How a chance meeting between academics launched an innovative medicine for multiple myeloma patients.
Pictured above: Craig Crews and Ray Deshaies
Therapies for multiple myeloma have come a long way since the turn of the century. Patients diagnosed with this form of blood cancer 20 years ago had few treatment options, and an average life expectancy of three to five years. A number of therapies have offered more treatment options for patients living with the disease, including KYPROLIS® (carfilzomib), Amgen’s medicine for multiple myeloma, which recently received regulatory approval in the U.S. to include a new regimen in its label following, in part, new positive results from the CANDOR clinical trial.
Known as DKd, the regimen combines carfilzomib with two other therapies—daratumumab and dexamethasone—for the treatment of adult patients with relapsed or refractory multiple myeloma. Amgen has also submitted marketing applications for DKd globally.
“This regimen provides a critically important option for multiple myeloma patients in first relapse—especially for patients who progress on maintenance with an immunomodulatory drug,” says Joseph Mikhael, MD, MEd, FRCPC, FACP, chief medical officer, International Myeloma Foundation. “It is a highly desirable non-immunomodulatory agent combination that leverages the synergy of daratumumab with the potent proteasome inhibitor carfilzomib.”
One scientist who is keenly aware of the progress achieved for multiple myeloma patients in this time is Ray Deshaies, Amgen’s senior vice president of Global Research. That’s because it was his innovative work on an intriguing cellular function that led to the development of KYPROLIS for multiple myeloma patients.
In the 1990s, Deshaies was a researcher and faculty member at the California Institute of Technology. “Initially I was studying yeast of all things, the same yeast that you make bread and brew beer with, and I had not thought about potential medical applications,” he says. But then he attended a meeting in Washington State, where he struck up a conversation with a fellow academic, Craig Crews, from Yale University.
“We had this idea for something that’s now known as PROTACs, which is actually becoming pretty popular in the industry now, and we began collaborating," Deshaies explains. “I was working on the proteasome, and Craig had just discovered a compound that was a proteasome inhibitor. We realized we could put all these things we were working on together and launch a company.”
So that’s exactly what they did. The two scientists co-founded Proteolix specifically to work on developing molecules called proteasome inhibitors into medicines. A proteasome inhibitor is a compound that blocks the function of a proteasome, which is a structure inside of living cells that acts like a garbage disposal, chopping up proteins that need to be thrown away.
“There are still no cures, but this is a disease that doctors may be able to manage for longer periods of time as they start combining these agents.”Ray Desahaies, SVP of Global Research, Amgen
It turned out that blocking proteasomes in patients with multiple myeloma could cause a buildup of proteins that may destroy the cancer cells in some patients, which is how their carfilzomib molecule eventually became the medicine KYPROLIS.
Proteolix would become part of Onyx Pharmaceuticals, which was later acquired by Amgen. Deshaies joined Amgen in 2017 to lead the company’s research efforts globally.
Deshaies is optimistic about the potential for new combinations of therapies to attack cancers like multiple myeloma from unique angles and continue to improve outcomes for patients. “KYPROLIS was a second-generation therapy and we’re now seeing third-generation therapies,” Deshaies says. “There are still no cures, but this is a disease that doctors may be able to manage for longer periods of time as they start combining these agents.”
Deshaies says the experience of seeing KYPROLIS become available for seriously ill patients around the world has been a highlight of his life’s work. “When we started this, Craig and I were young, inexperienced and filled with hope that our work would lead to something really important, but we were also aware of the tremendous challenges of drug development,” Deshaies says.
“The most gratifying thing is hearing the stories of patients who were able to get additional time with their families,” he adds. “There are still huge hurdles, but we have made a lot of strides in multiple myeloma, and the future is looking bright.”
U.S. KYPROLIS® (carfilzomib) Important Safety Information
IMPORTANT SAFETY INFORMATION FOR KYPROLIS
New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of administration.
Monitor patients for signs or symptoms of cardiac failure or ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse reactions until recovery, and consider whether to restart at 1 dose level reduction based on a benefit/risk assessment.
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate.
For patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment prior to starting treatment with KYPROLIS and remain under close follow-up with fluid management.
Acute Renal Failure
Cases of acute renal failure, including some fatal renal failure events, and renal insufficiency (including renal failure) have occurred. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.
Tumor Lysis Syndrome
Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred. Patients with a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly, and withhold until resolved.
Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred. Some events have been fatal. In the event of drug‐induced pulmonary toxicity, discontinue KYPROLIS.
Hypertension, including hypertensive crisis and hypertensive emergency, has been observed, some fatal. Control hypertension prior to starting KYPROLIS. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart based on a benefit/risk assessment.
Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed. Provide thromboprophylaxis for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone or with daratumumab and dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
For patients using hormonal contraception associated with a risk of thrombosis, consider an alternative method of effective contraception during treatment.
Infusion-related reactions, including life‐threatening reactions, have occurred. Signs and symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration. Premedicate with dexamethasone to reduce the incidence and severity of infusion-related reactions.
Fatal or serious cases of hemorrhage have been reported. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.
Hepatic Toxicity and Hepatic Failure
Cases of hepatic failure, including fatal cases, have occurred. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.
Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome have occurred. Monitor for signs and symptoms of TTP/HUS. Discontinue if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS is not known.
Posterior Reversible Encephalopathy Syndrome (PRES)
Progressive Multifocal Leukoencephalopathy (PML)
Cases of PML, including fatal cases, have occurred. In addition to KYPROLIS, other contributary factors may include prior or concurrent use of immunosuppressive therapy. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue and initiate evaluation for PML including neurology consultation.
Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-ineligible Patients
In a clinical trial of transplant-ineligible patients with newly diagnosed multiple myeloma comparing KYPROLIS, melphalan, and prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP), a higher incidence of serious and fatal adverse reactions was observed in patients in the KMP arm. KMP is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma.
KYPROLIS can cause fetal harm when administered to a pregnant woman.
Advise pregnant women of the potential risk to a fetus. Females of reproductive potential should use effective contraception during treatment with KYPROLIS and for 6 months following the final dose. Males of reproductive potential should use effective contraception during treatment with KYPROLIS and for 3 months following the final dose.
The most common adverse reactions in the combination therapy trials: anemia, diarrhea, fatigue, hypertension, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, dyspnea, and insomnia.
- The most common adverse reactions in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.
Please see accompanying full Prescribing Information.