Phase I/II study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma

Early-stage research suggests that when added to standard multiple myeloma therapy, an investigational oral proteasome inhibitor known as MLN9708 increases the efficacy of treatment with few side effects.

The last decade has seen an explosion of new therapies for myeloma, a disease that causes the plasma cells found in the bone marrow to grow uncontrollably and form tumours.

These tumour cells can destroy bones, damage kidneys, and make it difficult for the bone marrow to produce healthy blood cells and platelets, which puts patients at higher risk of infection and abnormal bleeding.

One therapy for myeloma is bortezomib, a drug classified as a proteasome inhibitor for its activity blocking the proteasome (a cell structure that regulates the proteins involved in cell replication and survival), which prevents the function of proteins essential for myeloma cell survival.

Another myeloma treatment strategy involves immunomodulatory agents, such as lenalidomide, which bolster the immune system's response to myeloma and alter the tumour microenvironment that sustains cancer cell growth. While each therapy is individually effective, when combined they offer improved response rates and lead to longer duration of response.

While immunomodulatory agents are produced in convenient oral pill form, bortezomib must be administered via injection and carries a risk of nerve damage, which can deter patient adherence to treatment regimens. MLN9708, the first oral proteasome inhibitor to enter clinical trials for the treatment of myeloma, may offer a more convenient and tolerable form of treatment that limits the risk of nerve damage.

In order to assess the efficacy, safety, and proper dose of MLN9708 in previously untreated myeloma patients, researchers enrolled 65 patients in a Phase I/II study and administered an oral dose of the proteasome inhibitor combined with lenalidomide and dexamethasone for up to 12, 28-day cycles, followed by maintenance therapy with MLN9708 every 28 days until disease progression.

Primary objectives in Phase I included safety, maximum tolerated dose, and recommended Phase II dose.

In Phase II, primary objectives included complete remission and very good partial response (VGPR, measured by a 90% or greater reduction in abnormal myeloma proteins in the blood).

In Phase I, the maximum tolerated dose was determined as 2.97 mg/m2 and recommended Phase II dose was selected as 2.23 mg/m2, which was later converted to a 4.0 mg/m2 dose based on encouraging results related to the body’s ability to tolerate the drug. In Phase II, the investigators observed an overall response rate of 92 percent with 55 percent of patients reaching VGPR or better, including 23 percent with a complete remission.

As the treatment cycles progressed, the rate and depth of response increased.

Minor adverse events, such as fatigue, nausea, and rash, were noted in approximately 40 percent of patients. Serious adverse events were minimal and primarily consisted of decreased blood counts, nausea and vomiting, diarrhea, rash, and electrolyte disturbances.

One patient died from pneumonia while on treatment, and seven patients discontinued treatment due to different side effects.

“As targeted therapies continue to evolve, we are now shifting our efforts to focus on making them safer and producing them in more convenient forms for patients. MLN9708 is a great example of how to accomplish this goal,” said Shaji K. Kumar, MD, lead author and Professor of Medicine and Consultant in Hematology at the Mayo Clinic in Rochester, Minn. “We are now planning ongoing studies to examine this drug in combination with other myeloma drugs in Phase II and Phase III clinical trials. Once approved for treatment of myeloma, this drug will allow patients the convenience of a completely oral, highly effective regimen for treatment of multiple myeloma.”

Source: ASH