A new study provides the first detailed look at Kyprolis when it is used in multiple myeloma patients with kidney damage.

The focus of the study is on determining how Kyprolis (car­filz­o­mib) is processed in the bodies of myeloma patients and, in particular, if the drug is processed differently depending on how much kidney damage a patient has.

In addi­tion, the study in­ves­ti­gates whether kidney damage affects how often patients experience side effects when treated with Kyprolis.

Based on the results of their study, the authors conclude that Kyprolis's dosing can be the same for all myeloma patients.

There is no need, the researchers argue, to take into account kidney damage when deciding how much Kyprolis should be given to a patient at each infusion, or how often infusions should occur.

A Beacon analysis of the study results, however, raises questions about the authors' interpretation of the trial data.

These questions, in turn, cast doubt on the authors' conclusion that the dosage and timing of Kyprolis treat­ment do not need to be adjusted based on the health of a patient's kidneys.

Due to the tension between the conclusions drawn by the study authors and the Beacon's own analysis of the study results, The Beacon's coverage of the study in this article will be more detailed than usual.

Background

The issue the authors address in their study is important because 20 to 50 per­cent of myeloma patients have some degree of kidney damage at the time of their myeloma diag­nosis.

This damage, which physicians usually describe as "renal impairment" or "impaired renal function,"  is mainly caused by the accumulation of anti­body proteins called free light chains, which are produced by myeloma cells.

Kidney damage in myeloma patients has been asso­ci­ated with shorter survival.  This is due, in part, to the fact that physicians are hesitant to use certain myeloma treat­ments in patients with kidney damage for fear that the treat­ments will be less safe in those patients.

One treat­ment that physicians in the U.S. do frequently use for myeloma patients with kidney damage is Velcade (bor­tez­o­mib).  Velcade's use in these patients is a reflection of guidelines developed by myeloma experts (see related Beacon news).  Those guidelines, in turn, are based on the results of several studies that have in­ves­ti­gated Velcade's use in patients with and without kidney damage.

Design Of The Study

The current study involving Kyprolis was commissioned by Onyx (NASDAQ:ONXX), the com­pany that developed and markets Kyprolis.

The study is based on a clinical trial that involved a total of 50 myeloma patients with a median age of 64 years.  Patient were enrolled in the study between November 2008 and January 2010. Prior to participating in the study, patients had received a median of five prior ther­a­pies.

Overall, 96 per­cent of patients had pre­vi­ously been treated with Velcade (bor­tez­o­mib), 88 per­cent had been treated with Revlimid (lena­lido­mide), and 68 per­cent had received a stem cell trans­plant.

Patients in the study were divided into five groups based on their degree of kidney damage, ranging from normal kidney function (Group 1) to very severe impairment (Group 5).

Slightly more patients were recruited into the groups having no kidney damage or only mild kidney damage (Groups 1 and 2, 12 patients each), compared to the groups having mod­er­ate (Group 3, 10 patients) and very severe kidney damage (Groups 4 and 5, 8 patients each).

Each patient in the trial received Kyprolis intravenously on days 1, 2, 8, 9, 15, and 16 of a 28-day treat­ment cycle for up to 12 cycles. If patients tolerated a dosage of 15 mg/m² of Kyprolis during cycle one, their dosage was increased to 20 mg/m² for cycle two, and up to 27 mg/m² for cycle three and beyond.  (The FDA-approved starting dose for Kyprolis is 20 mg/m², which can be increased to 27 mg/m² if there are no issues with side effects at the starting dose.)

As mentioned earlier, the primary objective of the study was to evaluate how Kyprolis is processed in the bodies of myeloma patients.

To accomplish this objective, the trial investigators took mea­sure­ments of the concentration of Kyprolis in each patient's blood on three different days when Kyprolis was given to patients during their par­tic­i­pa­tion in the trial.

Each of these three times, blood concentration mea­sure­ments were done at regular intervals over a 24-hour period after Kyprolis was given to the patient.

In addi­tion to these blood concentration mea­sure­ments, each patient's response to treat­ment was recorded, as was the frequency and type of any side effects that took place.

The Authors' Analysis Of The Results

In their study discussing the results of their trial, the investigators look first at the Kyprolis blood concentration data they collected.

After several statistical analyses of these results, they conclude that there is no rela­tion­ship between how long Kyprolis stays in a patient's body and the extent of any kidney damage the patient had.

The study authors also make a similar argument in regard to the response and side effect results they observed during the trial.

They find, for example, that 26 per­cent of the patients in the study had a partial response or better to treat­ment, and they note that kidney damage did not appear to reduce patient response rates.

Similarly, they describe the side effects observed during the trial, and say that how often side effects occurred did not seem to depend on how much kidney damage patients had.

The Beacon's Analysis Of The Results

The Beacon's own analysis of the study results, however, suggests that the study investigators may be understating the impact of kidney damage on how patients reacted to treat­ment with Kyprolis.

The authors of the study rely heavily on individual statistical analyses of specific sets of the trial data, particularly the Kyprolis blood concentration data, to support their conclusions.

Yet, in many ways, these statistical techniques were bound not to be able to pick up differences across the five groups of patients in the study. The patient numbers in the study are simply too small, and there was such a wide variation in the way patients reacted to treat­ment with Kyprolis, for any observed differences to be statistically significant.

More importantly, the individual statistical analyses ignore broad trends seen across all the trial results.  Those broad trends tell an internally consistent story that is very different from the author's interpretation of the results.

To understand the broad trends in the data and the story they tell, it is useful to start with the Kyprolis blood concen­tra­tion data collected during the trial.  One graph of those results from the current study is dis­played here on the right.

When reading the graph, recall that Group 1 is the set of patients with no kidney damage, Group 2 patients have mod­er­ate kidney damage, and so on, all the way to Group 5, which had patients who required dialysis. (Clicking on the graph will display a much larger version of it.)

The graph shows that, in all patient groups, the concentration of Ky­prolis in the blood dropped quickly after Kyprolis was given to patients.  The concentration then leveled off, however, at a higher level in the patients with kidney damage compared to the patients with no kidney damage.

Given these results, one would expect that patients with kidney damage will have responded better to treat­ment with Kyprolis, since the drug remained in their body longer than it did in the patients without kidney damage.

One also would expect, however, that, because the drug stayed longer in the bodies of patients with kidney damage, those patients also will have had more side effects than the patients without kidney damage.

These expectations are, in fact, reflected in the trial data published in the current study.

For example, more patients with kidney damage responded to Kyprolis than patients with no kidney damage.

Among the patients with at least some kidney damage (the patients in Groups 2, 3, 4, and 5), 28 per­cent achieved a partial response or better.  Among patients with no kidney damage (Group 1), only 18 per­cent achieved a partial response or higher.

In addi­tion, more patients with at least some kidney damage (Groups 2 through 5) reported serious side effects than patients with no kidney damage (Group 1).

Among the patients with at least some kidney damage, 32 per­cent developed seriously low red blood cell levels. Only 17 per­cent of patients with no kidney damage had that side effect.

Similarly, 24 per­cent of patients with at least some kidney damage developed seriously low platelet levels, while only 8 per­cent of patients with no kidney damage had that side effect.

It is true that none of the differences just outlined – in blood concentration levels, in response rates, or in side effects – are statistically significant in and of themselves.

Yet, together, the results point toward an internally consistent story, which is that Kyprolis seems to stay longer in the bodies of patients with kidney damage, and this leads to higher response rates as well as more side effects.

This interpretation of the trial results, however, is directly at odds with the interpretation offered by the study authors.

As a result, it is unclear whether there really is sufficient evidence for the authors to conclude, as they do at the end of their study, that "the results of this ... study indicate that car­filz­o­mib's [Kyprolis's] dose and treat­ment schedule do not need to be adjusted in patients with renal impairment [kidney damage]."

For more in­­for­ma­tion about the current study, please see the article in Leukemia (abstract).

Additional Information About The Study

For readers interested in further in­­for­ma­tion about the dosing used during the trial as well as the side effect and response results, here are some addi­tional details.

First, in regard to dosing, patients who dem­onstrated treat­ment-related fevers, chills, or shortness of breath were given 4 mg of dexamethasone (Decadron) prior to each Kyprolis dosage during cycle one. Furthermore, patients who did not reach a partial response by cycle three or a complete response by cycle five were eligible to receive 20 mg of dexa­meth­a­sone prior to each Kyprolis dosage.

Overall, patients received a median of four cycles of Kyprolis; 6 per­cent of patients completed all 12 cycles, and 26 per­cent con­tinued to receive treat­ment at the time of data evaluation.  The remaining 68 per­cent dis­con­tinued treat­ment due to progressive disease (48 per­cent), side effects (12 per­cent), or withdrawn consent (8 per­cent).

Second, in regard to side effects, the most common of all degrees, across all patients in the study, were fatigue (56 per­cent), anemia (50 per­cent), nausea (36 per­cent), diarrhea (36 per­cent), and low platelet counts (30 per­cent). Common severe to life-threatening side effects across all patients included low red blood cell counts (28 per­cent), low platelet counts (20 per­cent), and low white blood cell counts (18 per­cent).

Overall, 18 per­cent of patients required dose reductions due to side effects, and 12 per­cent of the patients dis­con­tinued treat­ment due to side effects.

Third, in regard to response to treat­ment, the median duration of response across all patients who responded to treat­ment was 7.9 months. There were no complete or very good partial responses observed during the trial. However, 26 per­cent of all the patients achieved a partial response, 6 per­cent achieved a minimal response, and 45 per­cent achieved stable disease.