Multiple Myeloma Therapy Often Causes Cardiovascular Complications

Mulitple myelomia is the 14th most common cancer, with an estimated 34,000 new cases diagnosed in the United States in 2022.¹ Although it is not curable, multiple myeloma is treatable, with a reported 5-year relative survival rate of approximately 58%.² Black patients are twice as likely to develop multiple myeloma compared with White patients, it affects more men than women, and the median age of diagnosis is 69 years.²

Multiple myeloma is a hematologic malignancy that affects plasma cells, which are differentiated from mature B lymphocytes within the bone marrow. One of the key functions of the plasma cell is to produce antibodies to combat the various antigens with which our bodies are presented.^3,4

In patients with multiple myeloma, the formation of cancerous B cells can accumulate and cause uncontrolled proliferation of clonal plasma cells within the bone marrow. This leads to uncontrolled nonfunctional antibody production. The antibodies produced are also known as monoclonal immunoglobulins, or M proteins, which are often present in excess on serum analysis in patients with uncontrolled or undiagnosed multiple myeloma.^3,4 The hallmark clinical manifestations of multiple myeloma are often remembered by the CRAB acronym: calcium elevation, renal impairment, anemia, and bone lesions.⁴ All these symptoms are related to the crowding of plasma cells within the marrow, impairing normal hematopoiesis and creating osteolytic lesions via plasmacytomas; the excessive deposition of antibody light chains in the distal renal tubules; or the suppression of osteoblasts and activation of osteoclasts by malignant plasma cells.

Despite cardiovascular complications not being included within the CRAB criteria, many patients with multiple myeloma have baseline risk factors or cardiovascular comorbidities because of the older median age of diagnosis and disease-related factors such as anemia, cardiac amyloidosis, cardiomyopathy, and renal dysfunction.⁵ An estimated 63% of patients with myeloma report having a prior cardiac event at the time of diagnosis.⁶

National Comprehensive Cancer Network (NCCN) guidelines recommend treating multiple myeloma with a combination of medications, most commonly consisting of certain monoclonal antibodies, a corticosteroid, an immunomodulatory drug (IMiD), and/or a proteasome inhibitor.⁴ Exposure to agents from each of these classes carries different cardiovascular toxicity risks. Because myeloma is incurable, patients are often exposed to several lines of therapy, often in combination, putting them at even higher risk for cancer therapy–related cardiovascular toxicity.^4,6

Proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib, are all used in the treatment of multiple myeloma.4 These agents carry a risk of thrombocytopenia and have recommended hold parameters for thrombocytopenia.^7-9 Thrombocytopenia is typically not considered a cardiovascular complication; however, it may prevent patients from safely taking their maintenance cardiac medications, such as dual antiplatelet therapy after percutaneous coronary intervention or therapeutic anticoagulation. Thrombocytopenia is also seen with the use of IMiDs, especially when used in combination with proteasome inhibitors. Carfilzomib has shown the greatest cardiac toxicity profile of the proteasome inhibitors. Hypertension was the most observed adverse event (AE), at 14.3% reported in the carfilzomib arm of the phase 1/2 ASPIRE trial (NCT01080391) that studied the use of carfilzomib, dexametha-sone, and lenalidomide in combination for relapsed multiple myeloma. Comparatively, in the control arm, when patients received dexamethasone and lenalidomide without carfilzomib, just 4.3% experienced hypertension.¹⁰ Carfilzomib was also associated with higher rates of cardiac failure, ischemic heart disease, and venous thromboembolism (VTE), and the results of a systematic review published in JAMA Oncology showed that patients were 2.5 times more likely to have a cardiovascular AE when treated with carfilzomib.^10,11 Although the mechanism of carfilzomib-induced cardiotoxicity is not well known, patients are thought to be at higher risk if they are older than 75 years or have a history of conduction abnormalities and arrhythmias, have had a recent myocardial infarction, have New York Heart Association class III or IV heart failure, or have a preexisting cardiovascular history.¹²

Daratumumab, elotuzumab, and isatuximab are monoclonal antibodies that either replace a proteasome inhibitor in triplet regimens or are added to quadruplet therapy regimens.⁴ These agents have also been shown to cause hypertension in 30% to 35% of patients. However, this incidence was observed when used in combination with carfilzomib and may be lower in regimens that do not contain carfilzomib.^13,14

The IMiDs lenalidomide, pomalidomide, and thalidomide exert their antimyeloma properties through various mechanisms and have been a long-standing part of multiple myeloma treatment. One mechanism in which IMiDs employ antitumor effects is through antiangiogenesis, which prevents malignant cells from forming new blood vessels that may be necessary for their survival. Unfortunately, this mechanism comes with the consequence of an increased risk of VTE. enalidomide, pomalidomide, and thalidomide hold a black box warning for arterial and venous thromboembolism.¹⁵ The risk of VTE is increased when these agents are used in combination with proteasome inhibitors and steroids, as frequently seen in multiple myeloma regimens.¹⁶

The NCCN guidelines recommend the use of the IMPEDE score and the SAVED score as risk stratification tools to help determine the risk of VTE for patients with multiple myeloma.⁴ These scoring systems include both patient-specific and treatment-related factors, such as the use of an IMiD and cumulative monthly steroid dosing. Based on the scores, VTE prophylaxis is recommended based on risk. For patients at lower risk, the guidelines recommend aspirin 81 mg to 325 mg once daily.⁴ For patients with higher risk scores, the guidelines recommend using prophylactic enoxaparin and provide dosing recommendations for prophylactic doses of direct oral anticoagulants.

In 2022, the European Society of Cardiology published the first guidelines on cardio-oncology, which provide guidance on appropriate cardiovascular monitoring for patients treated with anticancer therapies.¹² The guidelines provide clear definitions and severity scoring for terms that were previously left to the clinician to define, such as cancer therapy–related cardiovascular dysfunction and cancer therapy related hyper-tension.¹² Given the complexity of multiple myeloma regimens and the various cardiovascular toxicities associated with treatment, it is important that baseline cardiovascular risk assessments and continued monitoring is maintained throughout treatment. The guidelines dedicate a section strictly to multiple myeloma therapy. They recommend baseline scoring systems, such as the Heart Failure Association and International Cardio-Oncology Society (HFA-ICOS) multiple myeloma–specific baseline risk assessment tool that places patients into a moderate, high, or very high risk for treatment-related cardiovascular complications.¹² The guidelines also include a proteasome inhibitor surveillance protocol that recommends appropriate monitoring and frequency of monitoring for patients on a proteasome inhibitor based on their HFA-ICOS baseline risk estimations.¹²

Pharmacists can collaborate with providers to select the most appropriate agents for treatment, given a patient’s previous cardiovascular history, as well as provide supportive care recommendations by referencing appropriate risk stratification tools, employing guideline-based monitoring strategies, and ensuring that lab parameters for safe treatment are met.^4,12

References

1. Cancer facts & figures 2022. American Cancer Society. Accessed January 5, 2023. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2022.html
2. Cancer stat facts: myeloma. National Cancer Institute. Accessed November 20, 2022. https://seer.cancer.gov/statfacts/html/mulmy.html
3. Berenson JR. Multiple myeloma. Merck Manual. Updated September 2022. Accessed November 20, 2022. https://www.merckmanuals.com/professional/hematology-and-oncology/plasma-cell-disorders/multiple-myeloma
4. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 3.2023. Accessed December 5, 2022.
5. Yin X, Fan F, Zhang B, Hu Y, Sun C. Cardiovascular-specific mortality among multiple myeloma patients: a population-based study. Ther Adv Hematol. 2022;13:20406207221086755. doi:10.1177/20406207221086755
6. Plummer C, Driessen C, Szabo Z, Mateos MV. Management of cardiovascular risk in patients with multiple myeloma. Blood Cancer J. 2019;9(3):26. doi:10.1038/s41408-019-0183-y
7. Kyprolis. Prescribing information. Onyx Pharmaceuticals Inc; 2012. Accessed January 5, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf
8. Velcade. Prescribing information. Millennium Pharmaceuticals; 2014. Accessed January 5, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021602s040lbl.pdf
9. Ninlaro. Prescribing information. Takeda Pharmaceuticals America Inc; 2015. Accessed January 5, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208462lbl.pdf
10. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142-152. doi:10.1056/NEJMoa1411321
11. Waxman AJ, Clasen S, Hwang WT, et al. Carfilzomib-associated cardiovascular adverse events: a systematic review and meta-analysis. JAMA Oncol. 2018;4(3):e174519. doi:10.1001/jamaoncol.2017.4519
12. Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J.2022;43(41):4229-4361. doi:10.1093/eurheartj/ehac244.
13. Darzalex. Prescribing information. Janssen Biotech Inc; 2016. Accessed January 5, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761036s004lbl.pdf
14. Sarclisa. Prescribing information. sanofi-aventis US LLC; 2020. Accessed January 5, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761113s000lbl.pdf
15. Anderson SM, Beck B, Sterud S, Lockhorst R, Ngorsuraches S. Evaluating the use of appropriate anticoagulation with lenalidomide and pomalidomide in patients with multiple myeloma. J Oncol Pharm Pract. 2019;25(4):806-812. doi:10.1177/1078155218758500
16. Khorana AA, Mackman N, Falanga A, et al. Cancer-associated venous thromboembolism. Nat Rev Dis Primers.2022;8(1):11. doi:10.1038/s41572-022-00336-y

About the Authors

Julia Fadul, PharmD, is a PGY2 oncology pharmacy resident at the University of Rochester Medical Center Wilmer Cancer Institute in New York.

Jeremiah Moore, PharmD, BCOP, is a clinical pharmacy specialist in hematology/oncology at the University of Rochester Medical Center in New York.

Carissa Treptow, PharmD, BCOP, is a clinical specialist in malignant hematology and is the residency program director for the PGY2 Oncology program at the University of Rochester Medical Center Wilmot Cancer Center in New York.

Frank Lattuca, PharmD, BCOP, is a hematology/oncology clinical specialist at the a hematology/oncology clinical specialist through the University of Rochester Specialty Pharmacy in New York.