A Phase 2 clinical trial showed that plitidepsin alone had limited efficacy in heavily pretreated relapsed and refractory multiple myeloma patients. However, plitidepsin in combination with dexamethasone was effective enough to warrant further study. Plitidepsin alone or in combination with dexamethasone was well tolerated.

“Plitidepsin has not shown very significant efficacy when used in monotherapy,” explained Dr. María Mateos, the lead investigator of this study. “Nevertheless, in the present study we have seen some hints of activity in very heavily pretreated patients.”

Among the patients who received plitidepsin alone, 13 percent achieved at least a minimal response. When dexamethasone was added, the rate increased to 22 percent. These response rates indicate that plitidepsin may be a promising treatment for multiple myeloma in combination with other drugs.

Plitidepsin (proposed brand name: Aplidin) is a new agent being developed by the Spanish company PharmaMar for the treatment of multiple myeloma, other blood cancers, and solid tumors. This novel agent is a synthetic compound derived from primitive sea creatures, commonly called sea squirts, that dwell on the ocean floor. Preliminary studies have demonstrated that plitidepsin exhibits anti-tumor effects and causes cell death in myeloma cells.

Unlike many other multiple myeloma treatments, plitidepsin showed no toxic effects on the bone marrow in previous clinical trials. This makes plitidepsin an ideal candidate for the treatment of heavily pre-treated relapsed and refractory myeloma patients, who usually have poor bone marrow reserves. It is also believed that the anti-myeloma effects of plitidepsin occur through actions that differ from those of current multiple myeloma drugs. Therefore, plitidepsin may become an important treatment option for patients who become resistant to other drugs.

This Phase 2 study evaluated the antitumor activity and safety of plitidepsin in 51 heavily pretreated patients with relapsed and refractory multiple myeloma. Participants received a three-hour infusion of plitidepsin every two weeks. Those who did not achieve an optimal response to the treatment were supplemented with low-dose dexamethasone (Decadron). By the completion of the study, 37 percent of patients received dexamethasone in addition to plitidepsin and 18 percent of patients withdrew due to disease progression or side effects.

Of the 47 evaluable patients in the study, 13 percent responded to plitidepsin alone: 4 percent achieved partial response and 9 percent achieved minimal response. Of the 18 patients who received plitidepsin and dexamethasone, 22 percent achieved at least a minimal response. One patient who had achieved minimal response on plitidepsin alone improved to partial response, and one patient with stable disease achieved minimal response.

Additionally, 73 percent of participants on monotherapy experienced a decrease in paraprotein levels in the blood. Paraprotein is an abnormal protein present in high levels in myeloma patients. These decreases occurred even if patients did not achieve a measurable response to plitidepsin.

Median time to disease progression was 2.3 months for patients who only received plitidepsin. The addition of dexamethasone increased this to 4.2 months. However, the duration of response was similar between both treatment groups, with duration lasting up to 6 months. The one year overall survival rate for all study participants was 55 percent.

The researchers also noted that for patients who achieved partial or minimal responses, plitidepsin stayed in the blood longer, giving it a longer duration of action in those patients.

Side effects in both groups were similar in severity and frequency and were manageable, according to the study authors. Of the patients who received only plitidepsin, the most common severe side effects were low red blood cell counts (29 percent), low platelet counts (18 percent), fatigue (16 percent), and low white blood cell counts (12 percent).

Although hematological side effects were common, almost all patients had some degree of low red blood cells at the start of the trial and almost half of the patients had low platelet and white blood cells at the start. The researchers concluded that plitidepsin did not have a negative effect on the bone marrow, which makes it a good candidate for use in combination with other myeloma treatments.

While this study compared plitidepsin alone to plitidepsin in combination with dexamethasone, more can be learned by comparing the combination of plitidepsin and dexamethasone to dexamethasone alone. A Phase 3 trial comparing these two regimens is currently enrolling participants.

In response to the modest activity that plitidepsin had in combination with dexamethasone, Dr. Mateos said, “This has prompted the activation of a trial combining plitidepsin with Velcade (bortezomib). If this trial shows positive results, this combination could be interesting for relapsed and refractory myeloma patients.”

For more information, please refer to the abstract in Clinical Cancer Research (abstract).