New Approaches Explored in Relapsed/Refractory Multiple Myeloma

Kenneth C. Anderson, MD

Over the past decade, several new treatments for multiple myeloma have become available, including carfilzomib (Kyprolis) and pomalidomide (Pomalyst). These treatments and their combinations—often with low-dose dexamethasone—have changed the landscape of treatment for multiple myeloma, allowing some patients to live for up to 10 years. Despite this progress, relapse is inevitable, and improved strategies are needed.

Going forward, newer targeted therapies, including immunotherapy, and genomic analysis are under study, and will hopefully bring further progress, noted Kenneth C. Anderson, MD, Dana-Farber Cancer Center/ Brigham and Women’s Cancer Center, Boston, Massachusetts. Anderson discussed management of relapsed/ refractory multiple myeloma at the NCCN 8th Annual Congress on Hematologic Malignancies.

“Several protocols of novel immune and targeted agents show promise alone and in combination, including monoclonal antibodies, immune therapies, and newer proteasome inhibitors. Genomic analysis provides information about evolution of disease from diagnosis to relapse and can aid in identifying new targets for therapeutic approaches,” Anderson said.

The following drugs are FDA-approved for the treatment of multiple myeloma: bortezomib (Velcade), lenalidomide (Revlimid), thalidomide (Thalomid), doxorubicin, carfilzomib, and pomalidomide. These drugs target the tumor and the microenvironment, and are used clinically as initial therapy, consolidation therapy, and maintenance, as well as for advanced disease and relapse.

The most recently FDA-approved drugs for multiple myeloma, carfilzomib and pomalidomide, both provide meaningful response rates, duration of response, and may improve survival in the relapsed/refractory setting. Many patients in this setting have been heavily pretreated with up to five lines of prior therapy, and new options are needed, Anderson said.

Carfilzomib received accelerated approval from the FDA in 2012 for the treatment of patients with multiple myeloma who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of the last therapy. The approval was based on a single-arm study in which 266 patients with heavily pretreated, relapsed/refractory multiple myeloma received single-agent carfilzomib. The overall response rate was 23.7% with a median duration of response of 7.8 months. The drug is now being evaluated in the confirmatory phase III ASPIRE study (Figure).

Pomalidomide is a potent stimulator of autologous T cells and natural killer cells that directly targets the regulatory T cells and enhances the immune response. The triple combination of pomalidomide, bortezomib, and low-dose dexamethasone has shown promise in relapsed/refractory multiple myeloma, with rapid and ongoing responses, even in patients with adverse cytogenetic features. This combination is being evaluated in the phase III OPTIMISMM trial (NCT01734928).

Figure. Carfilzomib Phase III ASPIRE Study Design

Patients will receive treatment until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival. Secondary outcome measures include overall survival and overall response rate. Interim data are expected next year.

Anderson said that it is unlikely that carfilzomib and/or pomalidomide can be dose escalated. Studies suggest that higher doses are too toxic.

Progress is likely to come from novel approaches, said Anderson. These include monoclonal antibodies, such as daratumumab and elotuzumab, which are both in early clinical trials. In May, daratumumab received the FDA’s Breakthrough Therapy designation for the treatment of patients with doublerefractory multiple myeloma.

A vaccine approach that fuses myeloma cells with dendritic cells also shows promise, enhancing the immune response and disease stabilization, Anderson said.

New proteasome inhibitors and new IMiDs have shown promising activity in relapsed/refractory multiple myeloma. These include the first deubiquitinating enzyme inhibitor, P5091, and a broader proteasome inhibitor, marizomib. These drugs appear to have activity in patients resistant to bortezomib. Combining a proteasome inhibitor with a histone deacetylase (HDAC) inhibitor is another strategy being studied.

Other novel approaches to relapsed/refractory multiple myeloma include BTK inhibitors and BET bromodomain inhibitors.