SIZE XSSIZE SMSIZE MDSIZE LG

The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.


May 28, 2019–Lenalidomide (REVLIMID®, Celgene Corp.) in combination with a rituximab product for previously treated follicular lymphoma (FL) and previously treated marginal zone lymphoma (MZL).

February 22, 2017–Lenalidomide (Revlimid®, Celgene Corp.) as maintenance therapy for patients with multiple myeloma following autologous stem cell transplant.(With Pharmacist's Applications to Practice)


May 28, 2019

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021880s057lbl.pdf.

On May 28, 2019, the Food and Drug Administration approved lenalidomide (REVLIMID®, Celgene Corp.) in combination with a rituximab product for previously treated follicular lymphoma (FL) and previously treated marginal zone lymphoma (MZL).

Approval was based on two clinical trials: AUGMENT (NCT01938001) and MAGNIFY (NCT01996865). In AUGMENT, 358 patients with relapsed or refractory FL or MZL were randomized (1:1) to receive lenalidomide and rituximab or rituximab and placebo. In the single-arm component of MAGNIFY, 232 patients with relapsed or refractory FL, MZL, or mantle cell lymphoma received 12 induction cycles of lenalidomide and rituximab.

In AUGMENT, the primary endpoint was progression-free survival (PFS) in the intent-to-treat population, as determined by an independent review committee (IRC). Median PFS was 39.4 months (95% CI: 22.9, NE) in the lenalidomide arm and 14.1 months (95% CI: 11.4, 16.7) in the placebo-containing arm (HR 0.46; 95% CI: 0.34, 0.62; p<0.0001). The objective response rate (ORR) by IRC assessment for patients with follicular lymphoma was 80% (118/147; 95% CI: 73%, 86%) in the lenalidomide arm compared with 55.4% (82/148; 95% CI: 47%, 64%) in the control arm. For patients with marginal zone lymphoma, the ORR by IRC assessment was 65% (20/31; 95% CI: 45%, 81%) compared with 44% (14/32; 95% CI: 26%, 62%), respectively.

In MAGNIFY, the ORR by investigator assessment was 59% (104/177; 95% CI: 51%, 66%) for patients with follicular lymphoma. Median response duration was not reached with a median follow-up of 7.9 months (95% CI: 4.6, 9.2). For patients with marginal zone lymphoma, the ORR by investigator assessment was 51% (23/45; 95% CI: 36%, 66%). Median response duration was not reached with a median follow-up of 11.5 months (95% CI: 8.0, 18.9).

Across both trials, the most common adverse reactions occurring in at least 20% of patients were neutropenia, fatigue, diarrhea, constipation, nausea, and cough.

The prescribing information includes a Boxed Warning alerting health care professionals and patients about the risk of embryo-fetal toxicity, hematologic toxicity, and venous and arterial thromboembolism which may be life-threatening or fatal.

The recommended lenalidomide dose for FL or MZL is 20 mg once daily orally on days 1-21 of repeated 28-day cycles for up to 12 cycles.

View full prescribing information for REVLIMID.

FDA granted this application priority review and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.


February 22, 2017 with PAP

http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021880s049lbl.pdf

On February 22, 2017, the U.S. Food and Drug Administration approved lenalidomide (Revlimid®, Celgene Corp.) as maintenance therapy for patients with multiple myeloma following autologous stem cell transplant.

In 2006, lenalidomide, an orally administered thalidomide analogue, received FDA approval for use with dexamethasone in patients with multiple myeloma who received at least one prior therapy. In 2015, the indication was expanded for use in combination with dexamethasone for the treatment of patients with multiple myeloma, to include newly diagnosed multiple myeloma patients who are not eligible for autologous stem cell transplant. Lenalidomide is also approved in myelodysplastic syndromes and mantle cell lymphoma.

The current approval was based on two randomized, controlled trials evaluating the efficacy and safety of lenalidomide maintenance therapy for the treatment of multiple myeloma patients after autologous stem cell transplant (CALGB 100104 and IFM 2005-02 trials). These trials demonstrated approximately a 15-month (CALGB) and 18-month (IFM) progression-free survival advantage, at the time of the primary analysis, in patients treated with lenalidomide compared with patients receiving placebo (hazard ratio (HR) in CALGB=0.38; 95% CI: 0.27, 0.54; p<0.001 and HR in IFM=0.50; 95% CI: 0.39, 0.64; p<0.001). The median overall survival was 111 and 106 months for patients treated with lenalidomide compared with 84 and 88 months for patients receiving placebo in the CALGB and IFM trials, respectively.

The types, frequency, and severity of adverse events (AEs) observed in the two trials were similar to those previously described in the product label. Neutropenia, affecting 56% of the 517 patients treated with lenalidomide in both trials, was the most frequently reported grade 3/4 AE. An increased incidence of second primary malignancies was reported among patients treated with lenalidomide compared with those receiving placebo. The lenalidomide product label notes an increase in second primary malignancies in patients with multiple myeloma treated with lenalidomide.

The recommended dose and schedule for lenalidomide is 10mg once daily continuously on days 1-28 of repeated 28-day cycles.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021880s049lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist's Application to Practice

Lenalidomide (Revlimid) for Maintenance Therapy Following Autologous Stem Cell Transplant

Author: Marissa Olson, PharmD
PGY-2 Oncology Pharmacy Resident
Barnes-Jewish Hospital
Saint Louis, MO

What is the potential role for lenalidomide in the management of multiple myeloma?1-6

  • Lenalidomide maintenance therapy following autologous stem cell transplant is a strategy for improving disease-free survival in multiple myeloma patients. Current treatment for multiple myeloma includes induction therapy, followed by autologous stem cell transplant in eligible patients to improve outcomes. Unfortunately, most patients will eventually have disease recurrence or progression.
  • Maintenance strategies have been employed in the past in an attempt to improve outcomes following autologous stem cell transplant. Interferon and thalidomide have been used but are limited by their significant toxicities and conflicting reports on disease-free and overall survival (OS) benefits.
  • Lenalidomide is an orally available analog of thalidomide with less toxic and more potent effects than the parent compound. Treatment with lenalidomide following autologous stem cell transplant has been shown to result in a statistically significant improvement in progression-free survival (PFS) compared to placebo in two separate randomized, controlled studies, including CALGB 100104 (conducted by McCarthy et al.) and IFM 2005-02 (conducted by Attal, Lauwers-Cances, et al.).2 However, neither of these studies was powered for an OS end point.
  • An updated analysis of the CALGB 100104 data demonstrated a median PFS of 68.6 months with lenalidomide, versus 22.5 months with placebo, for a hazard ratio (HR) of 0.38 (95% confidence interval [CI], 0.28–0.5).
  • In an updated analysis of the IFM 2005-02 data, lenalidomide maintenance resulted in a median PFS of 46.3 months, versus 23.8 months with placebo, for an HR of 0.53 (95% CI, 0.44–0.64).
  • A recent abstract of a meta-analysis was presented at the 2016 American Society of Clinical Oncology Annual Meeting. This analysis included the CALGB 100104, IFM 2005-02, and GIMEMA RV-209 studies. An OS benefit was demonstrated in post–autologous stem cell transplant patients on lenalidomide maintenance versus placebo or no maintenance. The median OS for lenalidomide was not reached, versus 86 months with placebo or no maintenance, resulting in an HR of 0.74 (95% CI, 0.62–0.89). A benefit with lenalidomide was reported regardless of response obtained post–autologous stem cell transplant (complete response, very good partial response, and less than very good partial response).
  • Maintenance therapy will continue to be a heavily studied area of multiple myeloma treatment. Other agents that are currently used or that are being explored include pomalidomide, another immunomodulatory agent; proteasome inhibitors such as bortezomib, ixazomib, and carfilzomib; and the anti-CD38 monoclonal antibody daratumumab.

What role can the pharmacist play in the management of patients on lenalidomide?1

  • When prescribed as post–autologous stem cell transplant maintenance, lenalidomide is dosed at 10 mg by mouth once daily with or without food given continuously in 28-day cycles, and it is continued until disease progression or a level of unacceptable toxicity. The dose may be increased to 15 mg daily after three cycles if well tolerated.
  • Because lenalidomide is an analog of thalidomide, it has the potential to cause significant embryo-fetal toxicity. A risk evaluation and mitigation strategy (REMS) program exists to prevent embryo-fetal exposure and increase awareness of the potential risks.
    • Prior to dispensing, patients and prescribers must complete the patient and prescriber agreement form to be enrolled in the REMS program. Counseling should be performed, and each patient is to complete a mandatory patient survey.
    • Pregnancy must be excluded prior to treatment, and women of child-bearing potential must use two reliable forms of contraception while on therapy and for at least 4 weeks after discontinuation of the drug. Pregnancy tests must be performed at REMS program–specified frequencies.
    • Males should be instructed to use latex or synthetic condoms during sexual contact with women of child-bearing potential during treatment and for at least 4 weeks after discontinuation of therapy.
  • Antithrombotic prophylaxis should be considered in patients on lenalidomide maintenance therapy. McCarthy et al. used antithrombotic prophylaxis with aspirin or low-molecular-weight heparin in patients at a high risk of deep vein thrombosis and pulmonary embolism on lenalidomide maintenance therapy.3
  • Dosage reductions are recommended for renal dysfunction, thrombocytopenia, and neutropenia.
  • Lenalidomide may cause nausea and vomiting; however, antiemetic prophylaxis is not routinely recommended.

Clinical Pearls1-7

  • Standard dosing for lenalidomide in the frontline setting for multiple myeloma is 25 mg daily for 21 days of a 28-day cycle in combination with dexamethasone. However, when used as maintenance therapy, lenalidomide is dosed at 10 mg daily for 28 days of a 28-day cycle without dexamethasone. An alternative, non-FDA-approved dosing strategy for maintenance therapy is 10 mg daily for 21 days of a 28-day treatment cycle.
  • Lenalidomide maintenance should be initiated within the first 3 months post–autologous stem cell transplant after hematologic recovery has been achieved, which is defined as an absolute neutrophil count of >1,000/mm3 and a platelet count >75,000/mm3. There is no association between time to initiation of therapy and outcomes.
  • Patients are to continue maintenance until disease progression or an intolerable level of side effects. However, the optimal duration of therapy is unclear.
  • The use of lenalidomide maintenance therapy is associated with an increased risk of secondary malignancies, but it is generally recognized that the benefits of treatment outweigh this risk in most cases.

References

  1. Revlimid (Lenalidomide) [package insert]. Summit, NJ: Celgene; February 2017.
  2. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366(16):1782-91.
  3. McCarthy P, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366(19):1770-81.
  4. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 2014;371(10):895-905.
  5. Multiple Myeloma. Version 3.2017. National Comprehensive Cancer Network. Retrieved from: https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed April 2, 2017.
  6. Mellqvist UH, Gimsing, P, Hjertner O, et al. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood 2013;121:4647-54.
  7. Attal M, Palumbo A, Holstein SA, et al. Lenalidomide (LEN) maintenance (MNTC) after high-dose melphalan and autologous stem cell transplant (ASCT) in multiple myeloma: a meta-analysis (MA) of overall survival (OS). J Clin Oncol 2016;34(suppl; abstr 8001).

 

xs
sm
md
lg