Results from a small Phase 2 study conducted throughout Japan sug­gest that a com­bi­na­tion of Velcade, doxorubicin, and intermediate-dose dexa­meth­a­sone is effective in patients with re­lapsed or refractory multiple myeloma.

Most patients (89 per­cent) responded to treat­ment, with a third of them achieving a com­plete or near com­plete response.  In addi­tion, the medi­an pro­gres­sion-free survival was 12.1 months.

According to the Japanese researchers, the findings from this study are com­par­able to those from pre­vi­ous studies that examined the effective­ness of the Velcade (bor­tez­o­mib), doxorubicin (Adriamycin), and dexa­meth­a­sone (Decadron) com­bi­na­tion in multiple myeloma.

All of these studies show that the addi­tion of doxorubicin to the com­bi­na­tion produces higher response rates and longer pro­gres­sion-free survival than Velcade or dexa­meth­a­sone alone or in com­bi­na­tion together.

“The authors have identified a regi­men of Velcade, intravenous doxorubicin, and dexa­meth­a­sone with a dose and schedule that is asso­ci­ated with a high rate of over­all response in patients who have not pre­vi­ously received Velcade or Revlimid,” said Dr. Jacob Laubach, a myeloma expert at the Dana-Farber Cancer Institute, who was not involved with the study.

“Results of this study con­firm the high level of anti-myeloma activity of Velcade in com­bi­na­tion with doxorubicin and dexa­meth­a­sone. However, in the United States, a majority of patients receive Revlimid and/or Velcade as part of initial ther­apy, whereas in this study patients had not pre­vi­ously received either agent,” he added.

Background

Novel anti-myeloma agents such as Velcade, Revlimid (lena­lido­mide), and thalidomide (Thalomid) are com­mon­ly used to treat re­lapsed or refractory myeloma.

Doxorubicin is a traditional chemotherapy agent first approved by the U.S. Food and Drug Admin­istra­tion 40 years ago.  It interferes with the reproduction of cancer cells by binding to their DNA.  It is used to treat a wide range of cancers.

Combining novel myeloma agents with traditional chemotherapy agents such as doxorubicin, melphalan (Alkeran), and cyclophosphamide (Cytoxan) has been shown to increase treat­ment response rates and lengthen patient survival.

In 2010, the Japanese investigators conducted a Phase 1 trial to determine the optimal dose of Velcade when used in com­bi­na­tion with doxorubicin and intermediate-dose dexa­meth­a­sone (called the iPAD reg­i­men) against re­lapsed or refractory myeloma. Results from this study showed that 1 mg/m² of Velcade was well-tolerated.

In the current study, the researchers further examined the efficacy of this iPAD regi­men for patients with re­lapsed or refractory myeloma.

Study Design

A total of 27 patients, with a median age of 63 years, enrolled in this Phase 2 study between 2008 and 2010. All patients had pre­vi­ously received one to three lines of ther­apy, with about half of the patients having received just one pre­vi­ous line of ther­apy.

None of the patients had pre­vi­ously been treated with either Velcade or Revlimid.  About a fifth of the patients were pre­vi­ously treated with thalido­mide, and 59 per­cent had received a stem cell trans­plant.

Patients received four doses each of 1 mg/m² of intravenous Velcade on days 1, 4, 8, and 11; 9 mg/m² of intravenous doxorubicin on days 1 to 4; and 20 mg of oral dexa­meth­a­sone on days 1, 2, 4, 5, 8, and 9 during a 21-day treat­ment cycle. Study participants underwent a median of five treat­ment cycles.

Fifteen per­cent of the patients underwent a stem cell trans­plant after they com­pleted treat­ment with the Velcade-doxorubicin-dexamethasone regi­men.  No patients, however, received main­te­nance ther­apy after treat­ment with the regi­men.

The median follow-up period was 27 months.

Study Results

Results from the study showed that 89 per­cent of patients responded to the iPAD regi­men, with 22 per­cent of patients achieving a com­plete response, 7 per­cent a near com­plete response, and 59 per­cent a partial response.

Among the patients who reached a com­plete or near com­plete response, 88 per­cent did so within four treat­ment cycles.

According to the study investigators, these response rates are similar to those from pre­vi­ous studies of the PAD com­bi­na­tion.  In particular, pre­vi­ous studies have shown an over­all response rate of 67 per­cent for Velcade plus doxorubicin and low-dose dexa­meth­a­sone in re­lapsed and refractory myeloma patients and an over­all response rate of 95 per­cent for Velcade plus doxorubicin and high-dose dexa­meth­a­sone in newly diag­nosed myeloma patients.

The researchers also state that their findings compare favorably to those for single-agent Velcade (complete response rate of 9 per­cent) and Velcade plus dexa­meth­a­sone (complete response rate of 7 per­cent).

The median pro­gres­sion-free survival for iPAD was 12.1 months, and the two-year pro­gres­sion-free survival rate was 38 per­cent.

According to the researchers, these results are com­parable to those from a pre­vi­ous study of Velcade plus Doxil (doxorubicin liposomal), in which the median duration of response was 10.2 months.  They also state that the iPAD regi­men sub­stan­tially im­proved pro­gres­sion-free survival time, compared to pre­vi­ous studies of single-agent Velcade (time-to-progression of 6.2 months) and Velcade plus dexa­meth­a­sone (time-to-progression of 5.6 months).

Median over­all survival was not yet reached, but the two-year over­all survival rate was 85 per­cent.

Analysis of various subgroups showed that disease stage, chromosomal ab­nor­mal­i­ties, number of prior lines of treat­ment, and stem cell trans­plan­ta­tion after iPAD did not sig­nif­i­cantly affect the efficacy of the com­bi­na­tion.

The most common severe side effects of iPAD ther­apy were low platelet counts (67 per­cent of participants), low counts of certain white blood cells called neu­tro­phils (41 per­cent), sensory neu­rop­athy (pain, tingling, and loss of sensation in the extremities, 22 per­cent), and anemia (19 per­cent).

“iPAD is an active regi­men, but toxicity is a concern as evi­denced by toxicity data from this study,” said Dr. Laubach.

According to the investigators, studies indicate that Japanese patients are at higher risk of devel­op­ing neu­rop­athy compared to other patient pop­u­la­tions.  Based on results of other recent studies, the researchers suggest weekly admin­istra­tion of sub­cu­tane­ous Velcade (instead of intravenous admin­istra­tion) for future studies of the iPAD regi­men, particularly in Japanese patients.

For more in­­for­ma­tion, please see the study in the International Journal of Hematology (abstract).