ATLANTA, Georgia — Pomalidomide (Celgene) is the next new drug for multiple myeloma, expected to be approved early in 2013.
An immunomodulatory drug from the same stable as thalidomide (Thalomid, Celgene) and lenalidomide (Revlimid, Celgene), this new drug "is the most active by far," says David Siegel, MD, PhD, chief of multiple myeloma at the John Theurer Cancer Center at Hackensack University Medical Center, in New Jersey.
Pomalidomide is the most potent of the 3, he told Medscape Medical News in an interview here at the American Society of Hematology (ASH) 45th Annual Meeting. It is more potent when measured on the in vitro assay of TNF-alpha inhibition, and it is also more potent clinically, giving "more response for less drug when compared to thalidomide and lenalidomide," he said. Because it is more active, it 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.
Its potent activity means that it can overcome resistance to the other immunomodulatory agents, he continued, and "this is significant." It offers a treatment for those patients who have stopped responding to thalidomide and lenalidomide, he added.
Data showing activity in this resistant patient population, from a trial known as MM-003, will be presented at the meeting on December 11 in a late-breaking abstract by Meletios Dimopoulos, MD, professor and chairman of the Department of Clinical Therapeutics at the Alexandra Hospital in Athens, Greece. He gave a preview of the results at a press briefing held today.
A new drug for patients with resistant and refractory multiple myeloma, carfilzomib (Kyprolis, Onyx Pharmaceuticals), has recently been launched, as reported by Medscape Medical News. This is a new proteasome inhibitor and is administered intravenously, whereas pomalidomide is an immunomodulatory agent and is administered orally.
Activity in Highly Resistant Disease
Great progress has been made in recent years in the treatment of multiple myeloma, Dr. Dimopoulos told journalists; 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, and the best of these currently are bortezomib (Velcade, Millennium) and lenalidomide, he commented.
However, when patients become resistant to these therapies, there is little hope. 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.
Dr. Dimopoulos reported results from a phase 3 study involving 455 such resistant and refractory patients with multiple myeloma, showing that pomalidomide offers hope in this patient population.
In the trial, patients were randomly assigned in a 2:1 ratio to 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 arm, 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 arm. 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 arm (HR = .53; P < .001).
These results led to a discontinuation of the comparator arm, because an independent review by the study's Data Safety Monitoring Board recommended that all patients in the high-dose steroid arm 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% patients on the combination and 15% in the comparator arm), 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 arms 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.
"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 2 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 a different class of drugs is useful; eventually they may be used in combination with each other.
The MM-003 trial was funded by Celgene. Dr. Dimopoulos reports receiving honoraria from Celgene, and several coauthors are company employees. Dr. Siegel is on the speakers' bureaus for Celgene, Onyx, and Millennium.
American Society of Hematology (ASH) 54th Annual Meeting. Abstract LBA-6.
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Cite this: Pomalidomide: The Next New Drug for Multiple Myeloma - Medscape - Dec 09, 2012.