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Mount Sinai Hospital
New York, New York
Donna Catamero, ANP-BC, OCN, CCRC, has disclosed that she has received fees for non-CME/CE services from GlaxoSmithKline and Oncopeptides and has received consulting fees, has ownership interest in, and has previously received salary from Celgene/Bristol-Myers Squibb.
Cleveland Clinic Taussig Cancer Institute
Beth Faiman, PhD, MSN, APRN-BC, AOCN, has disclosed that she has received consulting fees from Bristol-Myers Squibb, GlaxoSmithKline, Karyopharm, and Sanofi.
Advanced Practice Provider Chief
Winship Cancer Institute
Nell Hodgson Woodruff School of Nursing
Charise Gleason, MSN, NP-BC, AOCNP, has no relevant conflicts of interest to report.
Department of Lymphoma/Myeloma
The University of Texas MD Anderson Cancer Center
Tiffany Richards, PhD, ANP-BC, AOCNP, has disclosed that she has received consulting fees from Celgene, GlaxoSmithKline, and Takeda.
The treatment landscape for multiple myeloma (MM) is evolving. For many years, we only had a handful of drugs available, but now we have multiple classes of drugs that can be used in newly diagnosed multiple myeloma (MM) and in the relapsed disease setting. Immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and corticosteroids used in combination are the backbone of initial therapy, and there are agents with novel mechanisms of action that are being used in the later disease setting. It is important to keep in mind the supportive care needs of patients with each therapy and to implement palliative care at diagnosis and throughout care. In this commentary, Donna Catamero, ANP-BC, OCN, CCRC; Beth Faiman, PhD, MSN, APRN-BC, AOCN; Charise Gleason, MSN, NP-BC, AOCNP; and Tiffany Richards, PhD, ANP-BC, AOCNP, discuss considerations for therapy and monitoring and supportive care measures that should be implemented when caring for patients with MM.
Considerations for Initial Therapy for Newly Diagnosed MM
The goal for MM management is to treat to maximum response and continued suppression of that malignant clone to reduce the risk of clonal evolution. When selecting initial therapy, it is important to consider older age, lower performance status, and any concurrent comorbidities, such as cardiac, renal, or lung disease. We also want to think about the types of toxicity that may occur, risk of myelosuppression, risk of infections, and the cost of administering the treatment. Finally, we should also take into account the biology of the tumor and the presence of cytogenetic risk factors like amplification of 1q, del(17p), t(4;14), t(14;16), and so on.
The tolerability of the regimen is important, especially in patients who are transplant ineligible or older. Currently, a triplet regimen is generally preferred for this patient population. The SWOG 777 study with bortezomib/lenalidomide/dexamethasone (VRd) vs lenalidomide/dexamethasone (Rd) showed favorable efficacy with the triplet regimen even in older patients, so it is a viable option for transplant-ineligible patients. For older patients who may not tolerate standard triplet therapy, we can also consider VRd lite—a regimen with low-dose lenalidomide, low-dose bortezomib, and lower-dose dexamethasone—which is well tolerated in the older patient population, with very few treatment discontinuations. The combination of daratumumab/lenalidomide/dexamethasone is also a favored regimen to use in this setting based on the MAIA study with this triplet regimen vs Rd. If tolerable, more aggressive therapies can lead to deeper responses that translate to improved progression-free survival, hopefully keeping patients in remission longer and suppressing malignant clones.
Younger, more fit patients can tolerate more aggressive treatments. For transplant-eligible patients, the IFM/Dana Farber study solidified the current standard of care as VRd with transplant. The CASSIOPEIA and GRIFFIN studies provided data for the addition of daratumumab to the standard triplet therapy and have demonstrated very high rates of measurable residual disease negativity, suggesting a role for quadruplet-based regimens for patients who can tolerate the most aggressive therapy.
Patients with high-risk cytogenetics might benefit more from carfilzomib plus Rd (KRd) vs VRd. The FORTE study included numerous treatment arms with a first randomization to KRd and stem cell transplant vs carfilzomib/cyclophosphamide/dexamethasone and stem cell transplant vs KRd for 12 cycles and no transplant and then a second randomization for maintenance. Results of the study, showed very deep measurable residual disease–negative rates in the 10-5 or 10-6 range, finding one in 1 million plasma cell clones in the bone marrow.
Considerations in the Relapsed Setting
When selecting therapy at the first relapse, it is important to consider the nature of the relapse. We need to know if the disease is progressing slowly or more quickly. For patients with high-risk cytogenetics, like del(17p), the disease tends to be more aggressive, and in this case, we would start a new therapy as soon as possible.
Several health-related factors are important when choosing second-line therapies and beyond. We always want to consider what previous therapies a patient has had and may be refractory to and what adverse events they may have experienced with those therapies, such as neuropathy. We also want to think about comorbidities. Most of our MM treatment regimens include dexamethasone, so patients with diabetes should be monitored closely.
There are multiple options available for MM treatment; treatment selection should be a part of the shared decision-making process. Social factors can greatly influence treatment selection for the patient. For example, is it easy for the patient to get to the clinic to get the treatment that we choose? What type of administration and schedule does the patient prefer? Can the patient afford treatment? These are just a few things that will help us to tailor our choice to each patient.
Managing Patients in the Relapsed Setting
For a patient who has had induction therapy in the first-line setting and is progressing on lenalidomide maintenance, the preferred treatment is an anti-CD38 monoclonal antibody (mAb) (daratumumab or isatuximab) triplet regimen with either carfilzomib or pomalidomide and dexamethasone. mAbs are very well tolerated, and patients do well with them with various backbone combinations.
For daratumumab or isatuximab, patients should be premedicated with corticosteroid, dexamethasone, an antipyretic, and antihistamine for the first doses. The first dose is also given more slowly because, as with any mAb, the greatest chance of experiencing an infusion-related reaction is during that first dose. There is less of a chance of experiencing an infusion-related reaction with the second dose, and after that, in many cases, you do not need to continue with prophylaxis medications.
For isatuximab, the recommendation is to administer premedications for the first 4 IV infusions.
The dosing for daratumumab is different depending on the mode of administration (IV vs subcutaneous). We currently recommend subcutaneous administration for most patients, and we monitor those patients for approximately 3.5-4.0 hours after the first dose. We also monitor after the second dose; after that, no extended monitoring is needed.
There can also be issues with the use of high-dose steroids, such as hyperglycemia, fatigue, hyperactivity, risk of infection, and muscle wasting. We use steroids (dexamethasone) in many of our regimens, and it can be quite challenging for our patients. We prefer to use steroids at a higher dose at the start of treatment and taper the dose down as therapy continues. For example, for a patient who is starting on pomalidomide/daratumumab/dexamethasone, we would start at a higher dose of dexamethasone and then reduce the dose once the patient achieves a response.
Supportive Care in the Relapsed Setting
Patients with MM receiving some combination regimens are at risk for thromboembolic events. Regimens including an mAb and/or IMiD have an increased risk of pulmonary embolisms and deep vein thrombosis, and per the International Myeloma Working Group, prophylactic aspirin is recommended for patients at a low risk for thromboembolic events. For patients at high risk who have had surgery, have had a previous clot, or are not very mobile, we use a low-molecular-weight heparin or a direct-acting oral anticoagulant (DOAC). The use of DOACs is not well studied in this population of patients, but we do recommend this for our patients in clinical practice.
Patients with MM are also at risk for infection, especially when receiving dexamethasone-containing regimens or for those receiving anti-CD38 mAbs. We prophylactically use antiviral agents and sometimes antibacterial agents. For our patients with MM who have recurrent infections, we also consider monthly IVIg, particularly during flu season.
We also recommend that our patients with MM remain up to date on all vaccinations. We check for hepatitis B before giving an mAb, and we also make sure they have received their pneumonia vaccine and that they get their yearly flu vaccine. We also recommend the COVID-19 vaccine to all our patients. According to the most recent guidance from the CDC, a third “booster” dose of the mRNA COVID-19 vaccine is recommended at least 28 days after the second dose for people with moderately to severely compromised immune systems, which includes patients with RR MM. However, guidelines regarding optimal use of COVID-19 vaccinations are rapidly changing, so always refer to the most recent guidance from the CDC and the FDA and discuss final recommendations with your team. In some cases, physicians may choose to hold MM treatment for 1 week before and 1 week after vaccination. But, depending on the patient’s disease status, that is not always possible. Others choose to hold any steroid the patient may be taking or delay mAb infusion.
All patients with MM should also be offered a bone-protecting agent. Typically, we prescribe bisphosphonates or subcutaneous denosumab, which is preferred if a patient has renal disease. Patients can also be at risk for osteonecrosis of the jaw while receiving these agents, so they should have a baseline dental examination, and if more extensive dental procedures, like an extraction or a root canal, are needed, we recommend holding treatment with bone-protecting agents and resuming treatment once they heal. Typically, treatment with bone-protecting agents should be held for 2 months before and 2 months after an extensive dental procedure, if possible. It is important to educate patients on informing their care team of any dental procedure ahead of time so that their care team to be prepared to hold their treatment and monitor them.
Finally, it is important to remember that mAbs are IgG antibodies that could potentially interfere with serum protein electrophoresis. When checking M-protein levels, therapeutic mAbs can look like an M-protein spike, and patients receiving these agents may not appear to have a complete response. However, if you look at the immunofixation, it will show circulating daratumumab or isatuximab and you can tease that out to determine the response.
Novel MM Therapies
BCMA‑Targeted Therapies: Belantamab Mafodotin and Idecabtagene Vicleucel
B-cell maturation agent (BCMA) is a novel therapeutic target that is universally expressed on MM cells and has increased expression in advanced MM. BCMA is a driver for cell proliferation and cell survival, so that makes it a good target for therapies.
Belantamab mafodotin is a first-in-class BCMA-targeting antibody–drug conjugate approved in MM. It is approved by the FDA for patients with relapsed/refractory MM after 4 or more previous lines of therapy including an anti-CD38 mAb, a PI, and an IMiD. The starting dose for belantamab mafodotin is 2.5 mg/kg given as an IV infusion over 30 minutes every 3 weeks. This is currently approved as a single-agent therapy, and it is not typically dosed with a steroid. The only time that a steroid should be considered is if the patient is having an infusion-related reaction, at which time we can certainly add a steroid as a premedication.
Belantamab mafodotin is only available through a Risk Evaluation and Mitigation Strategy (REMS) program because of its risk of ocular toxicity. The most common treatment-related adverse event is keratopathy, which is damage to the corneal epithelium. Patients with keratopathy can either present with decreased visual acuity, blurred vision, or dry eyes. Some patients may be asymptomatic, so it is important to stress the need for complying with the REMS program and to have patients undergo an eye examination at baseline that includes visual acuity with the slit lamp test. Eye examinations should be repeated before each dose so that we can monitor for worsening symptoms especially for those who are asymptomatic. To help manage ocular changes, advise patients to use preservative-free eye drops at least 4 times per day and to avoid contact lenses.
Other toxicities associated with belantamab mafodotin are thrombocytopenia and infusion-related reactions. If a patient is experiencing toxicity, we want to withhold the drug until resolution and then resume at a lower dose. In this case, dose reduction from 2.5 mg/kg down to 1.9 mg/kg is recommended, and if that dose is not tolerable, belantamab mafodotin should be discontinued.
Idecabtagene vicleucel (ide-cel) is a BCMA-directed CAR T-cell therapy that was recently approved for patients with relapsed/refractory MM who have received 4 or more lines of therapy and have been exposed to all 3 classes of drugs: a PI, an IMiD, and an anti CD38 mAb. The recommended dose for ide-cel ranges from 300-460 x 106 cells, and the dose is dependent on the manufacturing. Ide-cel can only be infused at certified healthcare facilities under a REMS program, and all patients will receive lymphodepleting chemotherapy, which typically consists of cyclophosphamide and fludarabine. We premedicate patients receiving ide-cel with acetaminophen and an H1 antihistamine to prevent any infusion-related reactions.
We must counsel patients and their caregivers about potential toxicities with ide-cel. The most common adverse events with ide-cel are cytokine-release syndrome (CRS), neurotoxicity, hypogammaglobulinemia, and prolonged cytopenias. When administering ide-cel, patients should be closely monitored for a minimum of 7 days and up to 2 weeks, and this will typically be in an inpatient setting. Once patients are discharged, we ask them to stay near the center for at least 4 weeks following their infusion and then we ask patients not to drive for approximately 8 weeks after their infusion. During that period, frequent monitoring blood counts is necessary as prolonged cytopenias are possible, and supportive care should be provided. This can consist of transfusion support as well as growth factors, as needed. Also, the patient’s IgG level should be monitored, and if it drops to <400 mg/dL IVIg should be administered on a monthly schedule.
There are a few potential life-threatening complications that may occur with ide-cel treatment. The first is CRS, and it can occur anywhere from Day 0 to 30 days post infusion. Most patients start exhibiting symptoms of CRS between Days 1 and 10. CRS typically exhibits as fever, malaise, and fatigue, but before we rule in CRS, we must rule out infection. If a patient is presenting with fever, the first action would be to do an infection workup. Other life-threatening complications with ide-cel include hypertension, tachycardia, neurologic changes, and respiratory distress, as well as coagulopathies.
The way CRS is managed differs depending on the severity. Typically, grade 1 CRS is something that can be managed with supportive care. If it is an early onset of CRS, tocilizumab can be administered at a dose of 8 mg/kg as an IV infusion over 1 hour. For grade 2 and 3 CRS, more aggressive management may be needed, and tocilizumab should be initiated with or without corticosteroids. For grade 4 CRS, patients should be transferred to the intensive care unit, and tocilizumab should be initiated with corticosteroids. Other anticytokine agents could also be considered if more than 3 doses of tocilizumab are needed over a 24-hour period.
Neurotoxicity can happen either concurrently with CRS or be an isolated event. As prophylaxis, antiseizure medications can be given at the time of the lymphodepleting chemotherapy. Patients should be monitored for signs and symptoms of neurotoxicity, and this is where caregivers become very crucial because there can be delayed neurotoxicity that becomes evident after a patient is discharged to home. Neurotoxicity can present as headaches, confusion, cognitive changes, tremors, or seizures. Supportive care with antiseizure medications and with steroids can be provided for patients who do experience any neurotoxicity.
XPO1 Inhibitor: Selinexor
When a patient’s disease has progressed after multiple lines of therapy, healthcare professionals should consider using agents with novel mechanisms of action. Selinexor is an oral XPO1 inhibitor that blocks tumor suppressor genes and leads to apoptosis. It is currently approved by the FDA in combination with dexamethasone and in patients who have had more than 4 previous lines of therapy and are refractory to 2 PIs, 2 IMiDs, and anti-CD38 mAb or in combination with bortezomib and dexamethasone after 1 previous line of therapy. The dosing and adverse event profiles are different for each selinexor indication, and the selinexor/bortezomib/dexamethasone combination has shown fewer associated adverse events based on the once-weekly dosing of selinexor with this combination.
One tool that can be helpful for our patients regardless of the regimen they are receiving is to give them a calendar to help keep track of when to take their medications. This is particularly helpful for patients who are receiving an oral agent, as well as therapy that they come into the infusion center to receive. For patients starting selinexor with bortezomib and dexamethasone, we have them come into the clinic for regular monitoring at the start of therapy. I typically recommend starting on selinexor on a Monday. We then have the patients come to the clinic on Day 2 and Day 5 so that we can monitor their blood counts and electrolytes twice during the week. If their absolute neutrophil count falls below 1 x 109/L, we use growth factor support. After the first week, we continue to monitor electrolytes and creatinine twice weekly for the first month. Most patients do better after the first month, so at that point, we monitor less frequently.
Patients receiving selinexor may experience gastrointestinal disturbances, and dose modifications may be necessary. When starting a patient on selinexor, consider beginning 2 antiemetics: a 5-HT3 receptor antagonist, such as ondansetron, and another antiemetic, such as low-dose daily olanzapine or aprepitant. If a patient is experiencing nausea or vomiting, the selinexor dose can typically be maintained and antinausea medication can be used as needed. However, if vomiting is severe, selinexor should be held until nausea is under better control.
Patients receiving selinexor should also see a nutritionist to make sure that they know how to manage any dietary issues they may experience while on the therapy. For example, some patients may be instructed to eat more salt-containing foods to prevent hyponatremia. For patients who do experience hyponatremia with a sodium level <130 mmol/L, we would hold the drug until the sodium level is >130 mmol/L. At that point, we restart the treatment with 1 dose reduction (a decrease of 20 mg).
Peptide–Drug Conjugate: Melphalan Flufenamide
Melphalan flufenamide, or melflufen, is a lipophilic peptide–drug conjugate that is approved in combination with dexamethasone after 4 or more lines of therapy in patients who are refractory to a PI, an IMiD, and 1 anti-CD38 mAb.
The FDA recently requested a partial hold on all trials with melflufen because of an apparent increased risk of death with this agent in the ongoing phase III OCEAN trial. For patients who are already receiving melflufen, their healthcare team should discuss the risks and benefits of continuing therapy vs switching to another treatment regimen based on the patients individual response, adverse events, and comorbidities.
Several supportive measures that should be taken for patients who do continue receiving melflufen. First, patients should be premedicated with a 5-HT3 receptor antagonist and given a prescription for ondansetron to take home to help manage nausea. Patients experiencing a lot of nausea may require IV hydration, and in general, all patients should be encouraged to stay hydrated.
Blood counts should be monitored weekly, particularly for the first month or two of treatment because hematologic events are common with melflufen. In the phase III HORIZON trial, grade 3/4 thrombocytopenia occurred in approximately 40% of the patients in the first cycle, and the median time to onset was 15 days. For neutropenia, grade 3/4 events occurred in approximately one half of the patients in the first cycle, and the median time to onset was also approximately 15 days.
Considerations for Selecting and Sequencing Novel Therapies
Many patients are eligible for more than 1 BCMA-targeted agent. Taking patient preferences and individual circumstances into consideration helps to make selection easier. Patients often know about a treatment, but they do not know the details of how the treatment is administered and what adverse events can be expected. For instance, ide-cel is only available at select institutions and inpatient care is required, so that would be a necessary consideration for therapy. We need to know if a patient is willing to travel and be admitted to the hospital for treatment. For others, the chance of having vision problems is not something they are willing to risk, so we may prescribe selinexor-based therapy rather than belantamab mafodotin. Of importance, if patients choose to be treated with belantamab mafodotin, we need to know if they have a caregiver to drive them back and forth to eye appointments.
Patients’ disease and physical statuses are also important considerations for treatment selection. For patients with explosive disease, the first choice would not be a CAR T-cell therapy—we would want to get the disease under control before a CAR T therapy, so belantamab mafodotin or selinexor-based therapy may be more appropriate. For melflufen, patient need to have adequate renal function and the recommended creatine clearance is 45-89 mL/min. If we wait too long to begin treatment, we might miss the opportunity to use it because a lot of our patients have a decreased kidney function.
The important thing to remember for our patients with MM is to provide excellent supportive care while trying to keep our patients active and well hydrated, eating a good diet, and advising them to not smoke. These things are important to keep them fit for the next therapy because there are many treatments that we want our patients to have access to.
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