Kyprolis-Revlimid-Dexamethasone Combination Continues To Show Promise For Relapsed Myeloma
Results from a recent Phase 2 trial indicate that the combination of Kyprolis, Revlimid, and dexamethasone is effective in relapsed multiple myeloma patients.
Specifically, the results show that 77 percent of patients responded to the treatment. The investigators point out the responses seen in the trial were rapid (median time to response was one month) and robust (median duration of response was 22 months).
According to the investigators, the results are particularly encouraging because one-quarter of the patients were refractory (resistant) to Velcade (bortezomib) and almost half were refractory to Revlimid (lenalidomide).
The researchers also note that the side effect profile of the combination was similar to that observed in previous trials. Most of the severe side effects were blood-related. Twenty percent of the patients left the trial due to side effects -- a discontinuation rate the investigators describe as "moderate."
Overall, the investigators describe the efficacy and safety of this three-drug combination as consistent with those of other three-drug combinations involving a proteasome inhibitor, such as Velcade; a immunomodulatory agent, such as Revlimid, thalidomide (Thalomid), or Pomalyst (pomalidomide, Imnovid); and dexamethasone (Decadron) in this patient population.
Based on these findings, the investigators believe that this three-drug combination may be a "compelling" treatment option for relapsed myeloma patients.
The combination is currently being investigated in a Phase 3 trial, which compares the three-drug combination to treatment with Revlimid and dexamethasone.
Kyprolis (carfilzomib) was approved last year by the U.S. Food and Drug Administration for the treatment of multiple myeloma patients who have received at least two prior therapies, including Velcade and an immunomodulatory agent, and who progressed within 60 days of completing their most recent regimen (see related Beacon news).
Kyprolis belongs to the same class of drugs as Velcade, called proteasome inhibitors. It is currently being investigated in combination with other anti-myeloma drugs in both newly diagnosed as well as relapsed and refractory myeloma patients.
Previous studies have shown that triple combination therapies including a proteasome inhibitor and an immunomodulatory agent improve outcomes in myeloma patients with advanced disease, compared to double combination therapies.
For example, in a Phase 2 study of Revlimid, Velcade, and dexamethasone, 64 percent of relapsed and/or refractory myeloma patients achieved at least a partial response (see related conference abstract).
The Phase 2 study enrolled 52 relapsed and refractory multiple myeloma patients at various treatment centers across the United States between June 2008 and February 2010.
The median age of study participants was 63 years, and over one-fifth had high-risk chromosomal abnormalities. The median time since diagnosis was 3.1 years.
The patients had received a median of three prior therapies, including Velcade (81 percent of patients) and Revlimid (73 percent). Approximately half of the patients (56 percent) had also received a stem cell transplant.
Overall, 25 percent of the patients were refractory to Velcade, 44 percent were refractory to Revlimid, and 27 percent had not previously received Revlimid.
The patients received 20 mg/m2 of Kyprolis intravenously on days 1 and 2 of the first treatment cycle. The dose was then increased to 27 mg/m2 on days 8, 9, 15, and 16 of the first treatment cycle and in all subsequent treatment cycles. The patients also received 25 mg of Revlimid per day for 21 days, and 40 mg dexamethasone once a week, during each 28-day treatment cycle.
The median follow-up time was 24 months.
Of the 52 patients, 77 percent responded to treatment, with 4 percent achieving a stringent complete response, 2 percent a complete response, 37 a very good partial response, and 35 percent a partial response.
The median time to response was one month, and the median duration of treatment was 22 months.
Further analysis showed that the overall response was also high among Velcade-refractory and Revlimid-refractory patients.
Of the Velcade-refractory patients, 69 percent responded to treatment for a median of 22 months. Of the Revlimid-refractory patients, 70 percent responded to treatment for a median of 11 months.
As might be expected, the response rate was particularly high among patients who had not previously been treated with Revlimid; 86 percent of these patients responded to the Kyprolis-Revlimid-dexamethasone combination, and the median duration of response had not been reached yet.
The median progression-free survival for all patients was 15.4 months. It was the same for Velcade-refractory patients and 7.9 months for Revlimid-refractory patients. In Revlimid-naïve patients, the median progression-free survival had not yet been reached.
The researchers note, however, that almost all of the patients (94 percent) experienced severe side effects. Most of them were blood-related and included low lymphocyte counts (48 percent), low neutrophil counts (33 percent), low platelet counts (19 percent), and low red blood cell counts (19 percent).
Overall, 27 percent of patients experienced peripheral neuropathy (pain, tingling, or loss of sensation in the extremities), but only 2 percent of the cases were severe.
In addition, 19 percent of the patients experienced heart-related side effects, such as an irregular heartbeat or heart disease.
Ultimately, 20 percent of the patients discontinued treatment due to side effects.
Furthermore, three patients died during treatment; however, progressive disease was determined to be the primary cause of death in these cases.
Comparison Of Results With Other Triplet Combinations For Relapsed Myeloma
Several other trials have investigated three-drug regimens in myeloma patients who have received one to three previous treatment regimens.
For example, in addition to the Phase 2 trial of Revlimid, Velcade, and dexamethasone (RVD) mentioned earlier, a Phase 1 trial of Pomalyst, Velcade, and dexamethasone (PVd), has been carried out in similar patients, as has a Phase 2 trial of elotuzumab, Revlimid, and dexamethasone.
A comparison of the results from the current study to those from the RVD trial suggest that the Kyprolis-Revlimid-dexamethasone combination has a higher response rate with noticeably lower levels of peripheral neuropathy.
In the Pomalyst-Velcade-dexamethasone Phase 1 trial, the overall response rate was 73 percent, and 40 percent of the patients in that trial reported some peripheral neuropathy (see related Beacon news). All patients in this trial, however, had previously been treated with both Revlimid and Velcade at some point. At the same time, the median number of previous therapies in the PVd trial was two, compared to three in the current Kyprolis-Revlimid-dexamethasone trial.
Finally, the overall response rate in the Phase 2 elotuzumab, Revlimid, and dexamethasone trial was 92 percent for the preferred dose, with no reported cases of peripheral neuropathy (see related Beacon news). However, none of the patients in this trial had previously been treated with Revlimid, and trial involved a drug (elotuzumab) that is not yet commercially available
Comparisons across clinical trials always should be made with caution. This is particularly the case for comparisons between Phase 1 and Phase 2 trials. More often than not, response rates seen in Phase 1 trials are lower than those seen in Phase 2 trials, because many of the doses tested in a Phase 1 trial are lower than those eventually used in Phase 2 and Phase 3 trials.
For more information, please refer to the study in the journal Blood (abstract).
- Kyprolis-Revlimid-Dexamethasone Combination Is Effective For Relapsed Myeloma
- Researchers Publish Results Of Revlimid-Velcade-Dexamethasone Trial In Relapsed Multiple Myeloma
- Revlimid-Velcade-Doxil-Dexamethasone Combination May Be Effective And Tolerable In Relapsed/Refractory Myeloma
- Panobinostat-Velcade-Dexamethasone Combination Continues To Show Promise For Heavily Pretreated Myeloma
- Study Confirms Survival Benefit Of Revlimid-Dexamethasone Combo In Elderly Relapsed / Refractory Myeloma Patients