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.).

Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study.

BACKGROUND: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma have few treatment options. We aimed to establish the safety and recommended phase 2 dose of epcoritamab, a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells. METHODS: For the dose-escalation part of this phase 1/2 study, we enrolled adults (aged ≥18 years) with relapsed or refractory CD20+ B-cell non-Hodgkin lymphoma at ten sites across four countries (Denmark, the Netherlands, the UK, and Spain). Eligible patients received priming and intermediate doses followed by full doses of subcutaneous epcoritamab administered in 28-day cycles; each subsequent cohort involved escalation of the priming, intermediate, or full dose (0·0128-60 mg). The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Safety, antitumour activity, pharmacokinetics, and immune biomarkers were also assessed. This study is registered with ClinicalTrials.gov, NCT03625037, with the dose-expansion part ongoing. FINDINGS: Between June 26, 2018, and July 14, 2020, we enrolled 73 patients with relapsed, progressive, or refractory CD20+ mature B-cell non-Hodgkin lymphoma. 68 patients received escalating full doses (0·0128-60 mg) of subcutaneous epcoritamab. No dose-limiting toxic effects were observed, and the maximum tolerated dose was not reached; the full dose of 48 mg was identified as the recommended phase 2 dose. All 68 patients received at least one dose of epcoritamab and were included in safety analyses: common adverse events were pyrexia (47 patients [69%]), primarily associated with cytokine release syndrome (CRS; 40 [59%], all grade 1-2), and injection site reactions (32 [47%]; 31 grade 1). There were no grade 3 or higher CRS events. No discontinuations occurred due to treatment-related adverse events or treatment-related deaths. Overall response rate in patients with relapsed or refractory diffuse large B-cell lymphoma was 68% (95% CI 45-86), with 45% achieving a complete response at full doses of 12-60 mg. At 48 mg, the overall response rate was 88% (47-100), with 38% achieving a complete response. Patients with relapsed or refractory follicular lymphoma had an overall response rate of 90% (55-100), with 50% achieving a complete response at full doses of 0·76-48 mg. Epcoritamab induced robust and sustained B-cell depletion, and CD4+ and CD8+ T-cell activation and expansion, with modest increases in cytokine levels. INTERPRETATION: Single-agent subcutaneous epcoritamab for treatment of patients with relapsed or refractory B-cell non-Hodgkin lymphoma merits investigation in ongoing phase 2 and phase 3 studies. FUNDING: Genmab and AbbVie.

Subcutaneous daratumumab plus standard treatment regimens in patients with multiple myeloma across lines of therapy (PLEIADES): an open-label Phase II study.

Daratumumab is a CD38-targeting monoclonal antibody approved for intravenous (IV) infusion for multiple myeloma (MM). We describe the Phase II PLEIADES study of a subcutaneous formulation of daratumumab (DARA SC) in combination with standard-of-care regimens: DARA SC plus bortezomib/lenalidomide/dexamethasone (D-VRd) for transplant-eligible newly diagnosed MM (NDMM); DARA SC plus bortezomib/melphalan/prednisone (D-VMP) for transplant-ineligible NDMM; and DARA SC plus lenalidomide/dexamethasone (D-Rd) for relapsed/refractory MM. In total, 199 patients were treated (D-VRd, n = 67; D-VMP, n = 67; D-Rd, n = 65). The primary endpoints were met for all cohorts: the ≥very good partial response (VGPR) rate after four 21-day induction cycles for D-VRd was 71·6% [90% confidence interval (CI) 61·2-80·6%], and the overall response rates (ORRs) for D-VMP and D-Rd were 88·1% (90% CI 79·5-93·9%) and 90·8% (90% CI 82·6-95·9%). With longer median follow-up for D-VMP and D-Rd (14·3 and 14·7 months respectively), responses deepened (ORR: 89·6%, 93·8%; ≥VGPR: 77·6%, 78·5%), and minimal residual disease-negativity (10-5 ) rates were 16·4% and 15·4%. Infusion-related reactions across all cohorts were infrequent (≤9·0%) and mild. The median DARA SC administration time was 5 min. DARA SC with standard-of-care regimens demonstrated comparable clinical activity to DARA IV-containing regimens, with low infusion-related reaction rates and reduced administration time.

Results of an Early Access Treatment Protocol of Daratumumab Monotherapy in Spanish Patients With Relapsed or Refractory Multiple Myeloma.

Daratumumab is a human CD38-targeted monoclonal antibody approved as monotherapy for heavily pretreated relapsed and refractory multiple myeloma. We report findings for the Spanish cohort of an open-label treatment protocol that provided early access to daratumumab monotherapy and collected safety and patient-reported outcomes data for patients with relapsed or refractory multiple myeloma. At 15 centers across Spain, intravenous daratumumab (16 mg/kg) was administered to 73 patients who had ≥3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double refractory to both. The median duration of daratumumab treatment was 3.3 (range: 0.03-13.17) months, with a median number of 12 (range: 1-25) infusions. Grade 3/4 treatment-emergent adverse events were reported in 74% of patients and included lymphopenia (28.8%), thrombocytopenia (27.4%), neutropenia (21.9%), leukopenia (19.2%), and anemia (15.1%). Common (>5%) serious treatment-emergent adverse events included respiratory tract infection (9.6%), general physical health deterioration (6.8%), and back pain (5.5%). Infusion-related reactions occurred in 45% of patients. The median change from baseline in all domains of the EQ-5D-5L and EORTC QLQ-C30 was mostly 0. A total of 18 (24.7%) patients achieved a partial response or better, with 10 (13.7%) patients achieving a very good partial response or better. Median progression-free survival was 3.98 months. The results of this early access treatment protocol are consistent with previously reported trials of daratumumab monotherapy and confirm its safety and antitumoral efficacy in Spanish patients with heavily treated relapsed or refractory multiple myeloma. European Clinical Trials Database number: 2015-002993-19.

Palliative care in patients with haematological neoplasms: An integrative systematic review.

BACKGROUND: Palliative care was originally intended for patients with non-haematological neoplasms and relatively few studies have assessed palliative care in patients with haematological malignancies. AIM: To assess palliative care interventions in managing haematological malignancies patients treated by onco-haematology departments. DESIGN: Integrative systematic review with data extraction and narrative synthesis (PROSPERO #: CRD42016036240). DATA SOURCES: PubMed, CINAHL, Cochrane, Scopus and Web-of-Science were searched for articles published through 30 June 2015. Study inclusion criteria were as follows: (1) published in English or Spanish and (2) containing data on palliative care interventions in adults with haematological malignancies. RESULTS: The search yielded 418 articles; 99 met the inclusion criteria. Six themes were identified: (1) end-of-life care, (2) the relationship between onco-haematology and palliative care departments and referral characteristics, (3) clinical characteristics, (4) experience of patients/families, (5) home care and (6) other themes grouped together as 'miscellany'. Our findings indicate that palliative care is often limited to the end-of-life phase, with late referral to palliative care. The symptom burden in haematological malignancies patients is more than the burden in non-haematological neoplasms patients. Patients and families are generally satisfied with palliative care. Home care is seldom used. Tools to predict survival in this patient population are lacking. CONCLUSION: Despite a growing interest in palliative care for haematological malignancies patients, the evidence base needs to be strengthened to expand our knowledge about palliative care in this patient group. The results of this review support the need to develop closer cooperation and communication between the palliative care and onco-haematology departments to improve patient care.

Cuidados paliativos en hematología clínica: experiencia de una consulta integrativa en pacientes con mieloma múltiple / Palliative care in clinical haematology: Experience of an integrative outpatient clinic in patients with multiple myeloma

OBJETIVO: Describir la experiencia tras el primer año de funcionamiento de una consulta integrativa de cuidados paliativos en pacientes con mieloma múltiple. Materiales y MÉTODOS: Se revisaron las historias clínicas de los pacientes visitados por primera vez en la consulta de cuidados paliativos en pacientes con mieloma múltiple. Durante la primera y las 3 siguientes visitas se evaluaron: dolor, anorexia, estreñimiento, insomnio, náuseas y vómitos, disnea, ansiedad y tristeza; mediante una escala visual numérica [0-10]. Se calculó la carga sintomática de los síntomas físicos y emocionales mediante el sumatorio de las puntuaciones de sus escalas visuales numéricas. La intensidad del dolor y su interferencia se evaluó mediante la versión española del Brief Pain Inventory modificada ad hoc. RESULTADOS: De febrero a diciembre 2013, se visitaron 67 pacientes (mediana desde el diagnóstico 355 días), y tras 3 visitas de seguimiento (mediana 60 días) la proporción de pacientes con dolor moderado-severo (escala visual numérica≥5) se redujo para el «dolor máximo» (57 vs.18%; p < 0,0001) y el «dolor promedio» (24 vs.2%; p < 0,0001). La proporción de pacientes sin interferencia por el dolor mejoró: actividad general (52 vs.82%; p = 0,0001), sueño (73 vs.91%; p = 0,01), estado de ánimo (52 vs.87,5%; p = 0,0001). La carga sintomática física y emocional, y la proporción de pacientes deprimidos (13 vs.5%; p = 0,001) mejoraron. CONCLUSIONES: La integración de los cuidados paliativos en la atención de los pacientes con mieloma múltiple no solo es posible, sino que mejora de forma significativa los síntomas emocionales y físicos

AIM: To describe the experience after the first year of operation of an integrative palliative care clinic for patients with multiple myeloma. MATERIALS AND METHODS: The medical records were reviewed of patients seen for the first time in the integrative palliative care clinic for patients with multiple myeloma. During the first, and the next 3 visits, pain, anorexia, constipation, insomnia, nausea and vomiting, dyspnoea, anxiety, and sadness were evaluated using a visual numeric scale [0-10]. The symptomatic burden of physical and emotional symptoms was calculated by summing the scores of their visual numeric scale. The pain intensity and its interference were assessed using the Spanish version of the Brief Pain Inventory modified ad hoc. RESULTS: From February to December 2013, 67 patients (median 355 days from diagnosis) were seen, and after 3 follow up visits (median 60 days from the first visit) the proportion of patients with moderate-severe pain (visual numeric scale ≥ 5) was reduced for 'worst pain' (57% vs.18%; P < .0001) and 'average pain' (24% vs.2%; P < .0001). The proportion of patients without interference from pain improved in, general activity (52% vs.82%; P=.0001), sleep (73% vs.91%; P =.01), and mood (52% vs.87.5%; P = .0001). There was also improvement in the physical and emotional symptom burden, and the proportion of depressed patients (13% vs.5%; P = .001). CONCLUSIONS: The integration of palliative care in the care of patients with multiple myeloma is not only possible, but also significantly improves the emotional and physical symptoms

Is Early Palliative Care Feasible in Patients With Multiple Myeloma?

CONTEXT: Evidence for the benefits of early palliative care (EPC) in patients with solid tumors is strong, but EPC has received scant attention in hematologic malignancies. OBJECTIVE: To assess the benefits of outpatient-based EPC for symptom control in patients with multiple myeloma. METHODS: Retrospective study of patients attending the Multiple Myeloma Palliative Care Clinic at our hospital in the year 2013 (February 1-December 31). The following symptoms were assessed at baseline and at three follow-up consultations using a Numerical Visual Scale (0 = no symptoms; 10 = worst possible): pain, anorexia, constipation, insomnia, nausea/vomiting, dyspnea, anxiety, and sadness. Physical and emotional symptom burden scores were calculated. Pain interference with general activity, sleep, and mood was also evaluated. RESULTS: About 67 patients were included. The proportion of patients reporting moderate-to-severe pain (Numerical Visual Scale ≥5) decreased significantly from baseline to the final follow-up: worst pain decreased from 57% to 18% (P < 0.0001), whereas average pain fell from 24% to 2% (P < 0.0001). The percentage of patients reporting no pain interference increased significantly from baseline: general activity (52% vs. 82%; P = 0.0001), sleep (73% vs. 91%; P = 0.01), and mood (52% vs. 87.5%; P = 0.0001). Physical and emotional symptom burden also improved, with significantly fewer patients reporting depression (13% vs. 5%; P = 0.001). Most patients (86.6%) were alive and still attending the Multiple Myeloma Palliative Care Clinic at study end. CONCLUSIONS: These findings indicate that EPC is feasible in patients with multiple myeloma. Pain and other symptoms were well controlled.