On November 21, 2016, the U.S. Food and Drug Administration granted regular approval to daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the ...treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on two randomized, open‐label trials in which daratumumab was added to these backbone therapies. The MMY3003 trial demonstrated substantial improvement in progression‐free survival (PFS) when daratumumab was added to lenalidomide and dexamethasone compared with lenalidomide and dexamethasone alone. The estimated median PFS had not been reached in the daratumumab arm and was 18.4 months in the control arm (hazard ratio HR = 0.37; 95% confidence interval CI: 0.27–0.52; p < .0001), representing a 63% reduction in the risk of disease progression or death. Similar results were observed in the MMY3004 trial comparing the combination of daratumumab, bortezomib, and dexamethasone with bortezomib and dexamethasone. The estimated median PFS was not reached in the daratumumab arm and was 7.2 months in the control arm (HR = 0.39; 95% CI: 0.28–0.53; p < .0001), representing a 61% reduction in the risk of disease progression or death. The most frequently reported adverse reactions (greater than or equal to 20%) in MMY3003 were infusion reactions, diarrhea, nausea, fatigue, pyrexia, upper respiratory tract infection, muscle spasm, cough, and dyspnea. The most frequently reported adverse reactions (greater than or equal to 20%) in MMY3004 were infusion reactions, diarrhea, peripheral edema, upper respiratory tract infection, and peripheral sensory neuropathy. Neutropenia and thrombocytopenia have been added to the Warnings and Precautions of the drug label.
Implications for Practice
Daratumumab, the first monoclonal antibody targeted against CD38, received U.S. Food and Drug Administration accelerated approval in 2015 based on data from single‐agent, single‐arm trials that provided response rate information. Results of the MMY3003 and MMY3004 trials established that daratumumab can be combined synergistically with some of the most highly active agents used to treat multiple myeloma, leading to daratumumab's regular approval in 2016. Daratumumab added to lenalidomide and dexamethasone, or bortezomib and dexamethasone, provides a substantial improvement in progression‐free survival in previously treated patients with multiple myeloma. These combinations will likely improve the survival outlook for patients with multiple myeloma.
Multiple myeloma is mostly an incurable disease. The U.S. Food and Drug Administration (FDA) granted daratumumab accelerated approval in November 2015 as monotherapy for patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double refractory to a proteasome and an immunomodulatory agent. This article describes the FDA review of the strength of evidence for this application and its clinical implications for the multiple myeloma population.
On August 5, 2020, the FDA granted accelerated approval to belantamab mafodotin-blmf (BLENREP; GlaxoSmithKline) for the treatment of adult patients with relapsed or refractory multiple myeloma who ...have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. Substantial evidence of effectiveness was obtained from the phase II, multicenter DREAMM-2 trial. Patients received belantamab mafodotin 2.5 or 3.4 mg/kg intravenously once every 3 weeks until disease progression or unacceptable toxicity. The trial demonstrated an overall response rate of 31% in the 2.5 mg/kg cohort and 34% in the 3.4 mg/kg cohort. Keratopathy was the most frequent adverse event, occurring in 71% and 77% of patients, respectively. Other ocular toxicities included changes in visual acuity, blurred vision, and dry eye. The U.S. prescribing information for belantamab mafodotin includes a boxed warning for ocular toxicity, and belantamab mafodotin is available only through a restricted program under a Risk Evaluation and Mitigation Strategy. This article summarizes the data and the FDA review process supporting accelerated approval of belantamab mafodotin 2.5 mg/kg intravenously once every 3 weeks. This approval may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
The development of novel agents has transformed the treatment paradigm for multiple myeloma, with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone ...marrow-based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in patients with multiple myeloma. Complementary liquid biopsy-based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid-based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real-world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory multiple myeloma, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in multiple myeloma is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes.
In January 2023, the FDA granted accelerated approval to pirtobrutinib for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic ...therapy, including a Bruton tyrosine kinase (BTK) inhibitor. Approval was based on BRUIN, a single-arm study of pirtobrutinib monotherapy in patients with B-cell malignancies. Efficacy was based on independent review committee-assessed overall response rate (ORR) supported by durability of response in 120 patients with relapsed or refractory MCL who had received a prior BTK inhibitor and received the approved pirtobrutinib dosage of 200 mg once daily. The ORR was 50% 95% confidence interval (CI), 41-59, and the complete response rate was 13% (95% CI, 7-20), with an estimated median duration of response of 8.3 months. The most common nonhematologic adverse reactions were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Warnings and Precautions in labeling include infection, hemorrhage, cytopenias, atrial arrhythmias, and second primary malignancies. Postmarketing studies were required to evaluate longer-term safety of pirtobrutinib and to verify the clinical benefit of pirtobrutinib. This article summarizes key aspects of the regulatory review, including the indication statement, efficacy and safety considerations, and postmarketing requirements.
In June 2020, the U.S. Food and Drug Administration granted accelerated approval to selinexor for the treatment of adult patients with relapsed or refractory diffuse large B‐cell lymphoma (DLBCL), ...not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. Approval was based on SADAL, a multicenter trial of selinexor monotherapy in patients with DLBCL after two to five systemic regimens. Efficacy was based on independent review committee–assessed objective response rate (ORR) and duration of response using Lugano criteria. In 134 patients treated with the approved dosage (60 mg orally on days 1 and 3 of each week), the ORR was 29% (95% confidence interval, 22–38), with complete response in 13% and with 38% of responses lasting at least 6 months. Gastrointestinal toxicity developed in 80% of patients, hyponatremia in 61%, central neurological toxicity (such as dizziness and mental status changes) in 25%, and ocular toxicity in 18%. New or worsening grade 3 or 4 thrombocytopenia, lymphopenia, neutropenia, anemia, or hyponatremia developed in ≥15%. Adverse reactions led to selinexor dose interruption in 61% of patients, dose reduction in 49%, and permanent discontinuation in 17%, with thrombocytopenia being the leading cause of dose modifications. Postmarketing studies will evaluate reduced dosages of selinexor and further evaluate clinical benefit in patients with relapsed or refractory DLBCL.
Implications for Practice
Selinexor is a new potential option for adults with relapsed or refractory diffuse large B‐cell lymphoma, not otherwise specified, in the third‐line setting or beyond. Toxicities are typically manageable but can be difficult to tolerate and necessitate close monitoring and supportive care.
This review provides a regulatory overview of the U.S. FDA approval of selinexor for the treatment of adult patients with relapsed or refractory diffuse large B‐cell lymphoma after at least two lines of systemic therapy.
Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of ...diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next-generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10
to 10
cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions.
.
Minimal residual disease (MRD) is increasingly used as a prognostic biomarker, a measure of clinical efficacy, and a guide for treatment decisions in various hematologic malignancies. We sought to ...characterize MRD data in registrational trials in hematologic malignancies submitted to the U.S. Food and Drug Administration (FDA) with the ultimate goal of expanding the utility of MRD data in future drug applications. We descriptively analyzed MRD data collected in registrational trials, including the type of MRD endpoint, assay, disease compartment(s) assessed, and the acceptance of MRD data in the U.S. prescribing information (USPI). Of 196 drug applications submitted between January 2014 and February 2021, 55 (28%) included MRD data. Of the 55 applications, MRD data was proposed by the Applicant for inclusion in the USPI in 41 (75%) applications but was included in only 24 (59%). Despite an increasing number of applications that proposed to include MRD data in the USPI, the acceptance rate decreased over time. Although MRD data have the potential to expedite drug development, our analysis identified challenges and specific areas for improvement, including assay validation, standardization of collection methods to optimize performance, and considerations in trial design and statistical methodology.
To describe a case of intentional ingestion of hand sanitizer in our hospital and to review published cases and those reported to the American Association of Poison Control Centers' National Poison ...Data System.
A case report, a literature review of published cases, and a query of the National Poison Data System.
Medical intensive care unit.
Seventeen-yr-old male 37-kg with an intentional ingestion of a hand sanitizer product into his gastrostomy tube.
Intubation, ventilation, and hemodialysis.
Incidence and outcome of reported cases of unintentional and intentional ethanol containing-hand sanitizer ingestion in the United States from 2005 through 2009. A literature search found 14 detailed case reports of intentional alcohol-based hand sanitizer ingestions with one death. From 2005 to 2009, the National Poison Data System received reports of 68,712 exposures to 96 ethanol-based hand sanitizers. The number of new cases increased by an average of 1,894 (95% confidence interval CI 1266-2521) cases per year (p =.002). In 2005, the rate of exposures, per year, per million U.S. residents was 33.7 (95% CI 28.4-39.1); from 2005 to 2009, this rate increased on average by 5.87 per year (95% CI 3.70-8.04; p = .003). In 2005, the rate of intentional exposures, per year, per million U.S. residents, was 0.68 (95% CI 0.17-1.20); from 2005 to 2009, this rate increased on average by 0.32 per year (95% CI 0.11-0.53; p = .02).
The number of new cases per year of intentional hand sanitizer ingestion significantly increased during this 5-yr period. Although the majority of cases of hand sanitizer ingestion have a favorable outcome, 288 moderate and 12 major medical outcomes were reported in this National Poison Data System cohort. Increased awareness of the risks associated with intentional ingestion is warranted, particularly among healthcare providers caring for persons with a history of substance abuse, risk-taking behavior, or suicidal ideation.
Molecularly targeted therapies such as tyrosine kinase inhibitors (TKI) are effective treatments for B-cell receptor (BCR)-ABL-bearing leukemias. We evaluated the impact of TKIs on historical chronic ...myeloid leukemia (CML) mortality trends compared with acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).
Because mortality trends reflect combined effects of leukemia incidence and survival, we also evaluated the contribution of incidence and survival trends to mortality trends by subtypes. We used data from 13 U.S. (SEER) registries (1992-2017) among U.S. adults. We utilized histology codes to identify cases of CML, ALL, and CLL and death certificate data to calculate mortality. We used Joinpoint to characterize incidence (1992-2017) and mortality (1992-2018) trends by subtype and diagnosis year.
For CML, mortality rates started declining in 1998 at an average rate of 12% annually. Imatinib was approved by the FDA for treating CML and ALL in 2001, leading to clear benefits for patients with CML. Five-year CML survival increased dramatically over time, especially between 1996 to 2011, 2.3% per year on average. ALL incidence increased 1.5% annually from 1992 to 2017. ALL mortality decreased 0.6% annually during 1992 to 2012 and then stopped declining. CLL incidence fluctuated during 1992 to 2017 while mortality decreased 1.1% annually during 1992 to 2011 and at a faster rate of 3.6% per year from 2011. Five-year survival increased 0.7% per year on average during 1992 to 2016.
Survival benefit from TKIs and other novel therapies for treating leukemia subtypes has been demonstrated in clinical trials.
Our study highlights the impact of molecularly targeted therapies at the population level.
PDF
