By: Brian Chung, PharmD Candidate c/o 2024, Peter Chung, PharmD Candidate c/o 2024, and Kevin Kim, PharmD Candidate c/o 2024

              Multiple myeloma is a blood cancer that affects an individual’s plasma cells. Plasma cells are white blood cells located in the bone marrow that are responsible for producing antibodies, also known as immunoglobulins.¹  Immunoglobulins play a vital role in fighting off infections by binding to foreign antigens on pathogens, resulting in an immune response.² In multiple myeloma, malignant plasma cells secrete nonfunctional antibodies called M proteins.¹ Asides from immunosuppression, complications of multiple myeloma also include anemia, bone disease, calcium elevations, and renal insufficiency.³ A variety of risk factors are known to increase a person’s risk of multiple myeloma, including older age, male gender, African American race, family history of multiple myeloma, and personal history of a plasma cell  disease (i.e., monoclonal gammopathy of undetermined significance).^4,5

Diagnosis and Treatment of Multiple Myeloma

The diagnostic workup for multiple myeloma will commonly involve a history and physical exam; CBC, differential, and platelet count; peripheral blood smear; basic metabolic panel; liver function tests; creatinine clearance; serum quantitative immunoglobulins; urine collection; computed tomography scan; bone marrow biopsy; and plasma cell fluorescence in situ hybridization (FISH) panel on bone marrow.⁶ Multiple myeloma is staged using the Revised International Staging System (RISS), which takes into account the albumin, beta-2-microglobulin, and lactate dehydrogenase (LDH) serum concentrations, as well as the specific gene abnormalities, or cytogenetics, of the cancer. Depending on these findings, multiple myeloma is staged from 1 to 3, with stage 1 being the least advanced stage and stage 3 being the most aggressive stage.⁷

Treatment is based on patient specific symptoms and disease stage and history. Common symptoms of multiple myeloma include bone pain, nausea, constipation, loss of appetite, fatigue, weakness in arms and legs, unexplained weight loss, confusion, frequent infections, excessive thirst, and fever.⁵ In general, standard treatment options for multiple myeloma consist of targeted therapy, immunotherapy, chemotherapy, corticosteroids, bone marrow transplant, radiation therapy, and supportive care.^6,8 In patients that are bone marrow transplant candidates, preferred treatment regimens include bortezomib / lenalidomide / dexamethasone or carfilzomib / lenalidomide / dexamethasone.⁶ In patients not eligible for a transplant, preferred treatment regimens include bortezomib / lenalidomide / dexamethasone or daratumumab / lenalidomide / dexamethasone.⁶

Bortezomib and Carfilzomib Overview

Protein homeostasis is a vital biological process for the survival of malignant cells. Cancer researchers looked to develop agents to target the regulation of protein production and destruction, particularly of proteins that mediate cell proliferation. The ubiquitin-proteasome pathway (UPP) is the primary mechanism for degradation of proteins, including those involved in cell cycle regulation, apoptosis, and angiogenesis.⁹ The UPP targets proteins for recognition and for subsequent degradation via the attachment of ubiquitin molecules. The 26S proteasome complex is comprised of a 20S core catalytic component that is capped at one or both ends by a 19S regulatory component. The 19S structure recognizes and binds the protein and feeds it into the 20S core for degradation.⁹ A complete blockade of the 26S proteasome complex would result in cancer cell apoptosis and obstruction of cellular homeostasis, resulting in cancer cell death.^9-11

Bortezomib is an antineoplastic agent indicated for the treatment of adults with multiple myeloma and for adults with mantle cell lymphoma.¹² Bortezomib is administered subcutaneously or intravenously at a starting dose of 1.3 mg/m². ¹² Bortezomib functions as a reversible inhibitor of the 26S proteasome. Studies have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro and is able to delay tumor growth in vivo in nonclinical tumor models, including multiple myeloma.¹²

   Carfilzomib is an antineoplastic agent indicated for the treatment of adults with relapsed or refractory multiple myeloma who have received one or more lines of therapy.¹³ Carfilzomib is administered intravenously at a starting dose of 20 mg/m². ¹³ Carfilzomib is a proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome. Carfilzomib exhibited antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells, as well as a delay in tumor growth in models of multiple myeloma, hematologic, and solid tumors.¹³

Randomized Control Trial Comparing Bortezomib and Carfilzomib

The ENDURANCE trial, conducted by Kumar et al., was a multicenter, open-label, phase III randomized controlled trial set to determine the superiority of carfilzomib, lenalidomide, and dexamethasone (KRd) over bortezomib, lenalidomide, and dexamethasone (VRd).¹⁴ The ENDURANCE trial included a total of 1053 patients divided randomly to receive induction therapy with either VRd (n=527) or KRd (n=526) for 36 weeks. Patients completing the induction phase were randomized a second time with equal allocation to indefinite vs 2 years of lenalidomide maintenance.¹⁴  In terms of baseline characteristics, the median age was 65 years with 59% of participants being male, 86% white, 12% black, 37% with an ISS stage of 1, 36% with stage 2, and 28% with stage 3.¹⁴ The study was conducted by the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network (ECOG-ACRIN) Cancer Research Group and funded by the National Institutes of Health (NIH), the National Cancer Institute (NCI), and Amgen.¹⁴

Patients 18 years and older with newly diagnosed symptomatic standard-risk multiple myeloma who were ineligible to undergo autologous stem-cell transplantation (ASCT) were enrolled in this study.¹⁴ To be included, patients must have a measurable disease defined by having one or more of the following: ≥ 1g/dL monoclonal protein (M-protein) on serum protein electrophoresis, ≥ 200 mg/24 hours of monoclonal protein on a 24-hour urine protein electrophoresis, involved free light chain ≥ 10 mg/dL and abnormal serum immunoglobulin kappa to lambda free light chain ratio of < 0.26 or > 1.65, or monoclonal bone marrow plasmacytosis ≥ 30%.¹⁴ 

The ENDURANCE trial excluded patients with high-risk multiple myeloma, defined by having one of the following: gene translocation t(14;16), t(14;20) or gene deletion del(17p) on FISH, serum LDH > 2x the upper limit of normal, > 20% circulating plasma cells on peripheral blood smear differential or 2000 plasma cells/µL on white blood cell differential of peripheral blood, or high-risk GEP70 signature by gene expression.¹⁴ Other notable exclusion criteria included uncontrolled seizure disorder, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina, or uncontrolled cardiac arrythmias.¹⁴

Patients in the VRd group received treatment in 3-week cycles for 12 cycles.¹⁴ Bortezomib was administered subcutaneously or intravenously at a dose of 1.3 mg/m² on days 1, 4, 8, and 11 for cycles 1 to 8. From cycle 9 through 12, bortezomib was administered on days 1 and 8. In the VRd regimen, lenalidomide 25 mg was administered by mouth once daily on days 1 to 14, and dexamethasone 20 mg was administered by mouth on days 1, 2, 4, 5, 8, 9, 11, and 12 for cycles 1 to 4. From cycle 5 through 8, the dose of dexamethasone was reduced to 10 mg. From cycle 9 through 12, dexamethasone 10 mg was administered on days 1, 2, 8, and 9.¹⁴

In the KRd group, patients received treatment in 4-week cycles for 9 cycles.¹⁴ On days 1 and 2 of cycle 1, carfilzomib was administered intravenously at 20 mg/m². After these first two reduced doses, carfilzomib was given at a dose of 36 mg/m² on days 1, 2, 8, 9, 15, and 16 of each cycle. In the KRd regimen, lenalidomide 25 mg was administered by mouth once daily on days 1 to 21, and dexamethasone 40 mg was administered by mouth on days 1, 8, 15, and 22 for cycles 1 to 9. From cycle 5 through 9, the dose of dexamethasone was reduced to 20 mg.¹⁴

The primary endpoint for the induction phase of the ENDURANCE trial was progression-free survival (PFS), defined as the time from induction randomization until the earliest progression or death due to any cause.¹⁴ The primary endpoint for the maintenance phase was overall survival (OS), defined as the time from maintenance randomization to death due to any cause.¹⁴ Secondary endpoints included overall response rate (ORR), time to progression (TTP), duration of response (DOR), OS, and minimal residual disease (MRD) negative rate measured by flow cytometry.¹⁴ The Kaplan-Meier method was used to estimate survival distributions by induction arm. A stratified log-rank test was used to compare survival distributions between induction arms. Treatment hazard ratios (HR) were estimated with the use of a stratified Cox proportional hazards regression model. It was estimated that there was 80% power at a 1-sided 0.025 significance level to detect a 25% reduction in the HR.¹⁴

Regarding efficacy data, results showed that the median PFS was 34.6 months (95% confidence interval [CI] 28.8 to 37.8) in the KRd group and 34.4 months (95% CI 30.1 to NE) in the VRd group. The overall HR of KRd compared to VRd was 1.04 (95% CI 0.83 to 1.31; p=0.74).¹⁴ The best ORR of a partial response or better during induction was achieved by 444 (84%) participants in the VRd group and 456 (87%) participants in the KRd group (p=0.26). A complete response or better was observed in 78 (15%) participants in the VRD group compared to 96 (18%) participants in the KRd group (p=0.13).¹⁴ In patients with a complete response, MRD negativity was seen in 38 (7%) participants treated with VRd compared to 54 (10%) treated with KRd (p=0.08).¹⁴ Lastly, the estimate for 3-year OS probability is 0.84 (95% CI 0.80 to 0.88) for the VRd group and 0.86 (95% CI 0.82 to 0.89) for the KRd group. The median OS was not able to be established by the time of publication. The HR for death in the KRd group compared to the VRD group was 0.98 (95% CI 0.71 to 1.36; p=0.92).¹⁴

Regarding safety data, the VRd group had 218 (41%) grade 3 or higher non-hematologic treatment-related adverse events (TRAE) observed (95% CI 37% to 46%) compared to 254 (48%) in the KRd group (95% CI 44% to 53%).¹⁴ Grade 4 to 5 hematologic plus non-hematologic TRAEs were reported in 61 (12%) of participants in the VRd group compared to 70 (13%) in the KRd group.¹⁴ Grade 3 to 5 serious adverse events occurred in 116 (22%) participants in the VRd group compared to 234 (45%) participants in the KRd group.¹⁴  A grade 3 or higher composite cardiac, pulmonary, and renal toxicity was noted among 84 (16%) participants in the KRd group compared to 25 (5%) participants in the VRd group (p < 0.001).¹⁴ The most common (≥ 3%) TRAEs were heart failure, diarrhea, fatigue, lung infection, hyperglycemia, peripheral sensory neuropathy, dyspnea, maculopapular rash, hypertension, and thromboembolic event.¹⁴ Overall, 91 (17.3%) participants in the VRd group and 52 (9.9%) participants in the KRd group discontinued therapy because of adverse events.¹⁴

Conclusion

The ENDURANCE trial concluded that carfilzomib was not superior to bortezomib when used in combination with lenalidomide and dexamethasone in refractory multiple myeloma.¹⁴ Overall, efficacy results regarding PFS and 3-year OS probability were similar between carfilzomib and bortezomib. Furthermore, there were more TRAEs with statistically significant margins observed in the carfilzomib regimen compared to the bortezomib regimen. Although both medications have a place in therapy for patients with multiple myeloma, the high incidence of adverse effects in carfilzomib makes it unconvincing to recommend first over bortezomib.

References

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5. ‌Multiple myeloma: symptoms & causes. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/multiple-myeloma/symptoms-causes/syc-20353378. Last Updated 12/14/2022.
6. Kumar S, Callander N, Adekola K, et al. Multiple myeloma. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Published 12/08/2022.
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8. Multiple myeloma: diagnosis & treatment. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/multiple-myeloma/diagnosis-treatment/drc-20353383. Last Updated 12/14/2022.
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14. Kumar SK, Jacobus SJ, Cohen AD, et al. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020;21(10):1317-1330. doi: 10.1016/S1470-2045(20)30452-6

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