On Friday, the U.S. Food and Drug Administration (FDA) approved Pomalyst ^[1] (pomalidomide ^[2]) for the treatment of multiple myeloma patients who have received at least two prior therapies (see related Beacon ^[3] news).

In this article, The Beacon addresses important questions multiple myeloma patients have been asking about the FDA decision.  The article is organized similarly to one the Beacon ^[4] published about Kyprolis ^[5] (carfilzomib) after it was approved by the FDA last summer.

What exactly did the FDA approve?

The FDA last Friday approved Pomalyst for the treatment of certain multiple myeloma patients.  These patients must have received at least two prior therapies, including Revlimid ^[6] (lenalidomide) and Velcade ^[7] (bortezomib), and the patients must have demonstrated disease progression on or within 60 days of completing their last therapy.

The last requirement means that, to be treated with Pomalyst, myeloma patients must be refractory (no longer responding) to an ongoing current therapy, or to a therapy that was stopped within the last 60 days.

The FDA approval does not require Pomalyst to be used in combination with dexamethasone ^[9] (Decadron).

What impact will the FDA decision have on myeloma patients in the United States?

Prior to the FDA decision, treatment with Pomalyst was only available through participation in a clinical trial, or through an expanded access program offered by Celgene (NASDAQ: CELG), the company that developed and will market Pomalyst, for patients who had no other available treatment options.

Now that Pomalyst has been approved by the FDA, physicians will be able to prescribe Pomalyst to myeloma patients throughout the U.S. without any clinical trial participation requirement.

Although Pomalyst has been approved by the FDA for a specific set of myeloma patients, once a drug is approved in the U.S., physicians have substantial freedom to prescribe the drug as they deem appropriate.  However, Medicare, Medicaid, and private insurance companies may decide to restrict reimbursement of Pomalyst treatment to patients meeting the FDA criteria described above.

How does Pomalyst work?

Pomalyst is an immunomodulatory agent, meaning that it works by inducing a patient’s immune system to attack and destroy myeloma cells. It belongs to the same class of drugs as thalidomide ^[10] (Thalomid) and Revlimid.  All three of these drugs are administered orally.

Pomalyst is also being studied as a potential new treatment for myelo­fibrosis, a disorder of the bone marrow in which the marrow is replaced by scar (fibrous) tissue.

How is Pomalyst pronounced?

POM-ah-list

When will Pomalyst be available?

Pomalyst will be available on the U.S. market in a week to ten days.

What is the recommended dosing for Pomalyst?

Pomalyst’s recommended dosing is 4 mg per day taken orally on days 1 to 21 of repeated 28-day cycles until disease progression.  Pomalyst is available as a capsule in four different doses: 1 mg, 2 mg, 3 mg, and 4 mg.

How effective is Pomalyst?

Pomalyst’s FDA approval is based on data from the Phase 2 “MM-002 ^[11]” clinical trial of Pomalyst plus dexamethasone compared to Pomalyst alone in relapsed and refractory myeloma patients.

Among myeloma patients treated with a median of five previous lines of therapy, 29 percent of those treated with Pomalyst plus dexamethasone achieved a partial response or better, compared to 7 percent of those treated with Pomalyst alone.

The median duration of response was 7.4 months for those who received Pomalyst plus dexamethasone and not yet reached for those who received Pomalyst alone.

Additional results from this study were presented at the American Society of Hematology (ASH) meeting in December (see related Beacon ^[12] news); however, these findings have not been approved by the FDA for inclusion in the official Pomalyst prescribing information, and they do sometimes differ from the results in the prescribing information.

Nevertheless, the ASH presentation indicated that the median progression-free survival was 4.6 months for the Pomalyst plus dexamethasone group and 2.6 months for the Pomalyst alone group.

The ASH results also indicated that the median overall survival was 16.5 months for the Pomalyst plus dexamethasone group and 13.6 months for the Pomalyst alone group.

What are the side effects of Pomalyst?

The most common side effects of Pomalyst of any degree, moderate or severe, listed in its prescribing information are: fatigue and loss of strength, low white blood cell counts, low red blood cell counts, constipation, nausea, diarrhea, difficulty breathing, upper respiratory tract infections, back pain, and fever.  These side effects occurred in at least 30 percent of patients treated with Pomalyst in the MM-002 clinical trial.

Other less common side effects of Pomalyst include dizziness, confusion, and peripheral neuropathy (pain, tingling, or loss of sensation in the extremities).

The prescribing information for Pomalyst also includes a warning that low white blood cell counts is the most common severe side effect of Pomalyst, and it advises that patients should be monitored for blood count-related side effects, particularly low white blood cell counts.

Pomalyst’s prescribing information also contains several so-called "black box" warnings.

The first warning is that Pomalyst is a chemical analogue of thalidomide, which is known to cause birth defects in embryos exposed to the drug via either parent.  The warning states that women who might be able to get pregnant while taking Pomalyst must confirm that they are not pregnant prior to starting treatment, and that both men and women taking Pomalyst must comply with contraception requirements.

Due to the risk of severe birth defects in embryos exposed to Pomalyst, the drug is only available through a program called Pomalyst REMS.  This program is similar to the Revlimid REMS program for Revlimid.

The second black box warning is that patients treated with Pomalyst are at risk of developing blood clots in the veins and lungs.  The warning states that physicians should consider prescribing along with Pomalyst a treatment to prevent blood clots.

How much will Pomalyst cost?

Pomalyst will cost about $10,500 per 28-day cycle, based on a 21-out-of-28-day dosing regimen.

At that price, Pomalyst will be the most expensive treatment for multiple myeloma.

In comparison, Revlimid costs $8,400 per 28-day period at the FDA-approved 21-out-of-28-day dosing; Velcade costs between $4,100 and $8,200 per 28-day period, depending on the frequency of dosing; and Kyprolis costs $10,000 per 28-day cycle at the recommended dose for a patient of average size.

Will Celgene offer a patient assistance program for Pomalyst?

Celgene offers a patient assistance program called Celgene Patient Support ^[13].  It is a service that will help patients and health care professionals facilitate insurance and Medicare coverage of Pomalyst, guide patients through Pomalyst REMS, and help patients apply for copayment assistance or free medication.

What additional testing is the FDA requiring Celgene to complete?

Pomalyst was approved through the FDA’s accelerated approval process, which allowed Celgene to file for approval based on Phase 2 trial data.  Normally, the FDA requires new drug applications to be based on data from more extensive Phase 3 clinical trials.

Therefore, the FDA is requiring Celgene to complete additional Phase 3 trials of the drug, and the FDA will review those results to verify the clinical benefit of Pomalyst.  If these trials confirm the safety and efficacy of Pomalyst, the FDA will grant it a traditional approval.  If not, the FDA could rescind Pomalyst's approval as a treatment for myeloma.

Specifically, Celgene is required to complete a Phase 3 trial, called MM-007 ^[14], to confirm the clinical benefit of Pomalyst.  The study is comparing the combination of Pomalyst, Velcade, and low-dose dexamethasone to Velcade and dexamethasone alone for the treatment of relapsed and refractory myeloma patients.

The company must also complete a study ^[15] to determine the effect of the gene CYP3A on the body’s metabolism of Pomalyst.

In addition, Celgene must conduct several studies to further assess the safety of Pomalyst.

Thus, the FDA is requiring a study in patients treated with Pomalyst to assess the effectiveness of different types of medications to prevent development of blood clots in the vein.

Celgene must also conduct one or more clinical trials to assess the safety of Pomalyst in patients with liver disease, kidney disease, or inhibition of the CYP3A gene.  The company also is required to conduct studies to asses the safety of Pomalyst when used in combination with dexamethasone or in the presence of food that increases the concentration of Pomalyst in the body.  Finally, the company must carry out a study to determine if Pomalyst increases patients’ risk of developing a certain type of heart problem called QT prolongation.

What impact will the FDA decision have on myeloma patients outside the U.S.?

Pomalyst is not currently approved outside of the U.S. and is therefore not available to myeloma patients outside of the U.S. other than through clinical trials.  Currently, only relapsed and refractory myeloma patients are being recruited for Pomalyst trials.

Myeloma patients throughout Europe are still being recruited for a Phase 3 trial, called STRATUS ^[16], which is studying Pomalyst in combination with dexamethasone.  In addition, myeloma patients who have certain chromosomal abnormalities are being recruited for a Phase 2 trial ^[17] of Pomalyst plus dexamethasone that is being conducted in France.

Myeloma patients in Japan are also being recruited for a Phase 1 study ^[18] of pomalidomide alone or in combination with dexamethasone.

Celgene filed an application last June to have Pomalyst approved in Europe, and it expects a decision on that application by the second half of this year.

The European application is drawing on data from two clinical trials: the Phase 2 MM-002 trial, whose data was used for the drug's approval in the U.S.; and an ongoing Phase 3 trial known as MM-003 ^[19].

Interim results from the MM-003 trial were presented at the ASH meeting in December.  They showed that Pomalyst plus low-dose dexamethasone significantly extended the survival of relapsed and refractory myeloma patients compared to high-dose dexamethasone alone (see related Beacon ^[20] news).  Full results from that study are expected to be available this summer.

Both the MM-002 and MM-003 trials involved only relapsed and refractory myeloma patients; no newly diagnosed myeloma patients were enrolled.  Thus, if Pomalyst gains approval in Europe later this year, it will be for the treatment of relapsed and refractory patients only.

This is an important consideration because European physicians generally are limited to prescribing drugs only for their officially approved uses.

For more information, see the Pomalyst prescribing information ^[21] (pdf).