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 ^[1] (car­filz­o­mib) or Poma­lyst ^[2] (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 ^[5] (bor­tez­o­mib) and Rev­limid ^[6] (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 ^[7] (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 ^[8] and Pomalyst ^[9])

Kyprolis belongs to the class of drugs known as proteasome inhibitors, which also includes Velcade as well as the investigational agents ixazomib ^[10] (MLN9708), oprozomib ^[11], and marizomib ^[12].

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 ^[13] 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 ^[14] news).  Pomalyst also was approved recently in Europe for use in a similar group of patients (see related Beacon ^[15] 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 ^[16] (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 ^[17] (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 ^[18] (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 ^[19] (abstract).