CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurse Practitioners: 1.00 Nursing contact hours, includes 1.00 hour of pharmacotherapy credit
Released: May 16, 2024
Expiration: May 15, 2025
Select Adverse Events and Prophylaxis by Drug Class
Finally, we will discuss AE management for common treatment regimens in NDMM. This is an important topic because nurses play a big role in managing AEs with the multidrug regimens we discussed earlier.
This slide is an overview of AEs of interest by drug class. PIs have a few unique AEs to be aware of, including peripheral neuropathy, risk of infection, cardiotoxicity, and risk of thrombosis. Peripheral neuropathy is primarily associated with bortezomib treatment, and can be managed with dose modifications.28 Bortezomib-associated neuropathy is less common now that we are almost exclusively doing subcutaneous rather than IV administration and using weekly dosing as appropriate.8,29 Cardiotoxicity is primarily associated with carfilzomib, and patients may experience new cardiac events or worsening of preexisting cardiac conditions, including myopathy, myocardial ischemia, or myocardial infarction.30 Patients receiving carfilzomib should have a baseline echocardiogram and should be monitored for signs of cardiac failure or ischemia during treatment.
For IMiDs, thromboembolisms and teratogenicity are a concern, and we will discuss both of these later.31 We also tend to see cytopenias with IMiD treatment. To mitigate this, the dosing schedule for IMiDs includes weeks off treatment to allow time for blood counts to recover. For myeloma, typical dosing is 3 weeks on 1 week off with lenalidomide during induction therapy.
Treatment with CD38 monoclonal antibodies is associated with infusion-related reactions. For the first dose of anti-CD38 monoclonal antibodies, like isatuximab and daratumumab, we premedicate with corticosteroids, antipyretics, and antihistamines to minimize the risk of infusion-related reactions.32,33 With isatuximab, an institution-preferred H2 antagonist may also be added as premedication.33 After the initial dose of isatuximab or daratumumab, most patients do well with their infusions. Now, most institutions are using subcutaneous daratumumab, and with that we see far fewer infusion-related reactions. Clinical trials are currently investigating the efficacy and safety of subcutaneous isatuximab, and so far the rate of infusion-related reactions with this formulation has been low.34 Keep in mind that anti-CD38 monoclonal antibodies can interfere with blood typing and response monitoring. These agents are IgG antibodies and will show up on serum immunofixation and serum protein electrophoresis assays. However, there are ways to distinguish myeloma disease from circulating anti-CD38 antibodies and they should be used for patients receiving these treatments.
Many myeloma regimens include high-dose corticosteroids. We give higher doses at the start of a regimen and then taper down. With corticosteroids, we need to look out for hyperglycemia, fatigue, and sometimes hyperactivity.35 Patients may have trouble sleeping and go through a period of hyperactivity before becoming extremely tired. Muscle wasting and myopathy (especially in the legs) can also occur with corticosteroids. So, these are things to keep in mind.
There is an increased risk of infections with PIs, IMiDs, and corticosteroids and we generally keep patients on infection prophylaxis throughout treatment. We will discuss this in more detail later. Anti-CD38 monoclonal antibodies also come with an increased risk of infections, including hepatitis B, so it is important to evaluate for hepatitis B viral serologies at baseline.
Myelosuppression and Infection
With the shift to quadruple-drug regimens, myelosuppression can be more substantial than with triplet therapy. Most myeloma centers are aggressive with their antimyeloma treatment in order to improve overall patient outcomes, and instead of holding treatment they opt to do a dose modification or utilize growth factor support (such as filgrastim for neutropenia) for myelosuppression.
Each drug’s prescribing information provides a good resource for finding the appropriate dose modification for hematologic toxicities, but, keep in mind that there are no recommended dose modifications for the anti-CD38 monoclonal antibodies.
Managing Infections With MM Treatments
Of course, with myelosuppression, we see an increased risk of infections.8,29,36,37 Patients who are neutropenic should receive antibacterial and antifungal prophylaxis, and this is especially important post transplant.
When patients on multidrug regimens have high burden of disease, they may get shingles. We prescribe herpes virus prophylaxis, such as acyclovir, when starting patients on therapy, especially for those receiving a PI or an anti-CD38 monoclonal antibody. We continue antiviral prophylaxis as long as their myeloma is being treated.
Patients on a multidrug regimen with anti-CD38 monoclonal antibodies and high-dose corticosteroids should be put on Pneumocystis jiroveci pneumonia prophylaxis. When you reduce the dexamethasone dose after a response has been achieved, you can reduce the Pneumocystis jiroveci pneumonia prophylaxis, but you do not want to stop it. For patients with recurrent or life-threatening infections, intravenous immunoglobulin therapy may be considered. We have begun to use intravenous immunoglobulin more frequently for patients receiving anti-CD38 antibodies especially if their IgG is <400.
We advise patients to stay current on appropriate vaccines, including COVID and annual influenza. Vaccines recommendations may vary from institution to institution, but in general, we follow the CDC guidelines.
Thrombotic Events With MM Treatments
We are accustomed to seeing thrombotic events with IMiDs like lenalidomide, but there has been some data to suggest that carfilzomib may also cause thromboembolism.30,31 Risk factors for developing blood clots include older age, history of thrombotic event, BMI ≥30 kg/m2, prior central venous catheter or pacemaker, immobilization, cardiovascular or renal disease, diabetes, trauma, blood clotting disorders, hyperviscosity, or acute infection.38 All patients should be aware of the signs of a thromboembolic event, including swelling, pain or tenderness in the arm or leg, trouble breathing, or a fast heartbeat.
The standard management approach we take in the clinic is to use prophylactic anticoagulation therapy as long as there are no contraindications. For patients with no risk factors, 81-325 mg of aspirin daily is sufficient. For patients who have a higher risk, including those who are not very mobile, have had surgery recently, or had a prior blood clot, we give LMWH, warfarin, or a DOAC, such as apixaban, rivaroxaban, or dabigatran, but they have not been widely tested in patients with MM.39
It is important to know that patients taking low-dose aspirin may still develop a clot. If that occurs, increasing the aspirin dose would not be optimal. These patients will need more aggressive anticoagulation therapy such as LMWH, warfarin, or a DOAC.8 Although the field is moving away from the use of warfarin. Anticoagulation therapy should be continued as long as patients are being treated for MM.
IMiDs: Drug Interactions and Teratogenicity
Patients with renal insufficiency should be advised that IMiDs may affect kidney function, and renal impairment can be worse if they are taking other drugs that affect kidney function. With lenalidomide, the starting dose is adjusted based on creatinine clearance and for patients on dialysis.31 But we should be mindful of concomitant use of drugs that affect kidney function.
Erythropoietin-stimulating agents or estrogen-containing therapies should be used with caution in patients receiving lenalidomide because they may increase the risk of thrombosis. Estrogen-containing therapies include many birth control products. Testosterone replacement for males also increases thrombosis risk.
Treatment with lenalidomide may result in birth defects or embryo-fetal death. To mitigate this risk, lenalidomide is only available through a Risk Evaluation and Mitigation Strategy program. For females of childbearing age, a pregnancy test should be administered before starting treatment, and 2 methods of contraception are required. If a patient is using birth control as a method of contraception, we should be mindful of the thrombotic risk with estrogen-containing products. Males should use a condom during sexual intercourse and must not donate sperm. Patients are also required to participate in a telephone survey, and they cannot donate blood or blood products.
Maintaining Bone Health in Patients With MM
We see a lot of bone issues in patients with MM. Lytic lesions can lead to fractures, so all patients should begin receiving a bone-modifying agent at the start of therapy.29,40 Commonly used bone-modifying agents include a bisphosphonate (zoledronic acid or pamidronate) or denosumab, which is administered via subcutaneous injection.
Patients may develop osteonecrosis of the jaw with long-term use of zoledronic acid; they should have a baseline dental exam and be monitored for dental issues. While on zoledronic acid, patients are advised to avoid extensive dental work, but if it is unavoidable zoledronic acid should be held for 2 months before and after the procedure. Dental procedures above the gumline, such as a filling or routine cleaning are fine, and a dose hold is not necessary. Conversations around dental procedures need to be ongoing, as patients sometimes forget to tell us about upcoming procedures.
Bisphosphonates may lead to renal impairment, so renal function should be monitored throughout treatment. As such, denosumab is often preferred for patients with renal disease.
Selected Patient Resources
Finally, there are resources available that can help patients understand their treatment options and act as reminders between visits. Patients may have questions after leaving your office, and you want them to get information from reputable sites. General myeloma and cancer resources include the American Cancer Society, CANCERCare, the International Myeloma Foundation, Leukemia and Lymphoma Society, Livestrong, MedLine Plus, and the MM Research Foundation.
Often, patients will need financial assistance. If a social worker is available at your center, get them involved with your patient’s case. Other resources for financial assistance include copayment assistance programs.
For psychological and social support, support groups are always a good recommendation. It is beneficial for patients to connect with peers.
Summary
The treatment landscape for NDMM is rapidly evolving. In the management of transplant-eligible MM, we are seeing improved response rates and progression-free survival as well as deeper response rates with MRD negativity with the addition of anti-CD38 monoclonal antibodies to conventional 3-drug regimens. Transplant-ineligible patients also benefit from the use of multidrug regimens, with DRd and VRd being the preferred regimens at this time.
With any multidrug regimens, we see an array of AEs including hematologic toxicities, infections, and thrombosis. As providers, it is important that we remain diligent in monitoring and managing AEs as well as in adequately educating our patients and their care partners on the potential risk of AEs with each treatment. As CAR T-cell therapies and bispecific antibodies begin to move to earlier lines of therapy, they will bring unique AEs that we should all be aware of.
Overall, I am excited about the direction the field is going. Over the last 20 years, we have seen a rise in the 5-year survival rate for MM, and I think we have much progress that we can still make. We can attribute the success to many new therapies and the ongoing enrollment of patients on clinical trials.
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