Kyprolis Or Pomalyst For Dual-Refractory Myeloma - What Is The Survival Impact?

A new retrospective study provides insight into the benefit the new mye­lo­ma drugs Kyprolis and Pomalyst may provide to patients who are re­sis­tant to, or cannot tolerate, both Velcade and Revlimid.

The study’s results highlight how challenging it can be to find an effective treat­ment for patients who are “dual refractory” (resistant to both Velcade and Rev­li­mid).

Patients in the study who received either Kyprolis (carfilzomib) or Poma­lyst (poma­lido­mide, Imnovid) after becoming dual refractory had longer overall survival than those who were not treated with the new drugs.

The improvement in survival, however, was just six months.

Specifically, dual-refractory patients who received the new drugs had a median overall survival of 12.6 months, versus 6.8 months for the dual-refractory patients who were not treated with the new drugs.

The study investigators also found that patients who are resistant to both Velcade (bortezomib) and Rev­limid (lena­lido­mide) show clear signs of advanced disease, such as more rampant bone damage and tumors outside the bone marrow.

Background

Novel agents such as thalidomide (Thalomid), Velcade, and Revlimid are highly effective in multiple mye­lo­ma, and have become commonly used to treat the disease.

However, many patients become resistant, or refractory, to these drugs over the course of their treatment.  These refractory patients tend to have lower overall and progression-free survival rates than other patients.

Previous studies indicate that the newly approved myeloma drugs Kyprolis and Pomalyst are effective in high-risk, relapsed and refractory myeloma patients (see related Beacon news for Kyprolis and Pomalyst)

Kyprolis belongs to the class of drugs known as proteasome inhibitors, which also includes Velcade as well as the investigational agents ixazomib (MLN9708), oprozomib, and marizomib.

Kyprolis was approved by the U.S. Food and Drug Administration (FDA) last year for the treatment of multiple myeloma patients who have received at least two prior therapies, including Velcade and an immuno­modu­la­tory agent – such as Revlimid or thalidomide – and who progressed within 60 days of completing their most recent regimen (see related Beacon news).  Kyprolis is not yet approved in any other country besides the United States.

Pomalyst belongs to the class of drugs known as immunomodulatory agents, which also includes Revlimid and thalidomide.

Pomalyst was approved by the FDA earlier this year for the treatment of multiple myeloma patients who have received at least two prior therapies, including Revlimid and Velcade, and have demonstrated disease progression on or within 60 days of completion of the last therapy (see related Beacon news).  Pomalyst also was approved recently in Europe for use in a similar group of patients (see related Beacon news).

The investigators of the current study sought to evaluate the survival benefits of Kyprolis and Pomalyst in patients who were refractory to both Velcade and Revlimid. In addition, the researchers sought to identify key characteristics of the myeloma present in these patients.

Study Design

Investigators from the Washington School of Medicine in St. Louis, Missouri, retrospectively analyzed the records of 65 patients who were treated at their institution and who became refractory to, or could not toler­ate, both Velcade and Revlimid between January 2007 and May 2012. The median patient age at diagnosis was 58 years.

The patients had received a median of five therapies, including Velcade (100 percent of patients), Revlimid (100 percent), stem cell transplantation (74 percent), and thalidomide (74 percent), before they became resistant to both Velcade and Revlimid.

The median time from diagnosis until the patients became resistant to or intolerant of both Velcade and Revlimid was 39 months. The median time to the next treatment after they became resistant to both Velcade and Revlimid was 3.5 months.

Patients received a median of two therapies after they became resistant to both Velcade and Revlimid.  These therapies included Pomalyst (23 percent of patients), Kyprolis (17 percent), and alkylating agents such as melphalan (Alkeran) (55 percent).

Results

After a mean follow up of 13.5 months, the median overall survival was 10.2 months after the patients in the study became resistant to or intolerant of both Velcade and Revlimid.

Survival was longer for the patients who were treated with either Kyprolis or Pomalyst, compared to the sur­vival of patients who were not treated with the new drugs.

The difference in survival, however, was less than half of a year — 12.6 months for the patients treated with either Kyprolis or Pomalyst, versus 6.8 months for those who were not treated with the newer drugs.

The one-year overall survival was also higher for patients who received either Kyprolis or Pomalyst (50 per­cent), compared to those who did not (32 percent).

When the researchers investigated clinical characteristics of the patients at the time they became resistant to both Velcade and Revlimid, they found that:

• 72 percent of the patients had advanced bone disease, defined as more than three bone lesions (no data available on what percentage had advanced bone disease at diagnosis)
• 31 percent had oligosecretory myeloma (compared to 9 percent at diagnosis)
• 28 percent had low white blood cell counts or low platelet counts (no data available at diagnosis)
• 24 percent had high-risk chromosomal abnormalities (no data available at diagnosis)
• 6 percent had extramedullary disease (compared to 0 percent at diagnosis).

Oligosecretory myeloma is a subset of multiple myeloma in which patients have very low monoclonal (M) protein levels in their blood and urine.

Extramedullary disease, or non-marrow tumors, occurs when malignant plasma cells develop in organs or soft tissues outside the bone marrow. It is commonly associated with relapsed/refractory myeloma.

According to the researchers, these findings about the nature of the myeloma in dual-refractory patients suggest that the characteristics of multiple myeloma evolve as the disease progresses.

Factors that appeared to be associated with poor survival in dual-refractory patients included receiving a combination of Velcade, Revlimid, and dexamethasone (Decadron) before becoming resistant to Velcade and Revlimid, a low hemoglobin count and advanced bone disease at the time of becoming resistant to Velcade and Revlimid, and not receiving Kyprolis or Pomalyst after becoming resistant to Velcade and Revlimid.

According to the researchers, it is not clear why the highly effective combination of Velcade, Revlimid, and dexamethasone was associated with poorer survival in their study. They speculate that this combination may have been specifically selected for patients with more aggressive disease, but also believe it would be advisable to further investigate the effects of the combination therapy in prospective clinical trials.

For more information, please refer to the study in the journal Leukemia and Lymphoma (abstract).