Ryan Nolan, PharmD Candidate 2021

On August 5, 2020, the FDA granted accelerated approval to belantamab mafodotin-blmf (Blenrep; GlaxoSmithKline).

Belantamab mafodotin-blmf is now indicated for adult patients with relapsed or refractory myeloma who have received at least 4 prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immune modulating agent. Belantamab mafodotin-blmf is a first-in-class, anti–B-cell maturation antigen (BCMA) immunoconjugate with afucosylated, humanized immunoglobulin G1 anti-BCMA monoclonal antibody conjugated by a protease-resistant maleimidocaproyl linker to a microtubule-disrupting agent, monomethyl auristatin F (MMAF).

 This conjugated drug allows delivery of cytotoxic MMAF to BCMA-expressing multiple myeloma cells causing apoptosis and tumor lysis through antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.

Accelerated approval of belantamab mafodotin-blmf stemmed from the results of the multicenter open-label, phase 2 DREAMM-2 (NCT03525678) study.

 The study enrolled patients with relapsed or refractory multiple myeloma with disease progression after 3 or more lines of therapy and who were refractory to immunomodulatory drugs and proteasome inhibitors, and refractory or intolerant to an anti-CD38 monoclonal antibody. The primary end point of patients achieving a partial response or better occurred in 31% (97.5% CI, 20.8-42.6) of patients in the 2.5 mg/kg cohort. Another key secondary end point was probability of having a duration of response 4 months or longer, which was estimated by the Kaplan Meier curve to be 78% (95% CI, 57-89) in the 2.5 mg/kg cohort.

The most common adverse effects (AEs) were keratopathy (71%), decreased visual acuity (53%), nausea (24%), blurred vision (22%), pyrexia (22%), infusion-related reactions (21%), and fatigue (20%). The most common grade 3 or 4 laboratory abnormalities are decreased platelet count (21%), decreased lymphocytes (22%), decreased hemoglobin level (18%), decreased neutrophils (9%), increased creatine level (5%), and increased γ-glutamyl transferase (5%).3 Because of the risks of ocular toxicity, the medication is restricted under the Risk Evaluation and Mitigation Strategy (REMS) program. Prescribers must be certified with the Blenrep REMS program. Patients must be enrolled in the program and adhere to monitoring.

This medication also carries a black box warning: corneal epithelium changes can occur, resulting in alteration in vision, including severe vision loss and corneal ulcer, and symptoms such as blurred vision and dry eyes. Ophthalmic examinations should occur at baseline (3 weeks prior to the first dose), prior to each dose (at least 1 week after previous dose and within 2 weeks prior to next dose), and promptly for worsening symptoms. 

Patients should be advised to use preservative-free lubricant eye drops at least 4 times per day starting with the first infusion and continuing until end of treatment, to avoid contact lens use, and to use caution when driving. Complete blood counts should occur at baseline and as clinically indicated thereafter. If applicable, patients should use contraception while on this medication because of the potential of embryo-fetal toxicity. Female patients of reproductive potential should continue to use contraception 4 months after the last dose and male patients with female partners of reproductive potential should use contraception for 6 months after the last dose.

The recommended belantamab mafodotin-blmf dose is 2.5 mg/kg as an intravenous infusion over approximately 30 minutes once every 3 weeks. For AEs requiring dose reductions, decrease to 1.9 mg/kg intravenously once every 3 weeks.

FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. FDA. August 5, 2020. Accessed November 18, 2020. 

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-granted-accelerated-approval-belantamab-mafodotin-blmf-multiple-myeloma#:~:text=On%20August%205%2C%202020%2C%20the,antibody%2C%20a%20proteasome%20inhibitor%2C%20and

Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. 

 2020;21(2):207-221. doi:10.1016/S1470-2045(19)30788-0

Blenrep. Prescribing information. GlaxoSmithKline; 2020. Accessed November 18, 2020. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761158s000lbl.pdf

Articles

Belantamab mafodotin-blmf is now indicated for adult patients with relapsed or refractory myeloma who have received at least 4 prior therapies. 

Belantamab mafodotin-blmf for Relapsed or Refractory Multiple Myeloma

On October 22, 2020, the FDA approved remdesivir (Veklury; Gilead) as the first treatment for coronavirus disease 2019 (COVID-19).

Remdesivir is now indicated for adult or pediatric patients 12 years of age and older weighing at least 40 kilograms for the treatment of COVID-19 requiring hospitalization. Remdesivir is an inhibitor of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RNA-dependent RNA polymerase, an essential component of viral replication. Remdesivir, an adenosine nucleotide prodrug, is metabolized into its active form after being distributed into cells, resulting in delayed chain termination during viral RNA replication.

Approval of remdesivir stemmed from the results of 3 large randomized controlled studies. The largest study was the double-blind, randomized, placebo-controlled ACTT study (NCT04280705).

 The trial enrolled 1062 hospitalized adult patients who met 1 of the following criteria suggestive of lower respiratory tract infection at the time of enrollment: radiographic infiltrates by imaging study, peripheral oxygen saturation (SpO2) less than or equal to 94% on room air, or requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Participants also had to have a laboratory-confirmed SARS-CoV-2 infection as determined by a positive reverse transcription, polymerase-chain-reaction assay result from any respiratory specimen collected less than 72 hours prior to randomization.

 Five hundred and forty-one participants were randomized to receive remdesivir 200 mg intravenously (IV) on day 1 and then 100 mg IV on days 2 through 10, and 521 participants were randomized to receive placebo. 

The primary outcome was the time to recovery based on the first day within the 28 days after treatment initiation that the patient was either not hospitalized or was hospitalized and did not require supplemental oxygen and ongoing medical care (eg, hospitalized for a non-COVID-reason). Participants who received remdesivir had a median time to recovery of 10 days (95% CI, 9-11) compared with 15 days (95% CI, 13-18) in the placebo group (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; 

<.001, by a log-rank test). The Kaplan-Meier estimates of mortality by day 15 were 6.7% with remdesivir and 11.9% with placebo and 11.4% with remdesivir and 15.2% with placebo by day 29 (HR, 0.73; 95% CI, 0.52-1.03).

In the second double-blind, randomized control trial GS-5734 (NCT04292730), standard of care was compared with a 5- and 10-day course of remdesivir in evaluating the clinical status of hospitalized patients. Only the 5-day course of remdesivir was shown to be statistically significant at improving patient’s COVID-19 symptoms compared with standard of care when assessed on day 11.1 The third trial (NCT04292899) compared a 5-day course with a 10-day course of remdesivir in hospitalized patients with severe COVID-19. When patients were evaluated on day 14, no significant difference in recovery and mortality rates between the 2 groups was reported.

In the ACTT trial, the placebo group experienced more adverse effects than the remdesivir group (31.6% vs 24.6%).

 The most common adverse reactions observed with treatment with remdesivir are nausea (5%), increased aspartate aminotransferase (3%), and increased alanine transaminase (ALT) (2%).

 Hepatic lab testing should be performed in all patients before and while receiving remdesivir. Consider discontinuation if ALT levels increase greater than 10 times the upper limit of normal and discontinue if ALT elevation is accompanied by signs or symptoms of liver inflammation. Avoid coadministration with chloroquine phosphate or hydroxychloroquine sulfate as cellular data has shown reduced antiviral activity.

 Other monitoring parameters include testing estimated glomerular filtration rate and prothrombin time before and throughout treatment.

The current dosage recommendation of remdesivir is a 200 mg IV infusion over 30 to 120 minutes on day 1 followed by a daily 100 mg IV infusion on days thereafter.

 For patients only on supplemental oxygen, the recommended duration is 5 days compared with patients on mechanical ventilation or extracorporeal membrane oxygenation where the recommended duration is 10 days.

Lisa Holle, PharmD, BCOP, FHOPA, FISOPP is an associate clinical professor at UConn School of Pharmacy.

Ryan Nolan is a 2021 PharmD Candidate at UConn School of Pharmacy.

1. FDA Approves First Treatment for COVID-19. Press release. FDA; October 22, 2020. Accessed November 19, 2020. 

https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19

2. Veklury. Prescribing information. Gilead; 2020. Accessed November 19, 2020. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214787Orig1s000lbl.pdf

3. Beigel JH, Tomashek KM, Dodd LE. Remdesivir for the treatment of Covid-19 – Final Report. 