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CME/CE

FDA Approvals: Pomalidomide for Multiple Myeloma

  • Authors: News Author: Zosia Chustecka and Nick Mulcahy
    CME Author: Laurie Barclay, MD
  • CME/CE Released: 3/13/2013
  • THIS ACTIVITY HAS EXPIRED FOR CREDIT
  • Valid for credit through: 3/13/2014, 11:59 PM EST
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Target Audience and Goal Statement

This article is intended for primary care clinicians, pharmacists, oncologists, hematologists, and other specialists who care for patients with multiple myeloma.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  1. Describe the new FDA approval of pomalidomide for use in the treatment of multiple myeloma.
  2. Describe efficacy of pomalidomide for treatment of multiple myeloma.
  3. Describe safety concerns regarding pomalidomide when used in the treatment of multiple myeloma.


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Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.


Author(s)

  • Zosia Chustecka

    Zosia Chustecka is the News Editor for Medscape Oncology. A pharmacology graduate based in London, UK, she has edited and written extensively for publications aimed at clinician audiences. Winner of a 2011 Award for Excellence in Urology Health Reporting for an article on prostate cancer, her work also has been recognized by the British Medical Journalists Association, and recently she was awarded a Harvard University Fellowship on Cancer Genetics (May 2011) as well as a US National Press Foundation Cancer Issues Fellowship (October 2010). She can be reached at [email protected].

    Disclosures

    Disclosure: Zosia Chustecka has disclosed no relevant financial relationships.

  • Nick Mulcahy

    Nick Mulcahy is a senior journalist for Medscape Medical News and covers oncology. He was a recipient of a journalism fellowship from the National Press Foundation in 2010. Formerly, Nick was a freelance medical news reporter for 15 years. His byline appeared on washingtonpost.com, usnews.com, yahoo.com, and many other Web sites. He previously reported for International Medical News Group (Elsevier), MedPage Today, and HealthDay. Nick is also the former managing editor of breastcancer.org. A graduate of the University of Pennsylvania, Nick is based in Philadelphia. He can be contacted at [email protected].

    Disclosures

    Disclosure: Nick Mulcahy has disclosed no relevant financial relationships.

Editor(s)

  • Brande Nicole Martin, MA

    CME Clinical Editor, Medscape, LLC

    Disclosures

    Disclosure: Brande Nicole Martin, MA, has disclosed no relevant financial relationships.

CME Author(s)

  • Laurie Barclay, MD

    Freelance writer and reviewer, Medscape, LLC

    Disclosures

    Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Joi Tisdale

    CME Program Manager, Medscape, LLC

    Disclosures

    Disclosure: Joi Tisdale, has disclosed no relevant financial relationships.


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CME/CE

FDA Approvals: Pomalidomide for Multiple Myeloma

Authors: News Author: Zosia Chustecka and Nick Mulcahy CME Author: Laurie Barclay, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED FOR CREDIT

CME/CE Released: 3/13/2013

Valid for credit through: 3/13/2014, 11:59 PM EST

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Clinical Context

Pomalidomide is an immunomodulatory drug chemically related to thalidomide and lenalidomide but is more active and more potent. It is the second drug approved in the past year to treat multiple myeloma, the first being carfilzomib. The US Food and Drug Administration (FDA) approved both of these drugs under its accelerated approval program.

Compared with thalidomide and lenalidomide, pomalidomide is more potent on the in vitro assay of tumor necrosis factor–alpha inhibition. It can also be used at a much lower dose, which reduces the risk for toxicity, such as peripheral neuropathy and bone marrow suppression.

Study Synopsis and Perspective

The oral therapy pomalidomide (Pomalyst) was approved by the FDA on February 8 for use in the treatment of multiple myeloma.

The new drug is specifically indicated for patients who have received at least 2 prior therapies, including lenalidomide (Revlimid) and bortezomib (Velcade), and whose disease did not respond to treatment and progressed within 60 days of the last treatment.

"Treatment for multiple myeloma is tailored to meet individual patient's needs, and [the] approval provides an additional treatment option for patients who have not responded to other drugs," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, in a press statement.

Pomalidomide is the second drug approved in the past year to treat multiple myeloma, pointed out Dr. Pazdur. Carfilzomib (Kyprolis) was approved in July. Both new drugs were approved under the FDA's accelerated approval program.

Pomalidomide is an immunomodulatory drug from the same stable as thalidomide (Thalomid) and lenalidomide, but this new drug "is the most active by far," said David Siegel, MD, PhD, chief of multiple myeloma at the John Theurer Cancer Center at Hackensack University Medical Center, in New Jersey. He is an investigator of the drug and recently spoke to Medscape Medical News.

Pomalidomide is more potent than the other 2 drugs when measured on the in vitro assay of tumor necrosis factor–alpha inhibition, and more potent clinically, giving "more response for less drug when compared to thalidomide and lenalidomide," he said. Because it is more active, pomalidomide can be used at a much lower dose, which decreases the risk for adverse events, including peripheral neuropathy and bone marrow suppression, he said.

The dose for pomalidomide is 4 mg, compared with 25 mg for lenalidomide and 800 mg for thalidomide, he noted.

The drug's potent activity means that it can overcome resistance to the other immunomodulatory agents. "This is significant," Dr. Siegel said. The new drug offers a treatment for those patients who have stopped responding to thalidomide and lenalidomide, he added.

Pomalidomide safety and effectiveness were evaluated in a clinical trial of 221 patients with relapsed or refractory multiple myeloma in which patients were randomly assigned to receive pomalidomide alone or pomalidomide with low-dose dexamethasone, a corticosteroid.

Results showed that 7.4% of patients treated with pomalidomide alone achieved an objective response rate (ORR), which was the primary outcome. The median duration of response has not yet been reached in these patients. However, in patients treated with pomalidomide with low-dose dexamethasone, 29.2% achieved ORR with a 7.4-month median duration of response.

Common adverse effects include neutropenia, fatigue and weakness, low red anemia, constipation, diarrhea, thrombocytopenia, upper respiratory tract infections, back pain, and fever.

Pomalidomide carries a boxed warning indicating that the drug should not be used in pregnant women because it can cause severe life-threatening birth defects and can cause blood clots.

Because of pomalidomide's embryo-fetal risk, it is available only through a Risk Evaluation and Mitigation Strategy (REMS) program.

Data Presented at ASH

Data from the MM-003 study of pomalidomide were presented in December 2012 at the annual meeting of the American Society of Hematology (ASH) by Meletios Dimopoulos, MD, professor and chairman of the Department of Clinical Therapeutics at the Alexandra Hospital in Athens, Greece.

Dr. Dimopoulos told journalists that great progress has been made in recent years in the treatment of multiple myeloma. The overall survival has increased from around 3 years to more than 10 years, he said. This is largely due to the availability of newer and more active drugs, he said, and treatment usually consists of both an immunomodulatory agent (given orally) and a proteasome inhibitor, which are administered intravenously, such as bortezomib or carfilzomib.

However, when patients become resistant to these therapies, there is little hope, Dr. Dimopoulos said. Once they become resistant to the best of these therapies, including bortezomib and lenalidomide, the prognosis becomes grim — the median overall survival is only about 8 months.

The phase 3 MM-003 study involved 455 such patients with resistant and refractory multiple myeloma, and showed that pomalidomide offers hope in this patient population.

In the trial, patients were randomly assigned in a 2:1 ratio to either a combination of pomalidomide with low-dose dexamethasone (n = 302) or high-dose dexamethasone (n = 153).

Pomalidomide was taken at a dose of 4 mg once daily; it was taken orally on days 1 to 21 in combination with low-dose dexamethasone 20 mg in patients older than 75 years and 40 mg in younger patients, also taken orally, on days 1, 8, 15, and 22.

In the comparator group, dexamethasone was given in the same doses of the steroid, but more frequently, on days 1 to 4, 9 to 12, and 17 to 20 in a 28-day cycle. This is the standard of care, but it is a palliative treatment, and patients often cannot tolerate these high doses of steroids, Dr. Dimopoulos commented.

The results after a median follow-up of 18 months showed a significant increase in progression-free survival, up to 15.7 weeks on the combination of pomalidomide with low-dose steroid vs 8 weeks on the high-dose steroid (hazard ratio [HR], 0.45; P < .001).

Overall survival was also longer in the combination group. Although the median has not yet been reached, it is expected to be around 11 to 12 months, Dr. Dimopoulos said, compared with a median of 35 weeks in the comparator group (HR, 0.53; P < .001).

These results led to a discontinuation of the comparator group, because an independent review by the study's data safety monitoring board recommended that all patients in the high-dose steroid group be switched over to treatment with pomalidomide and low-dose steroid.

The combination was well tolerated, although there were some expected toxicities in both groups, including neutropenia (reported in 42% of patients in the combination group and 15% in the comparator group), thrombocytopenia (21% vs 24%), and fever (7% vs 0%). The primary reason for discontinuation was progressive disease (in 35 vs 49 patients, respectively). Around 25% of patients in both groups died during the study, primarily from progressive disease and infections.

"We are excited about these results, as they show that a combination approach with pomalidomide and low-dose dexamethasone offers superior results to those seen with current treatment options for hard-to-treat myeloma patients," Dr. Dimopoulos commented in a statement at the time.

"We believe this study provides the basis to consider this combination as a new standard of care for patients who have exhausted most standard treatments to treat their refractory disease and may offer even greater benefit if studied among less heavily treated patients as a first-line therapy," he added. Such trials are now in progress, he said.

Asked how pomalidomide compares with the newly launched carfilzomib in the highly resistant multiple myeloma patient population, Dr. Dimopoulos told Medscape Medical News that it was not possible to compare the two because there have not been any head-to-head trials, but he added that both new drugs offer hope of responses in this very hard-to-treat patient population.

Dr. Siegel agreed and added that both new drugs are more active than their predecessors, and the fact that each is in a different class of drugs is useful; eventually they may be used in combination with each other.

More information on the approval of pomalidomide is available on the FDA Web site.

The MM-003 trial was funded by Celgene. Dr. Dimopoulos reports receiving honoraria from Celgene, and several investigators are company employees. Dr. Siegel is on the speakers' bureaus for Celgene, Onyx, and Millennium.

Clinical Implications

  • The FDA has approved pomalidomide for oral administration in the treatment of multiple myeloma in patients who have received at least 2 prior therapies, including lenalidomide and bortezomib, without response to treatment and with disease progression within 60 days of the last treatment. Because of its greater potency, the dose for pomalidomide is 4 mg, which is much lower than that of lenalidomide (25 mg) and thalidomide (800 mg).
  • In a randomized clinical trial of 221 patients with relapsed or refractory multiple myeloma, the ORR was 7.4%, and the median duration of response has not yet been reached in these patients. Among patients treated with pomalidomide and low-dose dexamethasone, 29.2% achieved objective response, and median duration of response was 7.4 months.
  • A boxed warning for pomalidomide indicates that it should not be used in pregnant women because of the risks for severe, potentially fatal birth defects and thrombosis. It is available only through a REMS program because of the embryo-fetal risk. Common adverse effects of pomalidomide include neutropenia, fatigue and weakness, anemia, constipation, diarrhea, thrombocytopenia, upper respiratory tract infections, back pain, and fever.

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