Recent Advancements and Future Directions in Frontline Treatment of Multiple Myeloma

The author of “Current Frontline Treatment of Multiple Myeloma,” provides a thorough review of the current standard of care for multiple myeloma in the frontline setting. It is becoming more apparent that multiple myeloma is a heterogenous disease that requires individually tailored treatment, dependent on patient factors and biologic characteristics, including disease stage and molecular features. We have traditionally divided patients into transplant eligible vs transplant ineligible, but there are important nuances in making these determinations. The literature has varying definitions of transplant eligibility. In addition, there are restrictions on medical financial resources in some countries outside the United States, sometimes limiting accessibility to transplant options. Supportive care for autologous stem cell transplants is continuously improving, allowing us to perform successful transplants in a greater number of patients.¹ As the FORTE trial (NCT02203643) highlights,² autologous stem cell transplant remains a standard of care in multiple myeloma even in the era of novel therapies. The experience at our center, and in numerous centers across the United States, is that successful transplants can be done in fit patients aged up to 80 years or a little older, without significant morbidity and mortality.³ The challenge has been to increase the number of patients referred to transplant centers to optimize this treatment strategy. According to statistics compiled by the Center for International Blood and Marrow Transplant Research, less than 50% of individuals who are transplant eligible actually receive a transplant, and for members of US minority populations, this percentage is substantially lower.⁴

Aside from chronologic age, many other factors can affect treatment options and outcomes. The authors successfully point out that geriatric and frailty assessments are becoming increasingly important in identifying optimal treatment strategies for each individual patient. Clinical trials are addressing these assessments as a more objective measure of morbidity and mortality. For non–transplant-eligible patients, equally important therapeutic advancements have been made with the triplet regimen daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone, which was studied in the MAIA trial (NCT02252172).⁵ This trial has provided a new standard of care for frail older adults. This regimen is both tolerable and has good long-term outcomes (the most recent update shows a 53% progression-free survival [PFS] rate at 5 years). Unfortunately, despite the PFS advantage, many practitioners in the community have not yet adopted this as first-line therapy and are most commonly utilizing RVd-lite (lenalidomide, bortezomib [Velcade], and dexamethasone),⁶ a regimen with a less favorable administration schedule, increased risk of toxicity (eg, peripheral neuropathy), and shorter PFS.

A critical goal for the multiple myeloma community is to identify treatment strategies that benefit patients with high-risk disease, because their outcomes remain poor, despite recent advances in therapy. Most outcomes for high-risk disease are focused on subgroup analyses, and they therefore lack statistical strength. As pointed out by the authors, an increasing number of trials are focusing on high-risk groups to help identify successful treatment strategies. Thus far, we have had conflicting results regarding the benefit of quadruplet therapies on outcomes in patients with high-risk disease. Additionally, this is a heterogenous group of patients with varying definitions of high-risk disease. For example, the revised International Staging System,⁷ the International Myeloma Work Group,⁸ and the Mayo Clinic’s mSmart⁹ all have different definitions of high risk. Regardless of which definition is utilized, optimal management of high-risk disease is a focus of active research as the field attempts to identify strategies to overcome its aggressive nature in these individuals.

As more knowledge emerges about patient outcomes with newer targeted therapies, clinicians are also learning about the importance of incorporating agents with different mechanisms of action and the role of minimal residual disease (MRD). MRD negativity, a surrogate marker of depth of response, is being incorporated as a biological end point in virtually all ongoing clinical trials. As the number of trials utilizing MRD negativity as a surrogate end point increases, we will hopefully gain deeper understanding into how to incorporate MRD data into our clinical decision making. Quadruplet therapies are likely going to become standards of care as they produce deep responses with high rates of MRD negativity and prolonged PFS. These include daratumumab + RVd as examined in the GRIFFIN trial (NCT02874742),¹⁰ daratumumab + VTd (bortezomib, thalidomide, and dexamethasone) in the CASSIOPEIA trial (NCT02541383),^11,12 and daratumumab + KRd (carfilzomib, lenalidomide, and dexamethasone) in the MANHATTAN¹³ and MASTER (NCT03224507)¹⁴ trials. The current dogma in multiple myeloma is to continue treatment until treatment intolerance or disease progression. In contrast, the MASTER trial is utilizing an MRD-adapted treatment approach, whereby after confirmation of MRD negativity, patients will enter a treatment-free phase. This would markedly change the current treatment paradigm of continuous therapy.

Lastly, the future of upfront therapy is likely to change as more targeted therapies and novel agents are being investigated in combinations with current standard of care. These therapies and agents include antibody-drug conjugates, cereblon E3 ligase modulating drugs, and T-cell engagers such as bispecific antibodies, chimeric antigen receptor T cells, and natural killer cells. These agents are revolutionizing the relapsed/refractory therapeutic landscape and are likely to make significant impact in the upfront setting as well. The advantage of many of these agents is their safety profile; their tolerability allows more patients to be successfully treated with fewer serious adverse effects. Studying these new agents and combinations in high-risk groups will be important.

We anticipate many ongoing changes in the frontline treatment setting over the next few years, with the goals of further increasing overall survival, PFS, and, importantly, quality of life.

AUTHOR BIOS

Doucette is a medical oncologist and hematologist specializing in multiple myeloma at the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. She is an assistant professor of medicine at Georgetown University.

Vesole is director of the myeloma program at MedStar Georgetown University Hospital. He is also codirector of the myeloma division and director of myeloma research at the John Theurer Cancer Center at Hackensack University Medical Center in Hackensack, New Jersey. He is also a professor of medicine at Georgetown Lombardi Comprehensive Cancer Center and Hackensack Meridian School of Medicine.

References

1. Nishimura KK, Barlogie B, van Rhee F, et al. Long-term outcomes after autologous stem cell transplantation for multiple myeloma. Blood Advances. 2020;4(2):422-431. doi:10.1182/bloodadvances.2019000524
2. Gay F, Musto P, Rota-Scalabrini D, et al. Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial. Lancet Oncol. 2021;22(12):1705-1720. doi:10.1016/S1470-2045(21)00535-0
3. Munshi PN, Hari P, Vesole DH, et al. Breaking the glass ceiling of age in transplant in multiple myeloma. Blood. 2019;134(suppl 1):abstr 782. doi:10.1182/blood-2019-124804
4. Auletta JJ, Kou J, Chen M, Shaw BE. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR US summary slides. Center for International Blook & Marrow Transplant Research. 2021. Accessed May 30, 2022. https://view.officeapps.live.com/op/view.aspx?src=https%3A%2F%2Fwww.cibmtr.org%2FReferenceCenter%2FSlidesReports%2FSummarySlides%2FDocuments%2FThe%2520US%2520Summary%2520Slides%25202021%2520-%2520COVID-19%2520Related%2520-%2520web%2520version.pptx
5. Facon T, Kumar SK, Plesner T, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(11):1582-1596. doi:10.1016/S1470-2045(21)00466-6
6. O’Donnell EK, Laubach JP, Yee AJ, et al. A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma. Br J Haematol. 2018;182(2):222-230. doi:10.1111/bjh.15261
7. Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015;33(26):2863-2869. doi:10.1200/JCO.2015.61.2267
8. Fonseca R, Bergsagel PL, Drach J, et al; International Myeloma Working Group. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009;23(12):2210-2221. doi:10.1038/leu.2009.174
9. Dispenzieri A, Rajkumar SV, Gertz MA, et al. Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo Clin Proc. 2007;82(3):323-341. doi:10.4065/82.3.323
10. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288
11. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1
12. Moreau P, Hulin C, Perrot A, et al. Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(10):1378-1390. doi:10.1016/S1470-2045(21)00428-9
13. Landgren O, Hultcrantz M, Diamond B, et al. Safety and effectiveness of weekly carfilzomib, lenalidomide, dexamethasone, and daratumumab combination therapy for patients with newly diagnosed multiple myeloma: the MANHATTAN nonrandomized clinical trial. JAMA Oncol. 2021;7(6):862-868. doi:10.1001/jamaoncol.2021.0611
14. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma. J Clin Oncol. Published online December 13, 2021. doi:10.1200/JCO.21.01935