated a higher incidence rate of AEs in frail patients compared to those in the intermediate or fit group: patients with at least one any grade toxicity (85.5% vs. 71.1%), patients with at least one ≥G3 AE (37.1% vs. 21.1%). In conclusion, our study is to the first to evaluate clinical outcomes according to MRP in a high risk real-world cohort of patients treated exclusively with the proteasome inhibitor-based VCD therapy. Our study demonstrated a trend for worse OS in addition to worse AE outcomes in the frail group, but no difference in PFS with this fixed-duration therapy. MRP is an easy-to-use tool in clinical practice; its prognostic value was validated in the real-world in a large cohort of patients from the Danish Registry. Further evaluation of MRP in the real-world when continuous therapies are used, can further support the generalisability of its prognostic value in elderly myeloma patients.

Comparison of venous thromboembolism incidence in newly diagnosed multiple myeloma patients receiving bortezomib, lenalidomide, dexamethasone (RVD) or carfilzomib, lenalidomide, dexamethasone (KRD) with aspirin or rivaroxaban thromboprophylaxis.

Incidence of venous thromboembolism (VTE) varies across different regimens in newly diagnosed multiple myeloma (NDMM) patients. Limited data exist on the use of direct oral anticoagulants as thromboprophylaxis in the setting of haematologic malignancies, specifically multiple myeloma. In this retrospective study of 305 NDMM patients, VTE rates in those treated with carfilzomib, lenalidomide, dexamethasone (KRD) + aspirin (ASA), bortezomib, lenalidomide, dexamethasone (RVD) + ASA, and KRD + rivaroxaban were statistically significant, 16·1%, 4·8%, and 4·8%, respectively. The findings confirm a higher incidence of VTE when using KRD induction compared to RVD induction and reveal that the use of low-dose rivaroxaban thromboprophylaxis can mitigate this risk without an observable increase in bleeding rates.

Pomalidomide, bortezomib, and dexamethasone at first relapse in lenalidomide-pretreated myeloma: A subanalysis of OPTIMISMM by clinical characteristics.

OBJECTIVE: We evaluated the efficacy and safety of pomalidomide, bortezomib, and dexamethasone (PVd) vs bortezomib and dexamethasone (Vd) by age, renal function, and high-risk cytogenetic abnormalities in lenalidomide-pretreated patients with multiple myeloma at first relapse. METHODS: OPTIMISMM was a phase 3, multicenter, open-label, randomized study (NCT01734928; N = 559). The primary endpoint was progression-free survival (PFS). RESULTS: Overall, 226 patients had received one prior line of therapy. PVd significantly prolonged PFS vs Vd in patients aged ≤65 years (median, 22.0 vs 13.1 months; P = .0258) and >65 years (median, 17.6 vs 9.9 months; P = .0369). Median PFS in patients with renal impairment (RI; creatinine clearance <60 mL/min) was 15.1 months with PVd vs 9.5 months with Vd (hazard ratio [HR], 0.67 [95% CI, 0.34-1.34]). In patients without RI, median PFS was 22.0 vs 13.1 months (HR, 0.45 [95% CI, 0.27-0.76]). In patients with high-risk cytogenetics, median PFS was 14.7 vs 9.9 months (HR, 0.39 [95% CI, 0.13-1.17]). PVd significantly improved overall response rate vs Vd in all subgroups. The safety profile of PVd was consistent with previous reports. CONCLUSIONS: These findings confirmed the benefits of PVd at first relapse, including in patients with poor prognostic factors.

Prognostic impact of resistance to bortezomib and/or lenalidomide in carfilzomib-based therapies for relapsed/refractory multiple myeloma: The Kyoto Clinical Hematology Study Group, multicenter, pilot, prospective, observational study in Asian patients.

BACKGROUND: Combinatory strategies with carfilzomib (CFZ), a second-generation proteasome inhibitor, plus dexamethasone (DEX) with or without lenalidomide (LEN) have shown promising efficacy for patients with relapsed/refractory multiple myeloma (RRMM) in pivotal clinical trials. However, their effects on patients who were resistance to bortezomib (BTZ) and/or LEN have not been fully evaluated in a daily practice setting. AIMS: To evaluate the real-world efficacy and safety of CFZ-based treatments; that is, CFZ with LEN plus DEX (KRD therapy) and CFZ with DEX (KD therapy), in Asian patients, we conducted a multicenter pilot prospective observational study in the Kyoto Clinical Hematology Study Group. METHODS AND RESULTS: All 50 patients with RRMM enrolled in this study were treated with CFZ-based treatments between 2017 and 2019. KRD and KD were administered to 31 and 19 patients, respectively. The overall response rates (ORRs) were 80.6% with KRD and 73.7% with KD. Two-year progression-free survival (PFS) and overall survival (OS) were 58.5% and 79.7% with KRD, and 23.1% and 52.6% with KD. By multivariate analysis, refractoriness to BTZ and to LEN were identified as independent unfavorable factors for both PFS and OS. The common non-hematologic AEs included hypertension (42.0%), fever (24.0%), fatigue (24.0%), and infection (16.0%). No serious heart failure was observed. This study is registered as UMIN000025108. CONCLUSION: This study suggests the need of the development of novel CFZ-containing strategy which can overcome the refractoriness to BTZ and/or LEN, while both KRD and KD were shown to be mostly feasible in Asian patients in a daily practice setting.

Targeting coenzyme Q10 synthesis overcomes bortezomib resistance in multiple myeloma.

During the development of drug resistance, multiple myeloma (MM) cells undergo changes to their metabolism. However, how these metabolic changes can be exploited to improve treatment efficacy is not known. Here we demonstrate that targeting coenzyme Q10 (CoQ) biosynthesis through the mevalonate pathway works in synergy with the proteasome inhibitor bortezomib (BTZ) in MM. We show that gene expression signatures relating to the mitochondrial tricarboxylic acid (TCA) cycle and electron transport chain (ETC) predispose to clinical BTZ resistance and poor prognosis in MM patients. Mechanistically, BTZ-resistant cells show increased activity of glutamine-driven TCA cycle and oxidative phosphorylation, together with an increased vulnerability towards ETC inhibition. Moreover, BTZ resistance is accompanied by high levels of the mitochondrial electron carrier CoQ, while the mevalonate pathway inhibitor simvastatin increases cell death and decreases CoQ levels, specifically in BTZ-resistant cells. Both in vitro and in vivo, simvastatin enhances the effect of bortezomib treatment. Our study links CoQ synthesis to drug resistance in MM and provides a novel avenue for improving BTZ responses through statin-induced inhibition of mitochondrial metabolism.