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.

Background

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).

Study Design

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.

Results

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).