The combination of pomalidomide and low-dose dexamethasone shows encouraging efficacy in patients with relapsed or refractory multiple myeloma, according to a study now online ahead of print in Blood (doi: 10.1182/blood-2013-11-538835).
“This is an exquisitely vulnerable population,” explained lead author Paul G. Richardson, MD, Clinical Program Leader and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Center and the R.J. Corman Professor of Medicine at Harvard Medical School.
All patients in the study had become refractory to lenalidomide, many were also refractory to bortezomib, and some had become resistant to carfilzomib. “In this context, pomalidomide plus dexamethasone proved to a very attractive and well-tolerated option,” he said.
Asked for his opinion, Elias J. Anaissie, MD, Director of Hematologic Malignancies in the Bone Marrow Transplant Program and Professor and the John & Gladys Strauss Endowed Chair in Cancer Research at the University of Cincinnati Cancer Institute, said that overall, the study data “do not represent a breakthrough, but rather, significant incremental progress in multiple myeloma for patients who have failed prior lines of therapy,” commented Elias J. Anaissie, MD, Director of Hematologic Malignancies in the Bone Marrow Transplant Program and Professor and the John & Gladys Strauss Endowed Chair in Cancer Research at the University of Cincinnati Cancer Institute.
The 221 patients (median age of 63) in the multicenter, open-label, randomized Phase II trial were followed for a median of 14.2 months. The median number of prior therapies was five; all patients had previously received lenalidomide and bortezomib, 99 percent had taken dexamethasone, 67 percent had received thalidomide, 23 percent had received carfilzomib, and 75 percent had undergone stem cell transplant. Sixty-two percent of patients were refractory to both lenalidomide and bortezomib.
A total of 113 patients received pomalidomide at 4 mg/day with low-dose dexamethasone at 40 mg per week, and 108 individuals received pomalidomide alone. Patients taking pomalidomide alone and who had disease progression were allowed to add low-dose dexamethasone to their regimen.
The median progression-free survival (PFS) time was 4.2 months in the pomalidomide-plus-dexamethasone group versus 2.7 months for patients receiving pomalidomide alone; median overall survival was 16.5 and 13.7 months, respectively. Overall response rates (ORR)—defined as at least a partial response—were 33 and 18 percent, respectively.
The complete response (CR) rate was three percent in the pomalidomide-plus-dexamethasone group and two percent in the pomalidomide-alone patients. The median times to response for the patients receiving the combination and those receiving pomalidomide alone were 1.9 and 4.3 months, respectively. Additionally, the median duration of response in patients with a partial response or better was 8.3 and 10.7 months, respectively.
In 30 patients taking pomalidomide and dexamethasone who had a t(4;14) translocation with or without a 17p deletion, median PFS was 3.1 months, ORR was 23 percent, and median response was 4.9 months. Response to the combination regimen was similar between age groups – namely, patients 65 and younger and those over age 65.
Being refractory to lenalidomide or to lenalidomide with bortezomib did not affect the outcomes of patients taking pomalidomide with low-dose dexamethasone. Median PFS was 3.8 months in both groups of refractory individuals, while the ORR was 30 percent in lenalidomide-refractory patients and 31 percent in lenalidomide with bortezomib-refractory individuals, and median overall survival was 16 and 13.4 months, respectively.
Those who had lenalidomide as their last prior therapy responded well, as did those with prior carfilzomib, Richardson noted. He added, however, that conclusions drawn about the carfilzomib-exposed patients should be considered preliminary because of the relatively small numbers of patients. In the same context, three of five patients with extramedullary disease responded to pomalidomide and dexamethasone.
A total of 219 patients received at least one dose of the study drug and were included in the safety population. Neutropenia was the most common grade 3-4 adverse event, occurring in 41 percent of patients receiving the combination therapy and in 48 percent of those taking pomalidomide alone, while the incidence of grade 3-4 febrile neutropenia was three and five percent in the two groups, respectively.
The most common grade 3-4 non-hematologic adverse event was pneumonia, occurring in 22 percent of patients in the combination group and 15 percent in the single-agent group.
Any grade of deep-vein thrombosis (DVT) was rare, occurring in about two percent of the combination group and three percent of the pomalidomide-alone group. There was no grade 3 or 4 peripheral neuropathy.
Asked for his opinion, Vivek Khemka, MD, MBA, FACP, a medical oncologist at Cancer Treatment Centers of America, Western Regional Medical Center, cautioned that while the results are encouraging, the study was an open-label design, meaning that there is the possibility of a bias in PFS assessment. In addition, 60 percent of patients assigned to pomalidomide received the combination at signs of progression, making it difficult to isolate the effect of pomalidomide alone.
Also commenting, Joshua Richter, MD, a myeloma specialist at John Theurer Cancer Center in Hackensack, NJ, said that overall, the combination is an important addition to the current myeloma drug arsenal because the efficacy was not affected by prior therapies. “Additionally, because it is an oral regimen, there are benefits for patients who don't want to go to their doctor multiple times a week for treatment.”
Another point to consider, he said, is that pomalidomide can also be given at full dose to patients with creatinine levels as high as 3.0 mg/dL—“This allows for safe effective dosing even for patients who have significant renal compromise.”
When considering the median progression-free survival in patients who took both agents, “you would think [the results show that] the drug combination is kind of disappointing,” noted Jason Valent, MD, a multiple myeloma specialist in the Department of Hematologic Oncology and Blood Disorders at Cleveland Clinic and a member of the speaker's bureau for Celgene. However, the most important factor to consider is overall response in the combined-therapy group, which was “quite good in this patient population.”
Richardson and his coauthors also point out that the average life expectancy of patients with disease progression on lenalidomide and bortezomib is only about nine months, based on registry data, regardless of available treatment options. In this study, though, overall survival was 16.5 months–“not a trivial difference,” Valent said. “You will certainly have patients who will live longer, because those are median numbers. It's a dramatic improvement.”
Valent added that anecdotally, he has treated several patients with pomalidomide and has seen one experience what he deemed a ‘miraculous’ response—It's very encouraging when you see things like that.”
Another point to consider is that pomalidomide is the most potent immunomodulator studied to date, said Richardson: “It's more active than thalidomide and lenalidomide preclinically, and it's very encouraging that it works clinically when these drugs have failed.”
Moreover, he added, while pomalidomide synergizes with low-dose dexamethasone, additional research has also shown that pomalidomide results in substantial efficacy when combined with proteasome inhibitors like bortezomib and carfilzomib.
Side Effects Treatable
Tolerability is another important factor to consider when treating these patients, Richardson said. “Combined pomalidomide and low-dose dexamethasone had a side-effect profile that proved generally manageable and was broadly predictable. It appears to be better tolerated than thalidomide overall, and seems often better tolerated than lenalidomide, which can be associated with muscle cramping and diarrhea.”
There was no grade 3 or 4 peripheral neuropathy; the rates of deep vein thrombosis were low with appropriate prophylaxis—and toxicities, which included fatigue and myelosuppression, proved manageable, he added.
Valent noted that neutropenia and thrombocytopenia are common side effects associated with pomalidomide, especially in heavily pretreated patients, and while they are not unique to this drug, the problems may be more pronounced. Fatigue is another common side effect, he said.
Neutropenia can be managed with a dose reduction or with the use of granulocyte colony-stimulating factors. Thrombocytopenia can be addressed with platelet transfusions or dose reductions.
“Fatigue is the one thing that is difficult to mange,” he said. “Usually, patients take the medication in the evening with the hope that fatigue will wear off by the next morning, but it is a significant problem.”
Anaissie said one drawback of the combination is that it resulted in more cases of pneumonia than use of pomalidomide alone did. However, this problem can be addressed with the use of prophylactic antibacterial antibiotics.
Richardson called the rates of pneumonia typical for this population and said that use of steroids would be a contributing factor.
Richter said he hopes that Phase III trial results will demonstrate that the combination of pomalidomide and dexamethasone is highly active. The availability of multiple drugs in various classes has led to progressively more combinatorial options for management of relapsing disease, he said.
Further research will likely evaluate the tolerability and effectiveness of sequential regimens and combinations with pomalidomide, Khemka said. “Overall, the outlook for multiple myeloma keeps improving, with newer drugs becoming available, in terms of both survival and quality of life.”
If an oral drug is effective and well tolerated, it has the potential to become “an important partner with other key therapeutic backbone agents, such as proteasome inhibitors,” Richardson said. Researchers are also learning that pomalidomide is active with other agents such as approved chemotherapies like cyclophosphamide and in combination with newer, next-generation novel agents that are now in development.