ABSTRACT Introduction: This study evaluated outcomes and risk factors for COVID-19 in 91 Brazilian multiple myeloma (MM) patients between April 2020 and January 2022. Results: Of the 91 MM patients diagnosed with COVID-19, 64% had comorbidities and 66% required hospitalization due to COVID-19, with 44% needing ventilatory support and 37% intensive care. Age (OR 2.02; 95%CI 1.02 – 7.7) and hypertension OR 4.5; 95%CI 1.3 – 15.5) were independently associated with hospitalization and certain MM therapies (corticosteroids and monoclonal drugs) were associated with ventilatory support (OR 4.3; 95%CI 1.3 – 14 and OR 5.7; 95%CI 1.8 – 18, respectively), while corticosteroids and immunomodulatory drugs were linked to ICU admission (OR 5.1; 95% CI 1.4 – 18 and OR 3.4; 95%CI 1.1 – 10, respectively). The overall mortality rate was 30%, with the highest rate observed in the ICU (73%). Additionally, the ECOG performance status was linked to increased mortality (OR 11.5; 95%CI 1.9 – 69). The MM treatment was delayed in 63% of patients who recovered from COVID-19. Conclusions: The findings highlight the need for preventing COVID-19 and prioritizing vaccination among MM patients, as they have high rates of severe outcomes in the event of COVID-19. It is also essential to monitor the potential clinical impacts of COVID-19 on MM patients in the long-term. Given the limited resources available in treating MM patients in Brazil during the COVID-19 pandemic, outcomes might be worse in this population. Introduction COVID19 COVID 19 COVID-1 9 (MM 202 2022 Results COVID19, 19, 64 66 44 37 care 2.02 2 02 95CI 95 102 1 1.0 7.7 77 7 4.5 45 4 5 13 3 1. 15.5 155 15 4.3 43 5.7 57 8 respectively, respectively , respectively) 5.1 51 3.4 34 11 10 respectively. . 30 30% 73%. 73 73% (73%) Additionally 11.5 115 69. 69 69) 63 COVID19. 19. Conclusions longterm. longterm long term. term long-term pandemic population COVID1 COVID- 20 6 2.0 0 7. 4. 15. 5. 3. (73% 11. 2. (73 (7 (

ABSTRACT Introduction Chimeric antigen receptor T (CAR-T) cell therapy is an emerging treatment option for relapsed/refractory multiple myeloma (RRMM) that is a multi-step process involving various stakeholders. Appropriate education on the practical logistics is therefore paramount to ensure treatment success. Methods A group of key opinion leaders met to explore the key elements of setting up and running a CAR-T center in Brazil. For each step in the CAR-T cell therapy process, the experts agreed on basic requirements, gave their key recommendations from practical experience, and considered any remaining unanswered questions. Results This paper presents best-practice recommendations and advice on how to overcome common challenges for each step in the CAR-T cell therapy process, with a focus on the current situation in Brazil. Key themes throughout the process are collaboration within the multidisciplinary team and with the referring physician, along with communication and education for patients and their caregivers. Conclusion We believe that the expert insights presented in this paper, in particular on optimal patient selection and timing of CAR-T cell therapy, will deepen understanding of the CAR-T process and aid implementation of this novel therapy for patients with RRMM in Brazil. CART CAR (CAR-T relapsedrefractory relapsed refractory (RRMM multistep multi stakeholders success Brazil requirements experience questions bestpractice best practice physician caregivers

Resumo O cumprimento dos prazos legais para incorporação e disponibilização de tecnologias no Sistema Único de Saúde (SUS) é fundamental para o acesso da população aos medicamentos considerados essenciais. Objetivou-se analisar o cumprimento destes prazos comparando a Oncologia e o Componente Especializado de Assistência Farmacêutica (CEAF). Comparou-se os processos de incorporação de medicamentos no SUS da Oncologia e do CEAF que foram submetidos à Conitec no período de 01 de janeiro de 2017 a 30 de abril de 2020. No período, 83 processos de incorporação de medicamentos foram recomendados para incorporação pela Conitec, dos quais 13 (15,66%) eram da Oncologia e 70 (84,34%) eram do CEAF. Verifica-se que o tempo de análise e recomendação pela Conitec até a publicação da decisão pelo Ministério da Saúde foi, em média, 15 dias maior para processos que continham medicamentos oncológicos e o tempo para disponibilização das tecnologias incorporadas da área da oncologia foi, em média, 389 dias maior que do CEAF. Reconhece-se o importante avanço obtido com a criação da Conitec no Brasil, porém os resultados deste estudo apontam para a necessidade de aprimoramento do processo de disponibilização de tecnologias incorporadas no SUS, em especial da Oncologia.

Abstract Compliance with legal deadlines for the assessment and incorporation of technologies in Brazil’s Unified Health System (SUS) is essential to ensure public access to essential medicines. The scope of this paper was to analyze the compliance with legal deadlines for incorporation and availability of medicines in the SUS, comparing Oncology and the Specialized Component of Pharmaceutical Assistance (SCPA). A comparison was made of the drugs incorporated that were submitted to Conitec in the period from January 1, 2017, to April 30, 2020. A total of 85 drugs were recommended for incorporation by Conitec, of which 15 (17.64%) were for Oncology and 70 (82.36%) were for SCPA. The time between analysis and recommendation by Conitec until the publication of the decision by the Ministry of Health was, on average, 86 days longer for oncological drugs and the availability timeframe of technologies incorporated in the oncology area was, on average, 389 days longer than for SCPA. The major progress achieved with the creation of Conitec in Brazil is acknowledged, but the results of this study point to a pressing need to improve the process of making available technologies incorporated into the SUS, especially in oncology.

Resumo O cumprimento dos prazos legais para incorporação e disponibilização de tecnologias no Sistema Único de Saúde (SUS) é fundamental para o acesso da população aos medicamentos considerados essenciais. Objetivou-se analisar o cumprimento destes prazos comparando a Oncologia e o Componente Especializado de Assistência Farmacêutica (CEAF). Comparou-se os processos de incorporação de medicamentos no SUS da Oncologia e do CEAF que foram submetidos à Conitec no período de 01 de janeiro de 2017 a 30 de abril de 2020. No período, 83 processos de incorporação de medicamentos foram recomendados para incorporação pela Conitec, dos quais 13 (15,66%) eram da Oncologia e 70 (84,34%) eram do CEAF. Verifica-se que o tempo de análise e recomendação pela Conitec até a publicação da decisão pelo Ministério da Saúde foi, em média, 15 dias maior para processos que continham medicamentos oncológicos e o tempo para disponibilização das tecnologias incorporadas da área da oncologia foi, em média, 389 dias maior que do CEAF. Reconhece-se o importante avanço obtido com a criação da Conitec no Brasil, porém os resultados deste estudo apontam para a necessidade de aprimoramento do processo de disponibilização de tecnologias incorporadas no SUS, em especial da Oncologia.

Abstract Compliance with legal deadlines for the assessment and incorporation of technologies in Brazil’s Unified Health System (SUS) is essential to ensure public access to essential medicines. The scope of this paper was to analyze the compliance with legal deadlines for incorporation and availability of medicines in the SUS, comparing Oncology and the Specialized Component of Pharmaceutical Assistance (SCPA). A comparison was made of the drugs incorporated that were submitted to Conitec in the period from January 1, 2017, to April 30, 2020. A total of 85 drugs were recommended for incorporation by Conitec, of which 15 (17.64%) were for Oncology and 70 (82.36%) were for SCPA. The time between analysis and recommendation by Conitec until the publication of the decision by the Ministry of Health was, on average, 86 days longer for oncological drugs and the availability timeframe of technologies incorporated in the oncology area was, on average, 389 days longer than for SCPA. The major progress achieved with the creation of Conitec in Brazil is acknowledged, but the results of this study point to a pressing need to improve the process of making available technologies incorporated into the SUS, especially in oncology.

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

ABSTRACT Objective: Adipose tissue-derived stromal/stem cells (ASCs) and vitamin D have immunomodulatory actions that could be useful for type 1 diabetes (T1D). We aimed in this study to investigate the safety and efficacy of ASCs + daily cholecalciferol (VIT D) for 6 months in patients with recent-onset T1D. Materials and methods: In this prospective, dual-center, open trial, patients with recent onset T1D received one dose of allogenic ASC (1 x 106 cells/kg) and cholecalciferol 2,000 UI/day for 6 months (group 1). They were compared to patients who received chol-ecalciferol (group 2) and standard treatment (group 3). Adverse events were recorded; C-peptide (CP), insulin dose and HbA1c were measured at baseline (T0), after 3 (T3) and 6 months (T6). Results: In group 1 (n = 7), adverse events included transient headache (all), mild local reactions (all), tachycardia (n = 4), abdominal cramps (n = 1), thrombophlebitis (n = 4), scotomas (n = 2), and central retinal vein occlusion at T3 (n = 1, resolution at T6). Group 1 had an increase in basal CP (p = 0.018; mean: 40.41+/-40.79 %), without changes in stimulated CP after mixed meal (p = 0.62), from T0 to T6. Basal CP remained stable in groups 2 and 3 (p = 0.58 and p = 0.116, respectively). Group 1 had small insulin requirements (0.31+/- 0.26 UI/kg) without changes at T6 (p = 0.44) and HbA1c decline (p = 0.01). At T6, all patients (100%; n = 7) in group 1 were in honeymoon vs 75% (n = 3/4) and 50% (n = 3/6) in groups 2 and 3, p = 0.01. Conclusions: Allogenic ASC + VIT D without immunosuppression was safe and might have a role in the preservation of β-cells in patients with recent-onset T1D. ClinicalTrials.gov: NCT03920397.

ABSTRACT Extraordinary progress has been made over the last decade in the treatment of multiple myeloma with the incorporation of new drugs, particularly proteasome inhibitors, immunomodulators, and monoclonal antibodies. The combined use of innovative drugs, already in the first lines of treatment, has led to an expressive increase in the survival of these patients. However, the approach to relapse remains a great challenge, and the disease continues to be incurable. In this scenario, modern immunotherapy has gained the limelight, especially with its recent use of CAR-T cells in clinical trials, as in the case of multiple myeloma, having the BCMA as the primary target. The results are impactful in the treatment of multiple myeloma patients who have had multiple relapses and are triple- and penta-refractory. In this Consensus, we have brought together a group of experts in multiple myeloma to discuss and forward their recommendations for the future, which we hope is very near, incorporating the CAR-T in our country.

ABSTRACT Since the World has been facing the COVID-19 pandemic, special attention has been taken concerning cancer patients; related to their immunosuppression status, adding risk for more aggressive COVID-19 and mortality, but also concerns about the access and the quality of care in cancer therapy. The COVID-19 pandemic impacts the number of infected, its related mortality, as well as the care of cancer patients. Multiple myeloma patients are a particular group with several important aspects to be considered during pandemic times. In essence, they are immunosuppressed in different intensities during their treatment. Most of them are elderly and all of them require long-term therapy, with prolonged contact with the health care system, possibly including a stem cell transplant during the treatment. A panel of experts in multiple myeloma and infectious diseases discusses pieces of evidence and the lack of the same in the scenario of COVID-19 in myeloma patients, while also exposing what is expected for the next phases of the COVID-19 pandemic.

ABSTRACT Background: The treatment of multiple myeloma (MM) has evolved significantly in the past decade, and new drug combinations have improved the response rates and prolonged survival. Studies comparing different induction chemotherapy regimens have shown that triple combinations have better results than double combinations. However, comparisons among different triple combinations are rare in the literature. Methods: We retrospectively compared two triple combinations comprising bortezomib, cyclophosphamide and dexamethasone (VCD) versus thalidomide, cyclophosphamide and dexamethasone (CTD), and aimed at identifying which of the two combinations would yield better response rates following four induction cycles prior to hematopoietic cell transplantation in patients with untreated multiple myeloma. Results: We retrospectively reviewed the medical records of 311 patients from 24 different centers.The VCD regimen was used as induction therapy by 117 (37.6%) patients, whereas 194 (62.4%) patients received the CTD regimen. After four cycles of induction on an intention-to-treat basis, 54% of the patients in the VCD group achieved at least very good partial response versus 42.8% in the CTD group (p = 0.05). We observed no difference in neuropathy or thrombotic events rates among the two regimens. Conclusion: Our results corroborate the superiority of the triple combination regimes containing bortezomib over the triple combination with thalidomide as pre ASCT induction therapy in MM.

ABSTRACT Objective: To describe the oral health status of patients with multiple myeloma and compare to a control group. Materials and methods: The medical history of the studied subjects was obtained from the medical records and through interviews. Trained examiners evaluated the oral mucosa, teeth, periodontium and imaging aspects. The dental status was evaluated by the decayed, missing and filled teeth index. The presence of bone lesions was investigated with cone beam computer tomography images of the jaws. Results: The most common oral mucosa features were paleness (31%) and coated tongue (14.3%) in the multiple myeloma group (N = 42); and coated (21.4%) and fissured tongue (10.7%) in the control group (N = 28). The mean DMFT index of patients with multiple myeloma was high, but not significantly different from controls (14.57 versus 19.69, p = 0.975). Hypodense lesions suggestive of multiple myeloma were observed in the jaws of 73.8% of the patients. Hypodense lesions related to teeth were detected in 33.3% of the patients and in 53.6% of the controls (p = 0.832). Conclusions: The studied population of multiple myeloma patients presented many oral health issues that needed attention. Thus, oral care should be included in the routine treatment to improve the quality of the oral status in these patients.

Abstract The treatment of patients with relapsed and/or refractory multiple myeloma has improved considerably in the last 15 years, after the introduction of proteasome inhibitors and immunomodulatory drugs. The first clinical trials with new proteasome inhibitors have produced exciting results, particularly those comparing triplet regimens with standard doublet regimens, with a gain in progression-free survival accompanied by an acceptable safety profile and either similar or better health-related quality of life. New proteasome inhibitors hold the potential to fill unmet needs in multiple myeloma management regarding improvement of clinical outcomes, including delayed progression of disease in high-risk patients. This review summarizes the main pharmacological properties and clinical outcomes of these agents, and discusses their potential to change the whole multiple myeloma therapeutic landscape.

ABSTRACT Background: Oral manifestations may be the first signs of hematologic diseases, and may occur due to the disease itself or to treatment. Objective: To evaluate the frequency and types of oral conditions presented by patients on a hematology ward. Methods: Data were collected by oral examinations during weekly visits to a hematology ward. Six trained dentists performed the oral assessment based on the principles of oral semiology. All patients who accepted to be examined were included in the study. Patients who were unavailable or unable to have oral examinations were excluded. Data were recorded on protocol forms and in the electronic records of the institution. A descriptive analysis was performed. Results: Seventy-nine patients were included in the analysis; 50.6% were female and the mean age was 41.49 years. The most common reasons for hospitalization were chemotherapy and complications (81%), relapse (13.9%) and pre-transplant preparation (5%). The most frequent underlying diseases were multiple myeloma (17.7%), acute myeloid leukemia (15.4%) and acute lymphocytic leukemia (11.5%). Oral conditions were found in 36 (45.6%) patients, some of whom presented more than one condition. The most common oral conditions were dry lips (12.6%), mucositis (10.1%), petechiae (8.9%) and candidiasis (7.6%). Of the detected oral conditions, 56.9% were related to the underlying disease or chemotherapy and 20.2% were not related to the disease. Conclusion: This study shows the types and frequency of oral conditions observed in hematological inpatients. Awareness of these conditions is important for prevention and planning the care of patients with hematological diseases.