A subanalysis of recent clinical trial results shows good response rates for single-agent Kyprolis in heavily pretreated multiple myeloma patients with high-risk chromosomal ab­nor­mal­i­ties.

Specifically, the investigators found that the response rates for patients with high-risk chromosomal ab­nor­mal­i­ties were similar to those for patients without high-risk chromosomal ab­nor­mal­i­ties.

However, the researchers also found that response duration and over­all survival remained significantly lower in patients with high-risk chromo­som­al ab­nor­mal­i­ties.

Nevertheless, the researchers describe the results as encouraging, and they suggest that treat­ment with Kyprolis ^[1] (car­filz­o­mib) may be beneficial for patients with high-risk chromo­som­al ab­nor­mal­i­ties.

To improve survival in this patient population, particularly patients with the chromosomal ab­nor­mal­ity del(17p), they recommend combining Kyprolis with other agents.

Background

Kyprolis is a new treat­ment for multiple myeloma that was approved by the U.S. Food and Drug Adminis­tra­tion (FDA) in July 2012 for myeloma patients who have received at least two prior ther­a­pies, including Velcade ^[2] (bor­tez­o­mib) and an immuno­modu­la­tory agent – such as Revlimid ^[3] (lena­lido­mide), thalidomide ^[4] (Thalomid), or Pomalyst ^[5] (poma­lido­mide) – and who have progressed within 60 days of complet­ing their most recent regi­men (see related Beacon ^[6] news).

The FDA's approval of Kyprolis was based on the results of a Phase 2 clinical trial that in­ves­ti­gated the effi­cacy and safety of single-agent Kyprolis in re­lapsed and progressing myeloma patients.

The investigators involved with the trial have further analyzed the trial results to assess the impact of chromosomal ab­nor­mal­i­ties on the efficacy of single-agent Kyprolis.

Patients with high-risk ab­nor­mal­i­ties, such as t(4;14) or del(17p), have been known to experience disease pro­gres­sion much more quickly than patients without these ab­nor­mal­i­ties. Furthermore, certain ab­nor­mali­ties can indicate that a patient may not respond as well to a particular treat­ment.

Previous research has shown that Velcade may improve out­comes in patients with certain high-risk chromo­somal ab­nor­mal­i­ties (see related Beacon ^[7] news). Kyprolis belongs to the same class of drugs as Velcade, called proteasome inhibitors.

In addi­tion, a recent analysis found that Pomalyst com­bined with low-dose dexamethasone ^[8] (Decadron) is active in re­lapsed myeloma patients with high-risk chromosomal ab­nor­mal­i­ties (see related Beacon ^[9] news).

Study Design

The Phase 2 Kyprolis trial included 266 re­lapsed and refractory myeloma patients who had received a median of five prior ther­a­pies. The median patient age was 63 years.

Almost every patient (99 per­cent) in the trial had pre­vi­ously been treated with Velcade; 73 per­cent were refractory to it.

Patients received 20 mg/m² of Kyprolis on days 1, 2, 8, 9, 15, and 16 during the first treat­ment cycle. The dose was increased to 27 mg/m² during sub­se­quent treat­ment cycles for a maximum of 12 cycles.

Study Results

Information on chromosomal ab­nor­mal­i­ties were available for 229 patients.  Among these patients, 73 per­cent were categorized as standard-risk and 27 per­cent as high-risk.

Patients were classified as high-risk based on the presence of one (19 per­cent) or more (8 per­cent) of the fol­low­ing chromosomal ab­nor­mal­i­ties: del(17p) (13 per­cent), t(4;14) (8 per­cent), or t(14;16) (1 per­cent) based on results from interphase FISH testing, and del(13) (6 per­cent) or missing chromosomes (10 per­cent) based on metaphase cytogenetic testing.

The researchers found that the over­all response rate was similar between high-risk and standard-risk patients (26 per­cent versus 25 per­cent, respectively).  However, depth of response was not as great for the high-risk group.  Specifically, no high-risk patients achieved at least a very good partial response, whereas 8 per­cent of standard-risk patients did.

Among patients with high-risk chromosomal ab­nor­mal­i­ties, those with the t(4;14) ab­nor­mal­ity had the highest over­all response rate (39 per­cent) and those with del(17p) had the lowest (17 per­cent). Patients with one ab­nor­mal­ity had a significantly higher over­all response rate (30 per­cent) to Kyprolis than those with two or more ab­nor­mal­i­ties (16 per­cent).

In addi­tion, the share of patients who did not respond to treat­ment, instead experiencing con­tinued disease pro­gres­sion, was also com­parable between patients with high-risk (23 per­cent) and standard-risk chromo­somal ab­nor­mal­i­ties (28 per­cent).

However, the investigators found that the response duration was shorter in high-risk patients (5.6 months) compared to standard-risk patients (8.3 months).

As a result, over­all survival was significantly shorter in high-risk patients (9.3 months) compared to standard-risk patients (19 months).

Among patients with high-risk chromosomal ab­nor­mal­i­ties, those with the t(4;14) ab­nor­mal­ity had the longest median over­all survival (11.8 months) and those with del(17p) had the shortest (7 months). Patients with one ab­nor­mal­ity had slightly longer median over­all survival (10.6 months) than those with two or more ab­nor­mal­i­ties (8.4 months).

Although the researchers did not report data about Kyprolis’s safety, since these data were reported with the results from the original study, they did note that the drug had a favorable safety profile in both the standard-risk and high-risk patient groups.

They added, however, that more high-risk patients (29 per­cent) dis­con­tinued treat­ment within the first two treat­ment cycles compared to standard-risk patients (20 per­cent).

For more in­­for­ma­tion, please refer to the study in the journal Leukemia ^[10] (abstract).