The results of a small Phase 1/2 clinical trial suggest that a com­bi­na­tion of Farydak and high-dose Kyprolis is effective as a treat­ment for re­lapsed multiple myeloma.

Participants in the trial were heavily pretreated, having had a median of five pre­vi­ous myeloma ther­a­pies. More than 70 per­cent of the patients, however, had at least a partial re­sponse to the trial regi­men at the target doses established during the trial’s first phase. The esti­mated two-year over­all survival rate among the patients was 67 per­cent.

A response rate of more than 70 per­cent is high for a myeloma ther­apy given to patients who have had five pre­vi­ous myeloma treat­ments. It is particularly noteworthy given that neither dexa­meth­a­sone nor pred­ni­sone was included in the tested treat­ment regi­men. Had one of those commonly used steroids been added to the trial regi­men, the response rate could well have been even higher.

The com­bi­na­tion of Farydak ^[1] and Kyprolis ^[2] was not easy, however, for patients to tolerate. As has occurred in pre­vi­ous trials that have tested treat­ment regi­mens containing Farydak, many patients in the current study experienced gastro­in­tes­ti­nal side effects.

In addi­tion, several patients in the trial experienced severe heart-related side effects, including one instance of heart failure that was fatal. These results are likely to be noted by physicians (and patients) concerned about the possibility of heart-related side effects during treat­ment with Kyprolis.

That said, the current study does appear to con­firm that adding Farydak to high-dose Kyprolis leads to a more effective treat­ment regi­men for re­lapsed myeloma than high-dose Kyprolis alone. A useful comparator for the current study is one that was done with a similar group of re­lapsed myeloma patients, using just high-dose Kyprolis and – in some cases – dexa­meth­a­sone (see related article ^[3] in the journal Blood).  In that study, 55 per­cent of the patients had a partial response or better to the treat­ment regi­men, as compared to 72 per­cent in the current study.

Background

Until treat­ment regi­mens are found that can routinely cure multiple myeloma, the key to extending the survival of a myeloma patients after their diag­nosis is finding new myeloma ther­a­pies – particularly ther­a­pies that are effective at relapse.

Kyprolis (car­filz­o­mib) was approved by the U.S. Food and Drug Administration (FDA) in 2012 as a new treat­ment for re­lapsed multiple myeloma (see related Beacon ^[4] news). It is admin­istered by infusion, and it belongs to the same class of drugs, known as proteasome inhibitors, that includes Velcade ^[5] (bor­tez­o­mib).

Since its FDA approval, Kyprolis has become an important option in the U.S. for the treat­ment of re­lapsed multiple myeloma. In that setting, it often is used in com­bi­na­tion with dexamethasone ^[6] (Decadron) and an immuno­modu­la­tory drug such as Revlimid ^[7] (lena­lido­mide) or Pomalyst ^[8] (poma­lido­mide, Imnovid).

Farydak was just recently approved by the FDA as yet another option for the treat­ment of re­lapsed multiple myeloma (see related Beacon ^[9] news). Farydak is an orally admin­istered drug that belongs to a class of drugs called histone deacetylase (HDAC) inhibitors.

Farydak’s approval is for use in com­bi­na­tion with Velcade and dexa­meth­a­sone. However, research indicates that the drug, in general, augments the ability of proteasome inhibitors such as Velcade and Kyprolis to combat myeloma.

The authors of the current study therefore decided to test how well the com­bi­na­tion of Farydak and Kyprolis works as a treat­ment for re­lapsed myeloma.

At least two other trials have in­ves­ti­gated the com­bi­na­tion of Farydak and Kyrpolis in re­lapsed myeloma patients. The current study is different from those studies, however, in that it uses a dosing schedule for Farydak that is different than the FDA-approved schedule.  The different dosing schedule was used to make it more compatible with the Kyprolis dosing schedule, and to (potentially) reduce some of the side effects seen in other studies that in­ves­ti­gated Farydak as a myeloma ther­apy.

Study Design

Between January 2012 and April 2013, researchers at multiple treat­ment centers in the United States re­cruited 44 re­lapsed / refractory multiple myeloma patients for par­tic­i­pation in the trial.  A total of 13 patients par­tic­i­pated in the Phase 1 part of the trial and 31 in the Phase 2 part of the trial.  Median patient age was 66.

Although trial participants were required to have just one prior myeloma ther­apy to par­tic­i­pate in the trial, the median number of pre­vi­ous ther­a­pies among the 44 patients was five.

Eighty-nine per­cent of the patients had pre­vi­ously received Velcade, and 89 per­cent had received treat­ment with a drug in the immuno­modu­la­tory class of ther­a­pies, which includes thalidomide ^[10] (Thalomid), Revlimid, and Pomalyst.  About half of the patients (52 per­cent) pre­vi­ously had received a stem cell trans­plant.

The Farydak dosing schedule used during the trial was different than the FDA-approved dosing schedule, which is 20 mg of Farydak given three times per week for two weeks, followed by a one-week break.

In the current study, Farydak was dosed three times a week every other week.  This allowed treat­ment to overlap well with the usual three-weeks on / one-week off treat­ment schedule for Kyprolis.  It also gave a one week break between weeks of Farydak treat­ment, which might make the drug easier for patients to tolerate.

The Phase 1 part of the trial was designed to establish the target dose to be used in the Phase 2 part of the trial.  Thus, during Phase 1, patients received between 20 mg and 30 mg of Farydak on days 1, 3, 5, 15, 17 and 19 of the 28-day cycle.

Also during Phase 1, patients received 20 mg/m² of Kyprolis on days 1 and 2 of the first treat­ment cycle, after which the Kyprolis dose was increased to between 27 mg/m² and 45 mg/m² on days 8, 9, 15, and 16 in the first cycle and days 1, 2, 8, 9 15, and 16 in sub­se­quent cycles.

In the Phase 2 part of the trial, all patients received 30 mg of Farydak and 20/45 mg/m² of Kyprolis.

For both drugs, these Phase 2 doses are higher than the FDA-approved dosing, although only slightly so for Farydak.  The Phase 2 dosing results in 180 mg of Farydak being admin­istered during each four-week period, compared to 160 mg during an average four-week period at the FDA-approved Farydak dose.

The Kyprolis Phase 2 dosing, on the other hand, is noticeably more than the FDA-approved dosing of the drug, which is 20 mg/m² twice weekly for three out of four weeks during the first cycle, and then 27 mg/m² (if tolerated) in later cycles.

Study Results: Efficacy

Among the patients who received the Phase 2 doses of the drugs, 72 per­cent had at least a partial response to treat­ment, with 38 per­cent achieving a very good partial response or better.

In addi­tion to the 72 per­cent who had at least a partial response to the two-drug regi­men, another 16 per­cent had a minor response to treat­ment, and 6 per­cent had stable disease for at least a short time while on treat­ment.

With a median follow-up time of 17 months for all evaluable patients, the median pro­gres­sion-free survival was 7.7 months and the median over­all survival has not been reached yet. The two-year over­all survival was 67 per­cent.

Response rates were similar across all patients regardless of whether they pre­vi­ously had been treated with Velcade or an immuno­modu­la­tory drug.  The presence of higher-risk chromosomal ab­nor­mal­i­ties at the start of the trial also did not appear to affect whether or not a patient responded to the trial regi­men.

Progression-free survival and over­all were somewhat shorter, however, in patients who were pre­vi­ously treated with, and had stopped responding to, Velcade or an immuno­modu­la­tory drug.  (The authors did not provide in­­for­ma­tion on whether the presence of higher-risk chromosomal ab­nor­mal­i­ties affected survival.)

Study Results: Tolerability And Safety

The most common severe side effects for all evaluable patients during the trial included low platelet counts (38 per­cent), low white blood cell counts (21 per­cent), fatigue (11 per­cent), anemia (9 per­cent), and high blood pressure (9 per­cent).

As has been the case in pre­vi­ous trials testing Farydak-containing treat­ment regi­mens, gastro­in­tes­ti­nal side effects occurred often during the current study. More than 80 per­cent of the patients experienced some degree of diarrhea while being treated with Farydak and Kyprolis, and three quarters of the patients reported instances of nausea or vomiting.

These Farydak-related side effects frequently resolved during the weeks patients were off treat­ment, the study authors note. However, the side effects also often recurred during sub­se­quent treat­ment.

The current trial was similar to other Kyprolis trials in that did not allow patients to enroll if they had certain heart-related health issues. In particular, patients could only par­tic­i­pate in the current study if they did not have impaired heart function or “clinically significant heart disease.”

Nevertheless, three patients (7 per­cent) experienced serious heart-related side effects during the trial, including one instance of heart failure resulting in the patient’s death. All three of these cases, the authors note, involved older patients (73, 74, and 80 years of age) who had risk factors for heart problems, such as diabetes, high cholesterol levels, and high blood pressure.

Overall, 59 per­cent of patients required Farydak dose reductions during the study, and 9 per­cent of patients dis­con­tinued Farydak. In addi­tion, 18 per­cent of patients required Kyprolis dose reductions; no patients dis­con­tinued treat­ment with Kyprolis.

For more in­­for­ma­tion, please see refer to the study by Berdeja, J. et al., “Phase I/II Study of the Combination of Panobinostat and Carfilzomib in Patients with Relapsed/Refractory Multiple
Myeloma,” in Haematologica, 2015 (full-text PDF of article ^[11]).

Additional Information

Progression-free survival was measured as the time from a patient’s start of treat­ment with the Farydak-Kyprolis regi­men until either disease pro­gres­sion or death due to any cause.

The fol­low­ing chromosomal ab­nor­mal­i­ties were considered by the authors to be markers of higher-risk disease: 1q+, del(1p), t(4;14); t(14;16), or del(17p) based on testing using FISH; or del(13q) based on conventional cytogenetic testing.