The 2013 annual meeting of the American Society of Hematology (ASH), which took place last month, featured many oral and poster presentations about Kyprolis, one of the newest drugs to be approved for the treat­ment of multiple myeloma.

The drug con­tinues to be tested in various com­bi­na­tions in both newly diag­nosed and re­lapsed/refractory multiple myeloma patients, as well as in patients with the myeloma precursor disease smol­der­ing myeloma.

In most trials, Kyprolis ^[1] (car­filz­o­mib) was com­bined with dex­a­meth­a­sone ^[2] (Decadron) and a third drug, some­times even a fourth drug, such as Revlimid ^[3] (lena­lido­mide), thalidomide ^[4] (Thalomid), cyclo­phos­pha­mide ^[5] (Cy­toxan), or clarithro­mycin ^[6] (Biaxin).

Most of these com­bi­na­tions are ones in which Kyprolis replaced Velcade ^[7] (bor­tez­o­mib) in a regi­men that has already been shown to be highly effective.  Kyprolis and Velcade belong to the same class of drugs called proteasome inhibitors.

Across all different patient populations, Kyprolis con­tinues to show strong results, with over­all response rates ranging from 100 per­cent in smol­der­ing multiple myeloma patients, to the 90 per­cent range in newly diagnosed (symptomatic) myeloma patients, and to the 60 to 70 per­cent range in re­lapsed patients.

Where comparisons can be made, Kyprolis-based com­bi­na­tions appear to have higher response rates, or deeper responses, than the equivalent Velcade-based com­bi­na­tions.

Kyprolis In Newly Diagnosed Myeloma Patients

Kyprolis-Revlimid-Dexamethasone Plus Revlimid Maintenance

Dr. Neha Korde from the National Cancer Institute and the National Institutes of Health presented updated results from a Phase 2 trial of Kyprolis, Revlimid, and dex­a­meth­a­sone followed by Revlimid main­te­nance ther­apy for newly diagnosed myeloma patients (abstract ^[8]).

Among the 43 patients included in the study, 98 per­cent responded, with 51 per­cent achieving a stringent or com­plete response, 16 per­cent a near complete response, 21 per­cent a very good partial response, and 9 per­cent a partial response.

Among all the patients who reached at least a near complete response, 100 per­cent of those tested were negative for minimal residual disease.

The one-year pro­gres­sion-free survival rate was 97 per­cent.

Dr. Korde also reported that the regi­men was an effective and tolerable regi­men for older patients.

Comparisons to Velcade-Revlimid-dex­a­meth­a­sone for newly diagnosed myeloma are not simple, in that most studies of the Velcade-based regi­men allowed patients to undergo stem cell trans­plan­ta­tion or Velcade main­te­nance ther­apy, while patients in the Kyprolis study received Revlimid main­te­nance ther­apy.

The studies show that response rates are nearly 100 per­cent for both the Velcade- and Kyprolis three-drug regi­mens, with around 40 per­cent of patients receiving the Velcade-based regi­men also undergoing stem cell trans­plan­ta­tion.

However, two studies of the Velcade-based regi­men show that 75 per­cent to 84 per­cent of patients treated with the regi­men responded within four cycles, while the Kyprolis study showed that 98 per­cent responded in just two cycles.

Kyprolis-Cyclophosphamide-Dexamethasone Plus Kyprolis Maintenance

Dr. Sara Bringhen from the University of Torino in Italy reported results from a Phase 2 study evaluating Kyprolis, cyclo­phos­pha­mide, and dex­a­meth­a­sone as initial ther­apy for older, newly diagnosed multiple myeloma patients (abstract ^[9]; presentation ^[10] [pdf] courtesy of Dr. Bringhen).  After initial ther­apy, patients re­ceived further Kyprolis main­te­nance ther­apy.

Overall 96 per­cent of study participants responded, with 64 per­cent reaching a complete or near complete response, 12 per­cent a very good partial response, and 20 per­cent a partial response.

The two-year pro­gres­sion-free survival rate was 76 per­cent, and the over­all survival rate was 87 per­cent.

According to Dr. Bringhen, Kyprolis-cyclophosphamide-dex­a­meth­a­sone ther­apy compares very favorably to other treat­ment options for older patients, both in terms of efficacy and safety.

Several pre­vi­ous studies have shown that the Velcade-based version of this induction ther­apy (commonly referred to as VCD or CyBorD) is highly effective for newly diagnosed myeloma patients.  One study demon­strated the com­bi­na­tion’s efficacy and safety specifically in older patients; however, the study did not include main­te­nance ther­apy.  Given that response rates prior to main­te­nance ther­apy were not presented for the current study, it is difficult to make direct comparisons between the Kyprolis- and Velcade-based cyclo­phos­pha­mide and dex­a­meth­a­sone regi­mens for older myeloma patients.

Kyprolis Plus Melphalan And Prednisone

Results were also presented from a Phase 1/2 study of Kyprolis in com­bi­na­tion with melphalan ^[11] (Alkeran) and prednisone ^[12] for older newly diagnosed myeloma patients (abstract ^[13]).

Overall, 91 per­cent of patients responded, with 55 per­cent achieving at least a very good partial response.  The median event-free survival was 22 months, and the two-year over­all survival was 84 per­cent.

This com­bi­na­tion appears to compare favorably to Velcade plus mel­phalan and pred­ni­sone for older newly diagnosed myeloma patients.  A pre­vi­ous study showed that the over­all response rate for this com­bi­na­tion was 79 per­cent, with 47 per­cent achieving at least a very good partial response.

In addi­tion, only 6 per­cent of patients treated with Kyprolis-melphalan-prednisone developed mod­er­ate or severe periph­eral neu­rop­athy (pain, tingling, or loss of sensation in the extremities), making it a safe and effective option for older patients.  Similarly, 8 per­cent of patients treated in a pre­vi­ous study with the Velcade-based com­bi­na­tion developed mod­er­ate to severe periph­eral neu­rop­athy.

Kyprolis Plus Cyclophosphamide, Thalidomide, And Dexamethasone

A poster presented at ASH summarized the final results of a Phase 1/2 study of Kyprolis plus cyclo­phos­pha­mide, thalido­mide, and dex­a­meth­a­sone – a com­bi­na­tion ther­apy known as “CYCLONE” – in newly diag­nosed myeloma patients (abstract ^[14]).

According to the researchers, the com­bi­na­tion is highly efficacious.  After four treat­ment cycles, 91 per­cent of patients responded, with 76 per­cent achieving at least a very good partial response.

The two-year pro­gres­sion-free survival was 77 per­cent, and the two-year over­all survival was 98 per­cent.

Kyprolis Plus Dexamethasone, Followed By Revlimid-Clarithromycin-Dexamethasone Consolidation and Revlimid Maintenance

Another poster summarized results of a study that in­ves­ti­gated a sequential approach of upfront Kyprolis plus dex­a­meth­a­sone, followed by consolidation ther­apy with Revlimid, clarithromycin (Biaxin), and dex­a­meth­a­sone, and finally Revlimid main­te­nance as first-line ther­apy for newly diagnosed myeloma patients (abstract ^[15]).

Overall, 83 per­cent of patients responded to Kyprolis-dex­a­meth­a­sone induction (9 per­cent stringent com­plete response, 39 per­cent very good partial response, and 35 per­cent partial response).  According to the researchers, these response rates compare favorably to similar studies using Velcade-based com­bi­na­tions.

The researchers point out that responses deepened with consolidation and main­te­nance ther­apy (13 per­cent stringent com­plete response, 48 per­cent very good partial response, and 26 per­cent partial re­sponse for an over­all response rate of 87 per­cent).

Kyprolis In Relapsed And Refractory Myeloma Patients

Weekly High-Dose Kyprolis

Results from a Phase 1 study of once-weekly (rather than twice-weekly), high-dose Kyprolis plus dex­a­meth­a­sone for re­lapsed or refractory myeloma were summarized in a poster presented at ASH (abstract ^[16]).

Eighteen patients, with a median of one prior treat­ment regi­men, have been enrolled and treated in the study thus far.  The patients were given Kyprolis infusions once a week for three weeks out of each four-week cycle.  After an initial starting dose of 20 mg/m², patients sub­se­quently received doses of Kyprolis ranging from 45 to 88 mg/m².

Patients also were given 40 mg of dex­a­meth­a­sone once every week.

Thus far, two-thirds of the patients have achieved at least a partial response to the weekly high-dose Kyprolis and dex­a­meth­a­sone ther­apy.  This compares favorably, the investigators note, to the 55 per­cent to 60 per­cent response rate seen in a separate study using twice-weekly Kyprolis.

The median time to response was one month, which the investigators described as rapid.

Kyprolis In Smoldering Myeloma Patients

Kyprolis-Revlimid-Dexamethasone Followed By Extended Revlimid

Another poster summarized results from a pilot study of Kyprolis in com­bi­na­tion with Revlimid and dex­a­meth­a­sone followed by extended Revlimid dosing for high-risk smol­der­ing myeloma (abstract ^[17]; full poster ^[18] [pdf] courtesy of Dr. Ola Landgren).  Earlier results from the study were presented at the Inter­na­tional Myeloma Workshop in April 2013 (see related Beacon ^[19] news).

Among the 12 patients evaluated for response, all achieved at least a near complete response.  In addi­tion, 92 per­cent had no minimal residual disease detected.

For more in­­for­ma­tion, please see the Beacon’s ASH 2013 Myeloma Gateway ^[20].

Tags: Multiple Myeloma, Carfilzomib, Kyprolis, ASH 2013 Meeting