Health-related quality-of-life results from the phase 3 OPTIMISMM study: pomalidomide, bortezomib, and low-dose dexamethasone versus bortezomib and low-dose dexamethasone in relapsed or refractory multiple myeloma

In the randomized phase-3 OPTIMISMM study, the addition of pomalidomide to bortezomib and low-dose dexamethasone (PVd) resulted in significant improvement in progression-free survival (PFS) in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM), including lenalidomide refractory patients. Here, we report health-related quality of life (HRQoL) results from this trial. Patients received PVd or Vd in 21-day cycles until disease progression or discontinuation. HRQoL was assessed using the EORTC QLQ-C30, QLQ-MY20, and EQ-5D-3L instruments on day 1 of each treatment cycle. Mean score changes for global QoL, physical functioning, fatigue, side effects of treatment domains, and EQ-5D-3L index were generally stable over time across treatment arms. The proportion of patients who experienced clinically meaningful worsening in global QoL and other domains of interest was similar. These HRQoL results with PVd along with previously demonstrated improvement in PFS vs Vd continue to support its use in patients with RRMM. © 2020 Informa UK Limited, trading as Taylor & Francis Group

Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial

Background As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide.Methods We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged >= 18 years) with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0-2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of beta(2) microglobulin at screening. Bortezomib (1.3 mg/m(2)) was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1,4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years]) was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1-14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled.Findings Between Jan 7, 2013, and May 15,2017,559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15.9 months (IQR 9.9-21.7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11.20 months [95% CI 9.66-13-73] vs 7.10 months [5.88-8-48]; hazard ratio 0.61, 95% CI 0.49-0-77; p<0-0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%] of 278 patients vs 23 [9%1 of 270 patients; nine p.m vs no patients had febrile neutropenia), infections (86 [31%] vs 48 118%1), and thrombocytopenia (76 [27%1 vs 79 [29%]). Serious adverse events were reported in 159 (57%) of 278 patients versus 114 (42%) of 270 patients. Eight deaths were related to treatment; six (2%) were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=11) and two (1%) were reported in patients who received bortezomib and dexamethasone (pneumonia In=11, hepatic encephalopathy [n=1.]).Interpretation Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Copyright (C) 2019 Elsevier Ltd. All rights reserved

Safety and efficacy of inactivated varicella zoster virus vaccine in immunocompromised patients with malignancies: a two-arm, randomised, double-blind, phase 3 trial

Background Patients who are immunocompromised because of malignancy have an increased risk of herpes zoster and herpes zoster-related complications. We aimed to investigate the efficacy and safety of an inactivated varicella zoster virus (VZV) vaccine for herpes zoster prevention in patients with solid tumour or haematological malignancies.Methods This phase 3, two-ann, randomised, double-blind, placebo-controlled, inulticentre trial with an adaptive design was done in 329 centres across 40 countries. The trial included adult patients with solid tumour malignancies receiving chemotherapy and those with haematological malignancies, either receiving or not receiving chemotherapy. Patients were randomly assigned (1:1) to receive four doses of VZV vaccine inactivated by v irradiation or placebo approximately 30 days apart. The patients, investigators, trial site staff, clinical adjudication committee, and sponsor's clinical and laboratory personnel were masked to the group assignment. The primary efficacy endpoint was herpes zoster incidence in patients with solid tumour malignancies receiving chemotherapy, which was assessed in the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of inactivated VZV vaccine or placebo). The primary safety endpoint was serious adverse events up to 28 days after the fourth dose in patients with solid tumour malignancies receiving chemotherapy. Safety endpoints were assessed in all patients who received at least one dose of inactivated VZV vaccine or placebo and had follow-up data. This trial is registered (NCT01254630 and EudraCT 2010-023156-89).Findings Between June 27, 2011, and April 11,2017,5286 patients were randomly assigned to receive VZV vaccine inactivated by gamma irradiation (n=2637) or placebo (n=2649). The haematological malignancy arm was terminated early because of evidence of futility at a planned interim analysis; therefore, all prespecified haematological malignancy endpoints were deemed exploratory. In patients with solid tumour malignancies in the modified intention-to-treat population, confirmed herpes zoster occurred in 22 of 1328 (6.7 per 1000 person-years) VZV vaccine recipients and in 61 of 1350 (18.5 per 1000 person-years) placebo recipients. Estimated vaccine efficacy against herpes zoster in patients with solid tumour malignancies was 63.6% (97.5% CI 36.4 to 79.1), meeting the prespecified success criterion. In patients with solid tumour malignancies, serious adverse events were similar in frequency across treatment groups, occurring in 298 (22.5%) of 1322 patients who received the vaccine and in 283 (21.0%) of 1346 patients who received placebo (risk difference 1.5%, 95% CI -1.7 to 4.6). Vaccine-related serious adverse events were less than 1% in each treatment group. Vaccine-related injection-site reactions were more common in the vaccine group than in the placebo group. In the haematological malignancy group, VZV vaccine was well tolerated and estimated vaccine efficacy against herpes zoster was 16.8% (95% CI -17.8 to 41.3).Interpretation The inactivated VZV vaccine was well tolerated and efficacious for herpes zoster prevention in patients with solid tumour malignancies receiving chemotherapy, but was not efficacious for herpes zoster prevention in patients with haematological malignancies. Copyright (C) 2019 Elsevier Ltd. All rights reserved

Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial

Background: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. Methods: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1–3c (modified to stage 2–3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1–3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. Findings: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1–5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57–0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3–91·8) in the neratinib group and 87·7% (85·7–89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3–4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo. Interpretation: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses—ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast—without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events

Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial

BACKGROUND: As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. METHODS: We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged 6518 years) with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0-2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of \u3b2(2) microglobulin at screening. Bortezomib (1\ub73 mg/m(2)) was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1, 4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age &gt;75 years]) was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1-14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled. FINDINGS: Between Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15\ub79 months (IQR 9\ub79-21\ub77). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11\ub720 months [95% CI 9\ub766-13\ub773] vs 7\ub710 months [5\ub788-8\ub748]; hazard ratio 0\ub761, 95% CI 0\ub749-0\ub777; p&lt;0\ub70001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%] of 278 patients vs 23 [9%] of 270 patients; nine [3%] vs no patients had febrile neutropenia), infections (86 [31%] vs 48 [18%]), and thrombocytopenia (76 [27%] vs 79 [29%]). Serious adverse events were reported in 159 (57%) of 278 patients versus 114 (42%) of 270 patients. Eight deaths were related to treatment; six (2%) were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1]) and two (1%) were reported in patients who received bortezomib and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]). INTERPRETATION: Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. FUNDING: Celgene

Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma

Rituximab plus chemotherapy has been shown to be effective in patients with advanced-stage, previously untreated follicular lymphoma; nevertheless, most patients will have a relapse. Combination immunotherapy with lenalidomide and rituximab is an immunomodulatory regimen that has shown promising activity in patients with indolent B-cell non-Hodgkin's lymphoma