A Variety of Multiple Myeloma Oral Oncolytic Drugs Are on the Horizon

With a variety of multiple myeloma therapies in the pipeline, approximately 25% to 35% of new oncology therapies in development are oral medications.¹ Oral oncolytic drugs offer advantages over parenteral treatment, including less invasive administration, patient convenience (eg, location and timing of administration), and prolonged drug exposure.¹

Ultimately, these factors are important in improving patients’ quality of life. Evidence demonstrates that pharmacists play a critical role in treating patients on multiple myeloma therapies, especially through a collaborative physician-pharmacist clinic that works to support oral oncolytic medication adherence.² The multiple myeloma pipeline is continuously expanding, and pharmaceutical companies are involved in research and development for novel oral oncolytic drugs and therapies already approved for other cancer indications.

Multiple Myeloma Drug Pipeline

Venetoclax

Venetoclax (Venclexta; AbbVie) is an oral BCL2 inhibitor drug currently FDA approved to treat chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), and acute myeloid leukemia. Additionally, venetoclax is being studied for the treatment of relapsed and refractory multiple myeloma and has shown promising results in patients positive for the t(11;14) translocation in phase 1/2 clinical studies.^3,4

However, the BELLINI phase 3 double-blind randomized trial (NCT02755597) interim results revealed an increased risk of death in patients receiving venetoclax compared with the control group.⁵ These results prompted the FDA to warn health care professionals of the risks of investigational use of venetoclax for multiple myeloma and to require that no new patients be enrolled in the BELLINI trial and other clinical studies.⁶ In patients with the t(11;14) translocation, mortality rates were lower, demonstrating that future studies should specifically focus on this patient population.⁵

In the CANOVA (NCT03539744) phase 3 ongoing study, investigators are evaluating the safety and efficacy of venetoclax plus dexamethasone compared with pomalidomide plus dexamethasone in participants with t(11;14)-positive relapsed or refractory multiple myeloma.⁷

Lisaftoclax

APG-2575 (lisaftoclax; Ascentage Pharma) is a novel oral BCL2 inhibitor being studied for several hematologic cancers including multiple myeloma.⁸ Additionally, the FDA has granted Orphan Drug Designation to lisaftoclax for the treatment of multiple myeloma.8 Lisaftoclax is being investigated in an ongoing phase 1b/2 clinical trial (NCT04942067) in combination with other therapies in patients with relapsed or refractory multiple myeloma.⁹

Ibrutinib

Ibrutinib (Imbruvica; Pharmacyclics and Janssen) is a novel first-in-class once-daily Bruton tyrosine kinase inhibitor that is FDA approved for CLL/SLL, Waldenström macroglobulinemia, chronic graft-vs-host disease, mantle cell lymphoma, and marginal zone lymphoma.¹⁰

Additionally, the safety and efficacy of ibrutinib were evaluated in a phase 1/2b study (NCT01962792) combined with carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma.¹¹ The study revealed that patients had an overall response rate of 71%, median progression-free survival of 7.4 months, and a median overall survival of 35.9 months.¹¹ The most common grade 3 or greater hematologic treatment-emergent adverse events were anemia and thrombocytopenia.¹¹

Myeloma-Developing Regimens Using Genomics (MyDRUG)

The MyDRUG phase 1/2 study (NCT03732703) is an ongoing precision medicine clinical trial that aims to develop new multiple myeloma regimens based on individual patients’ genomics.¹² Findings from the Multiple Myeloma Research Foundation CoMMpass study (NCT01454297) and the Multiple Myeloma Research Consortium Molecular Profiling Initiative revealed that genetic mutations can play a role in the disease, prompting the MyDRUG trial.^13,14

Additionally, this study includes high-risk multiple myeloma patients with 1 to 3 prior lines of therapy.^12,13 During this trial, investigators assign patients to the appropriate therapy based on their pharmacogenomic profile along with a standard-of-care regimen that includes ixazomib, pomalidomide, and dexamethasone.¹²

In this study, the oral oncolytic treatment options include investigational drugs and those approved for other cancers that have shown promise for multiple myeloma, such as abemaciclib (cyclin-dependent kinase mutations), enasidenib (isocitrate dehydrogenase mutations), cobimetinib (RAF/RAS mutations), and venetoclax (chromosomal translocation t[11;14]).^13,14

Furthermore, investigators in the MyDRUG trial plan to enroll 228 patients into one of 8 treatment arms.¹² Patients with a greater than 25% mutation to any of the genes being studied are eligible to be enrolled in one of these treatment arms.¹² Because the study enables multiple therapies to be evaluated at once, this has the potential to expand treatment to high-risk multiple myeloma patients.

REFERENCES

1. McBride A. The emerging role of oral oncolytics. Association of Community Cancer Centers. January-February 2020. Accessed September 8, 2021. https://www.accc-cancer. org/docs/documents/oncology-issues/articles/jf20/jf20-president.pdf
2. Sweiss K, Calip GS, Wirth S, Rondelli D, Patel P. Polypharmacy and potentially inappropriate medication use is highly prevalent in multiple myeloma patients and is improved by a collaborative physician-pharmacist clinic. J Oncol Pharm Pract. 2020;26(3):536-542. doi:10.1177/1078155219851550
3. Kaufman JL, Gasparetto C, Schjesvold FH, et al. Targeting BCL-2 with venetoclax and dexamethasone in patients with relapsed/refractory t(11;14) multiple myeloma. Am J Hematol. 2021;96(4):418-427. doi:10.1002/ajh.26083
4. Ehsan H, Wahab A, Shah Z, et al. Role of venetoclax in the treatment of relapsed and refractory multiple myeloma. J Hematol. 2021;10(3):89-97. doi:10.14740/jh844
5. Kumar SK, Harrison SJ, Cavo M, et al. Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2020;21(12):1630-1642. doi:10.1016/S1470-2045(20)30525-8
6. FDA warns about the risks associated with the investigational use of Venclexta in multiple myeloma. FDA. March 21, 2019. Accessed September 8, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/ fda-warns-about-risks-associated-investigational-use-venclexta-multiple-myeloma
7. A study of venetoclax and dexamethasone compared with pomalidomide and dexamethasone in participants with relapsed or refractory multiple myeloma (CANOVA). ClinicalTrials.gov. Updated June 29, 2021. Accessed September 8, 2021. https://clinicaltrials.gov/ct2/show/NCT03539744
8. Ascentage Pharma announces the fifth Orphan Drug Designation granted to Bcl-2 inhibitor APG-2575 by the US FDA, and the tenth obtained by the company. News release. Ascentage Pharma. January 28, 2021. Accessed September 9, 2021. https://www. ascentagepharma.com/press-releases/ascentage-pharma-announces-the-fifth-orphan-drug-designation-granted-to-bcl-2-inhibitor-apg-2575-by-the-us-fda-and-the-tenth-obtained-by-the-company/#:~:text=28%2C%202021%20%E2%80%94%20Ascentage%20 Pharma%20(,Drug%20Designation%20(ODD)%20to%20the
9. APG-2575 in combination with novel therapeutic regimens in subjects with relapsed or refractory multiple myeloma. ClinicalTrials.gov. Updated August 20, 2021. Accessed September 9, 2021. https://clinicaltrials.gov/ct2/show/NCT04942067
10. Imbruvica. Prescribing information. Janssen and Pharmacyclics; 2021. Accessed September 9, 2021. https://www.imbruvica.com/
11. Chari A, Cornell RF, Gasparetto C, et al. Final analysis of a phase 1/2b study of ibrutinib combined with carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma. Hematol Oncol. 2020;38(3):353-362. doi:10.1002/hon.2723
12. Myeloma-developing regimens using genomics (MyDRUG). ClinicalTrials.gov. Updated September 10, 2021. Accessed September 10, 2021. https://clinicaltrials.gov/ct2/ show/NCT03732703
13. Auclair D, Anderson KC, Avigan D, et al. The myeloma-developing regimens using genomics (MyDRUG) master protocol. J Clin Oncol. 2019;37(suppl 15):TPS8057. doi:10.1200/JCO.2019.37.15_suppl.TPS8057
14. MyDRUG. Multiple Myeloma Research Foundation. February 12, 2019. Accessed September 9, 2021. https://themmrf.org/2019/02/12/mydrug/