Posted: Tuesday, August 29, 2017
A Flurry of Drug Approvals in Multiple Myeloma
The treatment of multiple myeloma was revolutionized in 2003 with the approval of bortezomib, the first proteasome inhibitor for patients with newly diagnosed as well as relapsed or refractory disease.1 In 2012, carfilzomib was added to the roster of proteasome inhibitors approved for treatment of patients with multiple myeloma,2 and in 2015, ixazomib became the third approved agent in this class.3 Another class of agents, the immunomodulators (iMIDs) also entered the scene with the approval of lenalidomide in 20064 and pomalidomide in 2013.5 In addition, two monoclonal antibodies (mABs)—daratumumab and elotuzumab, both approved in 2015—were added to the mix.6,7 By the third quarter of 2017, at least nine drugs have been approved for the treatment of multiple myeloma, in addition to chemotherapy agents such as cyclophosphamide and doxorubicin and the steroid dexamethasone, all of which have been included in the NCCN Guidelines.8
Initial approval of daratumumab in 2015 was for use as a single agent.10 However, studies of daratumumab in combination with either a PI or an iMID (plus dexamethasone) demonstrated efficacy, and today most patients in myeloma programs receive the mAB as part of a combination regimen.11–13 “Those of us who work in high-volume myeloma centers are accustomed to administering daratumumab in combination because we worked with these drugs for a number of years before approval,” observed Professor Saad Usmani, MD, Director of Clinical Research in Hematologic Malignancies and Chief of Plasma Cell Disorders at the University of North Carolina at Chapel Hill, Levine Cancer Institute, and the Carolinas HealthCare System in Charlotte, North Carolina.
Charise Gleason, MSN, NP-BC, AOCNP, who is Chief of Advanced Practice Providers and part of the myeloma team headed by Sagar Lonial, MD, at the Emory Winship Cancer Institute in Atlanta, agrees that most patients now receive daratumumab as part of a combination regimen. A few patients, she pointed out, receive daratumumab as a single agent along with corticosteroids, but these are individuals who generally have difficulty tolerating multidrug regimens. The most commonly prescribed regimen among eligible myeloma patients in the Emory program is daratumumab plus pomalidomide,14 although they also use daratumumab in combinations with lenalidomide13 or bortezomib.12
Combination Regimens: Mixing and Matching Drugs and Drug Classes
Each of these drugs has its own nuances when used in combination, Dr. Usmani explained. Mechanistically, the iMIDs are better partners for daratumumab. “With a proteasome inhibitor, the mechanism of action for the combination [ie, daratumumab + bortezomib] is probably more of a direct cell kill effect.12 With an iMID,14 the effect is more immunomodulatory (in addition to the direct cell kill) via antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, induction of apoptosis, and modulation of CD38 enzyme activity resulting from the mAB itself.”10
According to Dr. Usmani, patients often prefer the iMID/daratumumab combinations because of treatment logistics. For instance, with an iMID combination, by the time treatment has progressed to the sixth or seventh infusion, patients continue their oral medications and only need to come to the center once a month. In contrast, those who receive bortezomib have to come to the clinic more frequently.
Dr. Usmani observed that pomalidomide should be started at a low dose when it is combined with daratumumab because of the potential for myelosuppression. “This combination is generally used in later relapses, so patients’ marrows are more depleted, and these patients are vulnerable to myelosuppression,” he explained.
First Things First: Blood Typing and Antiviral Prophylaxis
Switching treatment to a second-line regimen requires substantial patient education up front, Ms. Gleason said. “At our center, the physician or advanced practice provider will discuss changes with the patient; further education is provided by our nurse and our clinical pharmacist. We also make sure to provide handouts and remind the patient and caregiver to call with any questions.”
Dr. Usmani noted that T cells are dysregulated in myeloma and the immune system is suppressed, particularly in the relapsed setting. Patients are therefore at risk for herpes zoster reactivation. The general recommendation is to initiate antiviral prophylaxis with acyclovir or valacyclovir while on treatment for myeloma.15
In addition to standard antiviral prophylaxis, Ms Gleason said, “We add prophylaxis for Pneumocystis jirovecii in patients who will be treated with a multidrug regimen.”16
Both experts emphasized the need to perform blood typing before patients start on a daratumumab-containing regimen. CD38 is a cell-surface marker that is expressed on many different types of blood cells, including red blood cells. “Daratumumab can coat the red cells,” Dr. Usmani said, “which can interfere with accurate blood typing (ie, Coombs testing) and cross matching.”17 This effect can last for 3 to 6 months after daratumumab is discontinued. “We therefore recommend that patients have blood typing done before starting daratumumab and have that information available on a pocket card, in case a transfusion is needed,” he said.
Finally, Ms. Gleason added, “we also explain that daratumumab can interfere with serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE),18 which can be a problem because SPEP and IFE are used to assess disease response. The daratumumab IFE reflex assay has been developed to mitigate daratumumab interference.”
Getting Through the First Dose
The primary challenge with any daratumumab-containing regimen is getting the patient safely through the first dose, Ms. Gleason said. “When we talk about that first dose, patients may become anxious, but we like to point out that if about half of patients experience a reaction, that also means that half do not. Again, we stress that this agent is generally very well tolerated.”
With subsequent dosing (ie, after the first dose), Dr. Usmani said, daratumumab appears to be very well tolerated. “The advantage of antibodies is that the safety profile is very good. I have several patients in their early to mid-80s who tolerate daratumumab without a problem and are doing quite well.”
A little less than half of patients who receive daratumumab for the first time will develop some degree of infusion reaction.10 Most infusion reactions occur with the first dose. Most of those reactions, 95% to 96%, will be grade 1 or 2. In Dr. Usmani’s program, “patients are instructed to take dexamethasone or methylprednisolone the night before and the morning of the first infusion. Based on our experience in the extended access program, we also instruct patients to take montelukast [a leukotriene receptor antagonist]19 the day before, the day of, and the day after the infusion. We discovered that infusion reactions were further reduced when montelukast was on board.”
The Emory Winship myeloma team also recommends that montelukast be added to standard recommended premedications. “We do this at the infusion center on the day of the infusion,” Ms. Gleason explained. “We tried a number of different ways of giving the premedication, including the night before or the morning of the infusion at home. Our clinical pharmacist looked at the pharmacokinetics, and what we found was that it didn’t make a difference. So, we just have patients arrive at the center early and give the premedications an hour before infusion. This way, we know the montelukast is going to peak at the appropriate time,” she said.
A first daratumumab infusion can take 7 hours or more, Ms. Gleason remarked, so centers and providers are encouraged to start early in the day. If there is an infusion reaction, it can be managed in a timely fashion. Subsequent infusions take about 3.5 to 4 hours.
“In cycle one, we also give 2 days of oral prednisone at 20 mg after the infusion, as was done in the monotherapy trial.10 So, patients take the oral steroid on days 2 and 3, which helps mitigate the flu-like symptoms that some patients report during those first few days,” Ms. Gleason added.
Dr. Usmani noted that a grade 4 infusion-related reaction, such as profound respiratory distress requiring an ICU admission with monitoring, would be a contraindication to further treatment. “Having said that,” he noted, “we have used daratumumab in clinical trials since 2013 in hundreds of patients and have not had one instance where a patient was hospitalized due to a grade 4 infusion reaction.”
Ms. Gleason described the symptoms of a daratumumab-related infusion reaction: sinus congestion, throat irritation, cough, shortness of breath, sometimes some hypertension, and rarely arrhythmia. “We stop the infusion immediately, give additional premedications according to a protocol (ie, additional corticosteroids, antihistamine, and sometimes an inhaled B2-adrenergic agonist), and wait until the symptoms subside.” She noted that the infusion can be restarted at a reduced rate after the symptoms have resolved. “We have been using daratumumab in clinical trials since 2013 and have not had a patient unable to complete the infusion. Patients usually say the experience was better than expected.”
“If patients don’t have an infusion reaction with the first infusion, we don’t generally recommend premedication for subsequent administration, Dr. Usmani said. If patients are going to develop a reaction, it’s usually with the first infusion. “It’s one and done.”
According to Ms. Gleason, the key elements to safe administration of daratumumab for the first time include “getting ‘chair time’ early in the day, because the patient could be at the center all day; getting the appropriate premedications on board; and making sure the nurses know what to do if there is an infusion reaction.”
In terms of patient education and preparation, there may be more hype around infusion reactions than is warranted, Dr. Usmani remarked. “We do not expect anything dramatic, such as a need for resuscitation because of respiratory or cardiac issues.” Daratumumab infusion reactions start off similar to symptoms of seasonal allergies: scratchy throat, congested nasal passages, even itchy skin. The staff at experienced centers is vigilant during the first few hours of the infusion, checking patients frequently. “At the first sign of a reaction, antihistamine and another dose of steroid are given, along with other supportive care interventions, such as acetaminophen. Once the symptoms subside, the infusion can be continued,” Dr. Usmani said.
we have used daratumumab in clinical trials since 2013 in hundreds of patients and have not had one instance where a patient was hospitalized due to a grade 4 infusion reaction.
During early clinical trials of daratumumab, the treatment day seemed extraordinarily long—12 to 14 hours—due to the postinfusion blood draws and pharmacokinetic studies. “It may have been perceived at that time as being a difficult drug to give,” Ms. Gleason observed. “As soon as we started giving it routinely, and our infusion nurses became as familiar with it as the research nurses, the comfort level increased.” So, although the symptoms of an infusion reaction with daratumumab might be somewhat different compared with reactions to other antibodies, the nursing protocol, namely of using additional steroid and antihistamine, is the same.”
Dr. Usmani pointed out that “these reactions are not unique to daratumumab. Rituximab, a chimeric CD20 antibody, which has been used since the 1990s, once was associated with some dramatic, intense infusion reactions.20 There was a steep and long learning curve when rituximab emerged on the scene, but we are not as concerned about those reactions now because we know how to manage them.”
There’s a level of fatigue associated with these regimens, especially when the combination includes an iMID, Ms. Gleason noted. “We advise patients to stay well hydrated and to try to remain active,” as ways to cope with that fatigue, she said.
After the first dose or two of daratumumab, infusion times decrease to about 3.5 hours. Daratumumab is generally very well tolerated, especially when it is given only once a month,” Ms. Gleason noted.
A Safe Option for All Patients
“Daratumumab is generally well tolerated and effective, so with proper management, it is a safe treatment option. Prompt response to infusion reactions is essential, and again the risk of reaction is highest with the first dose. Proper timing of premedications and the addition of montelukast can significantly reduce the severity of reactions,” Ms. Gleason said.
“Clinicians should not be reticent to use daratumumab because of concerns about infusion reactions,” Dr. Usmani said. “These reactions are very similar to what you would see with other monoclonal antibodies. Pay attention to the first dose. Consider adding montelukast as part of premedication for the first dose. If you have questions or doubts, contact the nearest myeloma program. Once the first dose has been safely delivered, daratumumab represents a safe treatment option for any patient.”
Saad Usmani, MD, has served as a consultant for Celgene, Millennium Takeda, Onyx, and Sanofi; he has received speaker’s fees from Celgene, Millennium Takeda, and Onyx; and he has received research funding from Array Biopharma, Celgene, Janssen Oncology, Onyx, Pharmacyclics, and Sanofi.
Charise Gleason, MSN, NP-BC, AOCNP, has disclosed no conflicts of interest.
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- National Cancer Institute. FDA approval for carfilzomib. Available at https://www.cancer.gov/about-cancer/treatment/drugs/fda-carfilzomib. Accessed August 4, 2017.
- U.S. Department of Health and Human Services. U.S. Food & Drug Administration. FDA approves Ninlaro, new oral medication to treat multiple myeloma. Available at https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm473771.htm. Accessed August 4, 2017.
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- National Cancer Institute. FDA approval for pomalidomide. Available at https://www.cancer.gov/about-cancer/treatment/drugs/fda-pomalidomide. Accessed August 4, 2017.
- U.S. Department of Health and Human Services. U.S. Food & Drug Administration. FDA approves Darzalex for patients with previously treated multiple myeloma. Available at https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm472875.htm. Accessed August 25, 2017.
- U.S. Department of Health and Human Services. U.S. Food & Drug Administration. FDA approves Empliciti, a new immune-stimulating therapy to treat multiple myeloma. Available at https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm474684.htm. Accessed August 25, 2017.
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- National Cancer Institute. FDA approves new use for daratumumab in multiple myeloma. Available at https://www.cancer.gov/news-events/cancer-currents-blog/2016/daratumumab-fda-myeloma-new. Accessed August 4, 2017.
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- Dizon MF. The challenges of daratumumab in transfusion medicine. Lab Med 2017;48:6–9.
- Caillon H, Irimia A, Simon JS, et al. Overcoming the interference of daratumumab with immunofixation electrophoresis (IFE) using an industry-developed Dira test: Hydrashift 2/4 Daratumumab. Blood 2016;128:2063.
- Chari A, Mark TM, Krishnan A, et al. Use of montelukast to reduce infusion reactions in an early access treatment protocol of daratumumab in United States patients with relapsed or refractory multiple myeloma [abstract]. ASH 58th Annual Meeting & Exposition, San Diego, California, December 3–6, 2016. Abstract 2142.
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