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The Evolving Overall Survival Expectations of Patients with Relapsed or Refractory Multiple Myeloma

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.

Dr. Ruben Niesvizky

Dr. Ruben Niesvizky

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
USA-171-060934


IMPORTANT SAFETY INFORMATION
KYPROLIS® (carfilzomib) can cause serious side effects:
  • Heart problems: KYPROLIS can cause heart problems or worsen pre-existing heart conditions. Death due to cardiac arrest has occurred within one day of KYPROLIS administration. Before starting KYPROLIS, you should have a full medical work-up (including blood pressure and fluid management). You should be closely monitored during treatment.
  • Kidney problems: There have been reports of sudden kidney failure in patients receiving KYPROLIS. Your kidney function should be closely monitored during treatment.
  • Tumor lysis syndrome (TLS): Cases of TLS have been reported in patients receiving KYPROLIS, including fatalities. You should be closely monitored during treatment for any signs of TLS.
  • Lung damage: Cases of lung damage have been reported in patients receiving KYPROLIS, including fatal cases.
  • Pulmonary hypertension (high blood pressure in the lungs): There have been reports of pulmonary hypertension in patients receiving KYPROLIS.
  • Lung complications: Shortness of breath was reported in patients receiving KYPROLIS. Your lung function should be closely monitored during treatment.
  • High blood pressure: Cases of high blood pressure, including fatal cases, have been reported in patients receiving KYPROLIS. Your blood pressure should be closely monitored during treatment.
  • Blood clots: There have been reports of blood clots in patients receiving KYPROLIS. If you are at high risk for blood clots, your doctor can recommend ways to lower the risk.
  • If you are using KYPROLIS in combination with dexamethasone or with lenalidomide plus dexamethasone, your doctor should assess and may prescribe another medicine to help lower your risk for blood clots.
  • If you are using birth control pills or other medical forms of birth control associated with a risk of blood clots, talk to your doctor and consider a different method of birth control during treatment with KYPROLIS in combination with dexamethasone or with lenalidomide plus dexamethasone.
  • Infusion reactions: Symptoms of infusion reactions included fever, chills, joint pain, muscle pain, facial flushing and/or swelling, vomiting, weakness, shortness of breath, low blood pressure, fainting, chest tightness, and chest pain. These symptoms can occur immediately following infusion or up to 24 hours after administration of KYPROLIS. If you experience any of these symptoms, contact your doctor immediately.
  • Severe bleeding problems: Fatal or serious cases of bleeding problems have been reported in patients receiving KYPROLIS. Your doctor should monitor your signs and symptoms of blood loss.
  • Very low platelet count: Low platelet levels can cause unusual bruising and bleeding. You should have regular blood tests to check your platelet count during treatment.
  • Liver problems: Cases of liver failure, including fatal cases, have been reported in patients receiving KYPROLIS. Your liver function should be closely monitored during treatment.
  • Blood problems: Cases of a blood disease called thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal cases, have been reported in patients who received KYPROLIS. Your doctor should monitor your signs and symptoms.
  • Brain problems: A nerve disease called Posterior Reversible Encephalopathy Syndrome (PRES), formerly called Reversible Posterior Leukoencephalopathy Syndrome (RPLS), has been reported in patients receiving KYPROLIS. It can cause seizure, headache, lack of energy, confusion, blindness, altered consciousness, and other visual and nerve disturbances, along with high blood pressure. Your doctor can monitor your signs and symptoms.
  • KYPROLIS should not be combined with melphalan and prednisone: Newly diagnosed transplant ineligible multiple myeloma patients have shown an increased risk of serious and fatal side effects when using KYPROLIS in combination with melphalan and prednisone.
  • Possible fetal harm: KYPROLIS can cause harm to a fetus (unborn baby) when given to a pregnant woman. Women should avoid becoming pregnant during treatment with KYPROLIS. Men should avoid fathering a child during treatment with KYPROLIS. KYPROLIS can cause harm to a fetus if used during pregnancy or if you or your partner become pregnant during treatment with KYPROLIS.
You should contact your doctor immediately if you experience any of the following:
  • Shortness of breath
  • Prolonged, unusual or excessive bleeding
  • Yellowing of the skin and/or eyes (jaundice)
  • Headaches, confusion, seizures, or loss of sight
  • Pregnancy (women should not receive KYPROLIS if they are pregnant or breastfeeding)
  • Any other side effect that bothers you or does not go away
What are the possible side effects of KYPROLIS?
  • 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.
  • The most common side effects occurring in at least 20% of patients receiving KYPROLIS when used alone (monotherapy) in trials are: low red blood cell count, tiredness (fatigue), low platelets, nausea, fever, difficulty breathing, diarrhea, headache, cough, swelling of the lower legs or hands.
These are not all the possible side effects of KYPROLIS. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.
Please see accompanying Full Product Information.