A subgroup analysis of recent Phase 1/2 clinical trial results shows that Kyprolis in com­bi­na­tion with Revlimid and low-dose dexa­meth­a­sone is effective and well tolerated in newly diagnosed multiple myeloma patients over the age of 65.

All of the evaluated patients responded to treat­ment, with 83 per­cent of patients reaching at least a near complete response.

According to Dr. Andrzei Jakubowiak of the University of Chicago Medical Center, who presented the findings earlier this month at the Inter­na­tional Myeloma Workshop (IMW) in Kyoto, Japan, the response rates compare favorably to the best response rates of other induction ther­a­pies in this patient population.

He concluded that these findings warrant a Phase 3 study of the com­bi­na­tion regi­men in myeloma patients of all age groups.

Background

Kyprolis (car­filz­o­mib) was approved by the U.S. Food and Drug Administration last year for the treat­ment of multiple myeloma patients who have received at least two prior ther­a­pies, including Velcade (bor­tez­o­mib) and an immuno­modu­la­tory agent – such as Revlimid (lena­lido­mide), thalidomide (Thalomid), or Poma­lyst (poma­lido­mide) – and who progressed within 60 days of completing their most recent regi­men (see related Beacon news).

Kyprolis is a proteasome inhibitor in the same class of drugs as Velcade.

While many clinical trials target younger patients, the majority of multiple myeloma patients are over 65 years of age, and a third are over 75 years.

The National Comprehensive Cancer Network (NCCN) cur­rently recommends older myeloma patients be treated with Revlimid or Velcade plus dexamethasone (Decadron), or melphalan (Alkeran) and prednisone plus Velcade, Revlimid, or thalido­mide.  Most of these regi­mens have over­all response rates of 60 per­cent to 80 per­cent in older myeloma patients.

Recent studies have dem­onstrated that Kyprolis com­bi­na­tion ther­a­pies, such as Kyprolis, cyclo­phos­phamide (Cytoxan), and dexa­meth­a­sone, or Kyprolis, mel­phalan, and pred­ni­sone, are highly active in older myeloma patients, leading to response rates of approx­i­mately 90 per­cent.

Results from all patients who par­tic­i­pated in the Phase 1/2 study of Kyprolis plus Revlimid and low-dose dexa­meth­a­sone in newly diagnosed patients showed that the com­bi­na­tion is highly active in myeloma patients of all ages. Overall, 98 per­cent of patients responded to the treat­ment, and at two years, 92 per­cent of patients had not progressed (see related Beacon news).

Based largely on the results of this trial, the NCCN recently added the Kyprolis-Revlimid-dexamethasone regi­men to its guidelines as an alter­na­tive treat­ment option for newly diagnosed myeloma patients who are eligible for stem cell trans­plan­ta­tion (see related Beacon news).

Study Design

Given the promising results for the Kyprolis-Revlimid-dexamethasone com­bi­na­tion across all ages, the trial investigators decided to further analyze the results to determine the safety and efficacy of the com­bi­na­tion in older myeloma patients.

For this subgroup analysis, the researchers assessed treat­ment out­comes for the subset of 23 patients who were at least 65 years of age. The median patient age for this subgroup was 72 years.

Over the course of a 28-day treat­ment cycle, patients received 20 mg/m², 27 mg/m², or 36 mg/m² of Kyprolis on days 1, 2, 8, 9, 15, and 16; 25 mg of Revlimid on days 1 to 21; 40 mg of dexa­meth­a­sone weekly during cycles 1 to 4; and 20 mg of dexa­meth­a­sone weekly during cycles 5 to 8.

For cycles 8 to 24, patients con­tinued on the regi­men, but received Kyprolis only on days 1, 2, 15, and 16. After cycle 24, patients could con­tinue to receive 25 mg of Revlimid on days 1 to 21.

After the fourth cycle, trans­plant-eligible patients had the option of receiving a stem cell trans­plant.

Study Results

After a median of 12 treat­ment cycles, all of the older patients evaluated reached at least a partial response. Specifically, 61 per­cent reached a stringent complete response, 22 per­cent reached a near complete response, 4 per­cent reached a very good partial response, and 13 per­cent achieved a partial response. The share of patients who achieved a stringent complete response was higher among the older patients, compared to patients of all ages (61 per­cent versus 42 per­cent, respectively).

Response rates improved with longer duration of treat­ment. Of the 17 older patients who completed at least 8 cycles of treat­ment, all of them reached a near complete response and 76 per­cent reached a stringent complete response.

After a median follow-up of 13 months, all older patients were pro­gres­sion-free and alive. In comparison, 7 per­cent of younger patients progressed during that time.  The one-year and two-year pro­gres­sion-free survival rates were 97 per­cent and 92 per­cent, respectively, for patients of all ages.

According to Dr. Jakubowiak, side effects tended to be more common in older patients.  In addi­tion, dose modifications and dis­con­tinu­a­tions due to side effects were more common in older patients.

Common severe to life-threatening side effects in the older group included high blood sugar levels, low platelet counts, low red blood cell counts, low white blood cell counts, and low phosphate levels during the first eight treat­ment cycles. Peripheral neu­rop­athy was experienced by 13 per­cent of the older patients, but all cases were mild to mod­er­ate in nature

For more in­­for­ma­tion, please see Dr. Jakubowiak's presentation slides, which he has made available for download and viewing as a courtesy to The Beacon's readers.