Results of a small Phase 1 study indicate that the investigational drug mila­tu­zu­mab on its own has limited efficacy in patients with advanced relapsed and re­fractory multiple myeloma.

The best response the investigators observed in their study was stable disease, which 20 percent of the patients achieved. One patient con­tin­ued to have stable disease without progression for 17 months.

According to the investigators, these results are in line with those for sev­er­al other agents in the same class of drugs, such as siltuximab and elo­tuzumab, which have shown modest activity as single agents in pa­tients with advanced multiple myeloma.

At least one of the agents in this class of drugs, however, has gone on to show significant activity against myeloma when combined with standard myeloma therapies.  Specifically, in a clinical trial evaluating elo­tu­zumab in combination with Revlimid (lenalidomide) and dexamethasone (Decadron), 92 percent of the re­lapsed and refractory patients responded to the combination at its most effective dose (see re­lated Bea­con news).

Thus, the authors of the current study recommend that, as a next step, milatuzumab also be evaluated in combination with corticosteroids such as prednisone or dexamethasone plus Revlimid or Velcade (bor­tez­o­mib) as potential therapy for myeloma.

A modified version of milatuzumab, which earlier had the codename hLL1,  is also being tested in a Phase 1/2 clinical trial.  The compound consists of milatuzumab bound to doxorubicin (Adriamycin), and is referred to as milatuzumab-doxorubicin (hLL1-DOX).  In this bound form, milatuzumab helps guide doxo­ru­bi­cin, a chemotherapy drug, directly to myeloma cells.

Background

Milatuzumab, which is being developed by the biopharmaceutical company Immunomedics (NASDAQ:​IMMU), belongs to a class of drugs called monoclonal antibodies. Monoclonal antibodies work by identifying proteins on the surface of myeloma cells and signaling for the immune system to destroy the cancer cells.  Other compounds in this class of drugs include daratumumab, elotuzumab, and siltuximab.

Milatuzumab has received orphan drug designation in the United States and in Europe for the treatment of multiple myeloma and chronic lymphocytic leukemia (CLL).

The designation, which provides several benefits to encourage further development of the drug for the specified rare ("orphan") diseases, was based on the results of preclinical studies in which milatuzumab demonstrated encouraging efficacy against myeloma and CLL.

Based on the results of the preclinical studies, the study authors decided to test milatuzumab alone in patients with relapsed and refractory myeloma patients. The primary goal of this trial was to evaluate the safety of milatuzumab and to determine the maximum tolerated dose of the drug.

Study Design

The Phase 1 study included 25 patients with advanced relapsed or refractory multiple myeloma. Patients were enrolled at six different institutions across the U.S. between 2007 and 2009.

The median patient age was 63 years. The patients were heavily pretreated, having received a median of five prior therapies; 68 percent had previously completed at least one stem cell transplant. Of the 25 patients, 72 percent were relapsed and 28 percent were resistant (refractory) to their last treatment.

Study participants received one of four doses of milatuzumab, ranging from 1.5 mg to 16 mg, by intravenous infusion on days 1, 4, 8, 11, 15, 18, 21, and 25 of a single 28-day treatment cycle.

Patients were evaluated during treatment and for 12 weeks after treatment. Follow-up evaluations after 12 weeks continued every three months for two years until disease progression and resolution of any treat­ment-related side effects.

Results

The best response the investigators observed was stable disease, which 20 percent of the patients who started treatment with milatuzumab were able to achieve at the end of the 12-week post-treatment evaluation period. One of these patients, who had received five previous myeloma therapies prior to enrolling in the study, had stable disease for 17 months after the treatment with milatuzumab.

The rate of stable disease was higher (26 percent) if one excludes from consideration patients who were not able to complete the entire 28-day cycle of treatment with milatuzumab.

Treatment-related side effects occurred in 76 percent of patients, with most caused by mild infusion reac­tions. Infusion reactions are a common side effect of monoclonal antibody treatment, previously observed in studies of elotuzumab and daratumumab.

After the first two patients experienced severe reactions to the milatuzumab infusion, the investigators changed the treatment protocol to address the problem. They administered corticosteroids before the in­fu­sion, slowed the infusions, and repeated the pre-infusion medications after the infusion.

After these adjustments, the milatuzumab infusions resulted in less frequent and less severe reactions.

About half of all patients (48 percent) experienced severe to life-threatening side effects, with anemia being the most common (20 percent).

One-quarter (24 percent) of patients discontinued treatment before receiving all eight doses, 8 percent due to side effects and 16 percent due to disease progression.

The maximum tolerated dose was not reached.

For more information, please refer to the study in the British Journal of Haematology (abstract).