The treatment of multiple myeloma (MM) has dramatically changed over the past year and the new standard of care in 2016 may not only lead to improved quality of life for patients but also improved overall survival (OS). In 2015, The U.S. Food and Drug Administration approved an unprecedented number of new agents for multiple myeloma, including daratumumab, elotuzumab, ixazomib, panobinostat, and carfilzomib.
Ravi Vij, MD, MBA, who is a professor of medicine in the Division of Medical Oncology at Washington University School of Medicine, St. Louis, MO, said the approval of these agents marks a dramatic change in the management of patients with MM and is a significant milestone.
“With approval of these new drugs over the last 12 months we have more options for the treatment of patients with MM. In the future, these drugs will be explored in novel combination regimens and several may move into earlier lines of therapy which will likely add further to improvements in outcomes for patients with myeloma,” said Dr Vij.
New Classes of Agents
Elotuzumab is an immunostimulatory monoclonal antibody. It targets signaling lymphocytic activation molecule F7 (SLAMF7). Daratumumab, a human IgG1κ monoclonal antibody, has the ability to help destroy CD38-expressing malignant plasma cells. Panobinostat is a cinnamic hydroxamic acid analogue and selectively inhibits histone deacetylase (HDAC).
It induces hyperacetylation of core histone proteins, which may result in modulation of cell cycle protein expression, cell cycle arrest in the G2/M phase and apoptosis. Panobinostat appears to modulate the expression of angiogenesis-related gene (hypoxia-inducible factor-1alpha [HIF-1a] and vascular endothelial growth factor [VEGF]).
Dr Vij said the ability to incorporate an immune-based treatment into the myeloma treatment paradigm may lead to significant improvements in outcomes while adding little additional toxicity. However, he cautioned that there are still many unanswered questions about the best use of these new agents in terms of combination therapies.
“The full impact of these treatments will become apparent in the years to come. However, I think the introduction of new classes of drugs has the potential to add significantly to the lifespan of patients with myeloma. Hopefully, these will get us one step closer to the goal of curing patients with the disease,” Dr Vij told Cancer Therapy Advisor.
Ixazomib is the first oral proteasome inhibitor indicated in combination with lenalidomide and dexamethasone for the treatment of patients with MM who have received at least one prior therapy. Proteasome inhibitors prevent the breakdown of protein in cancer cells and subsequently trigger cancer cell death. Carfilzomib binds to and inhibits the chymotrypsin-like activity of the 20S proteasome. This subsequently leads to a build-up of polyubiquinated proteins, causing cell cycle arrest, apoptosis, and inhibition of tumor growth.
Studies presented at the 57th American Society of Hematology (ASH) Annual Meeting and Exposition showed that new drug combinations can significantly extend the time in which MM is controlled in patients with relapsed or treatment-resistant forms of the disease.
Several trials paired the oral drugs lenalidomide and dexamethasone with other agents, each of which exploits a different vulnerability in tumor cells.1-4 The various combinations are at different stages of clinical testing. However, all are proving effective at producing at least partial remissions and increasing the duration of those remissions with tolerable side effects for most patients.
Paul Richardson, MD, clinical program leader and director of clinical research at Dana-Farber Cancer Institute’s Jerome Lipper Multiple Myeloma Center in Boston, MA, said with the approvals of daratumumab, ixazomib, elotuzumab, and now panobinostat there has been an unprecedented pace of progress in MM therapy over the past 24 months.
“It is a grand slam in terms of drug approvals in 2015,” Dr Richardson said in an interview with Cancer Therapy Advisor. “The benefits will become clinically evident over the next year or 2. The impact on survival data will take a little longer, but we know that 3 drugs are essential.”
In a combined phase 1 and phase 2 trial of lenalidomide/dexamethasone plus daratumumab, researchers found that 11 of 32 patients had a partial response to the drug regimen.1 The most common adverse side effects were neutropenia, muscle spasms, cough, diarrhea, fatigue, and hypertension.
In a phase 3 trial of lenalidomide/dexamethasone plus ixazomib, patients receiving all 3 drugs experienced a 35% improvement in progression-free survival (PFS) compared to those receiving lenalidomide and dexamethasone alone. The study included 722 patients and it showed that the addition of ixazomib increased median PFS to 20.6 from 14.7 months without a substantial increase in overall toxicity.2
A phase 3 trial of lenalidomide/dexamethasone with elotuzumab demonstrated a 30% reduction in the risk that the disease would progress over a 3-year period compared to a course of lenalidomide and dexamethasone alone.3
Overall, 79% of the 321 patients who received the 3-drug regimen responded to it, compared to 66% of the 325 patients in the 2-drug group. The most common adverse side effects were lymphopenia, neutropenia, blood platelet deficiency, and infection.
Dr Richardson said these encouraging data build upon the real success of translational efforts in myeloma over the last decade, and provide exciting new options with the real promise of improving patient outcomes.