Results from a Phase 1b clinical trial indicate that Kyprolis in com­bi­na­tion with Revlimid and low-dose dexa­meth­a­sone is effective and safe for re­lapsed multiple myeloma patients.

Moreover, at the higher doses of Kyprolis and Revlimid tested during the trial, a greater share of patients responded to treat­ment than was the case in a trial testing Revlimid, Velcade, and dexa­meth­a­sone in a similar patient population.

In addi­tion, noticeably fewer cases of periph­eral neu­rop­athy – that is, pain, tingling, or loss of sensation in the extremities – were observed in the current study in comparison to the Revlimid, Velcade, and dexa­metha­sone trial.

Based on the results of this study, the Kyprolis-Revlimid-dexamethasone com­bi­na­tion is being tested further in ongoing Phase 2 and Phase 3 clinical trials.

Background

Prior clinical studies have shown that com­bi­na­tion ther­a­pies including a proteasome inhibitor – such as Velcade ^[1] (bor­tez­o­mib) – and an immuno­modu­la­tory agent – such as Revlimid ^[2] (lena­lido­mide), or thalidomide ^[3] (Thalomid) – are effective in myeloma patients with advanced disease.

For example, in a Phase 2 study of Revlimid, Velcade, and dexamethasone ^[4] (Decadron), 64 per­cent of re­lapsed and/or refractory myeloma patients achieved at least a partial response (see related confer­ence abstract ^[5]).

However, this three-drug com­bi­na­tion also was asso­ci­ated with a high rate of periph­eral neu­rop­athy (64 per­cent).

Kyprolis ^[6] (car­filz­o­mib) belongs to the same class of drugs as Velcade. In July, Kyprolis was approved 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 ^[7] news).

As a single agent, Kyprolis has dem­onstrated efficacy and tolerability in re­lapsed and refractory myeloma patients (see related Beacon ^[8] news). Furthermore, patients treated with Kyprolis do not typically experience much periph­eral neu­rop­athy.

According to the lead author of the current study, Dr. Ruben Niesvizky of the Cornell Weill Medical College, “The value of Kyprolis is its low incidence of dose-limiting side effects that allows for longer duration of treat­ment.”

Based on these pre­vi­ous studies, the current Phase 1b study was designed to assess the efficacy and safety of Kyprolis in com­bi­na­tion with Revlimid and dexa­meth­a­sone in re­lapsed and/or progressing myeloma patients.

Study Design

The current study was conducted at multiple research centers in the United States.  It included 40 myeloma patients who enrolled in the study between June 2008 and November 2012.

The median patient age was 62 years, and the median time since diag­nosis was 3.3 years. All patients had received one to three prior treat­ment regi­mens, with the majority receiving two or more prior lines of ther­apy.

Overall, 75 per­cent of study participants had pre­vi­ously been treated with, and 15 per­cent did not respond to, Velcade.  Additionally, 70 per­cent had pre­vi­ously been treated with, and 25 per­cent did not respond to, Revlimid.

A total of six different dosing regi­mens were tested during the trial, with each patient receiving one of the six regi­mens.  All regi­mens involved a 28-day cycle.

Across the six regi­mens, doses for the three drugs ranged as follows: Kyprolis - between 15 mg/m² to 27 mg/m² intravenously on days 1, 2, 8, 9, 15, and 16 (and days 1, 2, 15, and 16 after cycle 12);  Revlimid - between 10 mg to 25 mg on days 1 to 21; and dexa­meth­a­sone - 40 mg on days 1, 8, 15, and 22.

Results

Patients underwent a median of 8.5 cycles of treat­ment with Kyprolis, Revlimid, and dexa­meth­a­sone.

Overall, 62 per­cent of the study participants responded to the com­bi­na­tion ther­apy, with 2 per­cent achieving a complete response, 32 per­cent a very good partial response, and 28 per­cent a partial response.

Among the patients treated with the two highest dosing regi­mens, the over­all response rate was 79 per­cent.

The median pro­gres­sion-free survival time across all patients was 10.2 months.  No over­all survival times were reported.

Common side effects of all severities included fatigue (62 per­cent), low white blood cell counts (55 per­cent), diarrhea (52 per­cent), low red blood cell counts (48 per­cent), cough (42 per­cent), and low platelet counts (40 per­cent).

The most common severe side effects were low platelet counts (32 per­cent), low lymphocyte counts (28 per­cent), and high blood sugar (22 per­cent).  Ten per­cent of the patients dis­con­tinued treat­ment due to side effects.  There were no treat­ment-related deaths.

In total, 10 per­cent of patients in the trial reported mild to mod­er­ate periph­eral neu­rop­athy; all of these patients had a prior history of periph­eral neu­rop­athy.

All dose com­bi­na­tions tested were tolerated.  Therefore, the highest tested com­bi­na­tion of doses (27 mg/m² of Kyprolis, 25 mg of Revlimid, and 40 mg of dexa­meth­a­sone) is being further studied in a Phase 2 trial and a Phase 3 trial that are ongoing.

“We are awaiting the final results of the Phase 2 trial. Once these mature, we will know more about the safety and efficacy of the regi­men. A [Phase 3] ran­domized trial comparing Kyprolis-Revlimid-dexamethasone versus Revlimid-dexamethasone is underway,” said Dr. Niesvizky.

Comparison Of Results With Those From Other Trials

As has already been indicated, the current trial is not the first to test a three-drug regi­men in myeloma patients with 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 ^[9] (poma­lido­mide), Velcade, and dexa­meth­a­sone (PVd), has been carried out in similar patients, as has a Phase 2 trial of elotuzumab ^[10], 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, at the higher doses tested during the trial, may have a higher response rate with noticeably lower levels of periph­eral neu­rop­athy.

The over­all response rate across all patients in the PVd trial was 73 per­cent, and 27 per­cent of the patients in that trial reported some degree of periph­eral neu­rop­athy (see related Beacon ^[11] news).

The PVd response rate is higher than the response rate seen across all patients in the current Kyprolis-Revlimid-dexamethasone study (62 per­cent).  However, the PVd regi­men also seems to be accompanied by more periph­eral neu­rop­athy (27 per­cent versus 10 per­cent).

Finally, the over­all response rate in the elotuzumab, Revlimid, and dexa­meth­a­sone trial was 92 per­cent for the preferred dose, with no reported cases of periph­eral neu­rop­athy (see related Beacon ^[12] news). However, this trial involved a drug (elotuzumab) which 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 trials.

For more in­­for­ma­tion regarding the Kyprolis, Revlimid, and dexa­meth­a­sone study, please see related journal article in Clinical Cancer Research ^[13] (abstract).