Many Targeted Drugs in Development for Multiple Myeloma: Monoclonal Antibodies Close to Approval

May 2015, Vol 6, No 4

Hollywood, FL—New targeted agents in multiple myeloma will turn it into a chronic illness, with sustained complete response possible in a significant fraction of patients, predicted Kenneth C. Anderson, MD, Director, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, at his presentation at the 2015 National Comprehensive Cancer Network (NCCN) conference.

New monoclonal antibodies and proteasome inhibitors are in development for the treatment of patients with multiple myeloma, as well as agents that target protein degradation, in addition to novel classes of targeted therapies, Dr Anderson said.

Monoclonal Antibodies

“Monoclonal antibodies have been elusive in myeloma…but I think we are going to find some this year, not 1 but 2,” said Dr Anderson.

Elotuzumab is a humanized immunoglobulin G1 monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7, formerly known as CS1). It activates natural killer cells directly and via a CD16-mediated pathway.

When used in combination with lenalidomide (Revlimid) and dexamethasone (Decadron) in a phase 2 trial in patients with relapsed multiple myeloma, elotuz­umab was associated with a 92% response rate at the 10-mg/kg dosage and a progression-free survival of 32.5 months.

“These responses can last almost 3 years, even in high-risk myeloma,” Dr Anderson said. “I do think that this particular antibody is highly likely to be FDA-approved by the end of the year.”

The target for the human monoclonal antibody daratumumab is CD38. After showing enhanced killing of multiple myeloma cells in vitro when used with lenalidomide, this antibody has gone forward into the clinic. The complete resolution of monoclonal proteins has been achieved with the combination of daratumumab, lenalidomide, and dexamethasone, “and my prediction is…this particular antibody will likely be FDA-approved by the end of 2015,” said Dr Anderson.

The other CD38-targeting antibody is SAR650984. When combined with lenalidomide and dexamethasone, response rates as high as 67% have been observed in patients with relapsed or refractory multiple myeloma.

These antibodies have been associated with responses in some patients who have disease that is refractory to all currently FDA-approved drugs included in the current NCCN guideline.

“I do think they will confer additional benefit,” Dr Anderson said, “especially in patients who have refractory disease.”

“Immunotherapies are coming to a clinic near you in myeloma,” he said. A potent antibody-drug conjugate directed at CD138, which is highly expressed on all multiple myeloma cells, is indatuximab ravtansine (BT062). The overall ­response rate was 83% in 35 evaluable patients who received indatuximab ravtansine, lenalidomide, and dexamethasone.

HDAC and Proteasome Inhibitors

Histone deacetylase (HDAC) inhibitors block the shuttling of ubiquitinated protein to the aggresome for its degradation. Vorinostat (Zolinza), used for the purpose of blocking the aggresomal degradation pathway, together with bor­tezomib (Velcade), which blocks the ­proteasome degradation pathway, significantly improved the response rate compared with bortezomib alone in a phase 3 trial in patients with relapsed or refractory multiple myeloma. However, diarrhea, fatigue, and thrombocytopenia limited tolerability.

The broad-acting type 2 HDAC inhibitor panobinostat (Farydak) was approved by the FDA in February 2015 for the treatment of patients with relapsed or refractory multiple myeloma based on data from the PANORAMA 1 study, in which patients who received panobino­stat, bortezomib, and dexamethasone had an improvement in median progression-free survival of >4 months compared with bortezomib plus dexamethasone alone.

Panobinostat was approved with a boxed warning alerting patients and physicians that severe diarrhea and severe and fatal cardiac events, arrhythmias, and electrocardiographic changes have occurred with this drug in clinical trials.

ACY-1215 is a selective HDAC inhibitor with a much more favorable side-effect profile. The response rates with ACY-1215 have been approximately 45%, including 33% of patients who have bortezomib-refractory multiple myeloma, said Dr Anderson.

“I think we will need to have an open mind as to whether we can use an HDAC inhibitor…in a way that’s tolerated to appreciate its benefit,” he said. At higher doses of ACY-1215, the full resolution of the myeloma protein is realized, even in patients with lenalidomide-refractory disease.

Additional Targets

Additional agents in development for multiple myeloma are Bruton’s tyrosine kinase inhibitors and kinesin spindle protein (KSP) inhibitors.

The KSP inhibitor filanesib (ARRY-520) blocks mitosis, and is being tested primarily with bortezomib in patients with low serum levels of a binding protein known as AAG.

Protein kinase B (AKT) inhibitors may also be useful, because proteasome inhibitors activate AKT.

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