Every March, the blood cancer community recognizes Multiple Myeloma Awareness Month – an opportunity to encourage the public to raise awareness of multiple myeloma, a form of blood cancer that starts in the plasma cells in the bone marrow and interferes with the immune system’s ability to fight infection.
When plasma cells become cancerous, they multiply quickly, crowding out the healthy blood cells and hindering the patient’s ability to fight infection, sometimes leading to untimely death.
Multiple myeloma was expected to impact approximately 30,000 patients in the US in 2017. Unfortunately, the disease remains incurable, with patients facing ever-tightening cycles of success and failure on treatment. Four out of 10 patients who start treatment after their first relapse may not start their next therapy.
“There are several challenges and opportunities in treating a patient with multiple myeloma,” said Ruben Niesvizky, MD, director of the Multiple Myeloma Center at Weill Cornell Medicine and New York-Presbyterian/Weill Cornell Medical Center.
Treating Multiple Myeloma
While multiple myeloma remains incurable, patients’ outcome expectations have improved significantly in recent years. In the 1990s, patients typically lived two to three years following a multiple myeloma diagnosis. Now, patients are living seven to 10 years, and sometimes longer.
“Once the disease returns we strive to offer the longest survival with the least amount of toxicity,” said Dr. Niesvizky. “Fortunately, we have seen dramatic changes in the outcomes over the last five years, and we are now obtaining long and durable responses.”
This change in survival expectations is directly linked to the array of novel therapeutic regimens that have become available. Up until a decade ago, cytotoxic chemotherapy-based regimens were the main options for patients. Today, multiple myeloma is commonly treated using multiple modalities, including cytotoxic chemotherapy, immunomodulators, corticosteroids, etc. Multiple treatments are used in combination that attack the disease in different ways and are tailored to the individual patient’s needs, with the goal of getting them into remission and keeping them there as long as possible.
One class of agents used to treat multiple myeloma, known as proteasome inhibitors, leads to accumulation of abnormal proteins within the cell and eventually cell death. Myeloma cells are particularly dependent on proteasomes to survive.
“Proteasome inhibitors are often used as a cornerstone in the treatment of myeloma,” said Dr. Niesvizky. While multiple myeloma can be treated with a single agent, more often different kinds of drugs are used in combination.
The Gold Standard Endpoint
While there’s been a significant increase in the number of available multiple myeloma therapies over the past five years, few have proven in clinical trials to improve overall survival (OS), or the total length of a person’s life after beginning treatment.
Progression-free survival (PFS), the measurement of the time a person lives without their disease getting worse, is by far the most common primary endpoint in Phase 3 multiple myeloma clinical trials. Progression-free survival is considered a surrogate endpoint for OS, which takes a longer time to measure.
While PFS often correlates with an improvement in OS, this is not always the case. Overall survival remains the gold standard of endpoints because it clearly demonstrates a drug’s value in extending the patient’s life.
“There are many factors that are considered in tailoring treatment programs for a particular patient,” said Dr. Niesvizky. “But certainly, overall survival appears to be one of the most powerful arguments in favor of a drug or drug combination.”
Quite an ENDEAVOR
Earlier this year, the U.S. Food and Drug Administration (FDA) announced the approval of a supplemental New Drug Application to add overall survival data for the Kd vs Vd indication to the Prescribing Information for KYPROLIS® (carfilzomib).
Originally approved by the FDA in 2012, KYPROLIS is approved for use in combination with dexamethasone or with lenalidomide plus dexamethasone, which are other medicines used to treat multiple myeloma. KYPROLIS® is a prescription medication used to treat patients with relapsed or refractory multiple myeloma who have received one or more previous treatments for multiple myeloma.
Data added to the label showed KYPROLIS and dexamethasone (Kd) in combination helped patients with relapsed multiple myeloma live nearly eight months longer than Velcade® (bortezomib) and dexamethasone (Vd), a recent standard of care.
“For the first time, it was determined that carfilzomib at this [56 mg/m2] dose is superior to bortezomib –not only in terms of PFS, but also overall survival,” said Dr. Niesvizky, who was a clinical investigator on the Phase 3 ENDEAVOR trial. “That is highly significant because moving forward, we should consider using carfilzomib over bortezomib in the right clinical scenario.”
In addition, the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®), which clinicians often reference to help guide decision-making in the management of cancer, now lists KYPROLIS and dexamethasone as the only preferred doublet regimen at relapse for multiple myeloma.
The most common side effects occurring in at least 20% of patients receiving KYPROLIS in the combination therapy trials are: low red blood cell count, low white blood cell count, diarrhea, difficulty breathing, tiredness (fatigue), low platelets, fever, sleeplessness (insomnia), muscle spasm, cough, upper airway (respiratory tract) infection, and decreased potassium levels.
A Brighter Future for Patients
Several novel agents have received FDA approval over the past five years for the treatment of patients with multiple myeloma, and drug development isn’t slowing down any time soon.
For now, the emergence of a therapeutic regimen that is proven to improve overall survival may provide hope for appropriate patients.
Image: Michele Augusto