The treatment paradigm for multiple myeloma continues to evolve at a rapid pace with the introduction of new drugs and the development of drug combinations, particularly the initial approach to the treatment of newly diagnosed multiple myeloma.1 One major shift in the treatment of newly diagnosed multiple myeloma during the past decade has been the adoption of continuous therapy, both for those undergoing autologous stem cell transplantation (ASCT) as part of the initial therapy and those considered ineligible for this procedure.2 Standard treatment used to consist of a defined duration of therapy—eg, 4 to 6 cycles of induction therapy followed by ASCT or 9 to 18 cycles of a melphalan-containing regimen depending on the eligibility for transplantation. We now use some form of maintenance until disease progression after ASCT and continued treatment with an attenuated form of initial therapy until disease progression for transplant-ineligible patients.
These shifts have borne dividends in the near doubling of progression-free survival and twofold to threefold increases in overall survival for patients with multiple myeloma. However, these changes have also altered the profile of patients experiencing their first relapse; the majority become refractory to one or more drugs, making treatment choices more challenging.
Enter Monoclonal Antibodies
The advent of monoclonal antibodies, particularly those targeting CD38 (daratumumab and isatuximab), have dramatically altered the treatment choices for patients with relapsed multiple myeloma.3 These agents, along with the introduction of the next generation of immunomodulatory agents such as pomalidomide and proteasome inhibitors such as carfilzomib, have resulted in the examination of a variety of triplet combinations in the setting of relapsed myeloma.
The initial phase III trials of daratumumab with lenalidomide (POLLUX4) or bortezomib (CASTOR5) firmly established a prominent role for this class of drugs in the setting of initial relapse; however, these results rapidly became irrelevant, given the increasing proportion of patients presenting with disease refractory to lenalidomide and with many patients having bortezomib-related peripheral neuropathy after exposure to the agent as part of initial therapy. As a result, combinations of monoclonal antibodies with pomalidomide or carfilzomib have been studied in a series of phase III trials, with results supporting their use for relapsed multiple myeloma.
One major shift in the treatment of newly diagnosed multiple myeloma during the past decade has been the adoption of continuous therapy…— Shaji K. Kumar, MD
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APOLLO Results Join Those From ICARIA
The APOLLO trial, reported by Dimopoulos et al and summarized in this issue of The ASCO Post, confirms the prior observation of the activity of daratumumab combined with pomalidomide and dexamethasone in relapsed multiple myeloma.6 Chari et al had previously reported on 103 patients with relapsed myeloma with a median of four prior therapies; for these patients, treatment with daratumumab plus pomalidomide and dexamethasone produced an overall response rate of 60%, with a median progression-free survival of 8.8 months and an overall survival of 17.5 months.7 The addition of daratumumab was well tolerated, with the exception of infusion-related reactions (50%) and a higher rate of neutropenia than expected with pomalidomide alone.
In the current phase III trial, patients should have had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor. Patients with primary refractory disease were excluded and were required to be refractory to lenalidomide if only one previous line of therapy was received. Overall, 304 patients were randomly assigned to receive pomalidomide and dexamethasone alone (n = 153) or with daratumumab (n = 151). Patients received a standard dose and schedule of pomalidomide (4 mg, once daily on days 1–21) and dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those > 75 years) in 28-day cycles. In the daratumumab-containing arm, daratumumab was given weekly during cycles 1 and 2, every 2 weeks during cycles 3 through 6, and then every 4 weeks, with treatment continued until disease progression.
At a median follow-up of 16.9 months, the daratumumab combination therapy was associated with improved progression-free survival (median = 12.4 vs 6.9 months, hazard ratio = 0.63, P = .0018). Progression-free survival was better than that seen in the phase II trial, albeit among patients with less advanced myeloma in the phase III trial. It is important to note that the improvement in progression-free survival observed here is comparable to that seen in the ICARIA trial,8 in which isatuximab, the other CD38-directed monoclonal antibody, was added to pomalidomide plus dexamethasone, though the trials had differences in the populations studied. Hematologic toxicity, especially neutropenia, was the most common adverse event observed in APOLLO, in addition to an increased risk of infections, particularly respiratory tract infections.
Data From CANDOR and IKEMA Join the Mix
The data from the APOLLO and ICARIA trials provide important guidance for selection of treatment for patients who have been exposed to lenalidomide and bortezomib and who are often refractory to the former at the time of initial relapse. The pomalidomide-based regimens allow patients to receive a triplet that includes a drug class they have not been exposed to before (monoclonal antibody) and an immunomodulatory agent that has been shown to be effective in the face of lenalidomide refractoriness. However, these agents are not the only contenders as potential treatment choices at this stage of the disease.
Two randomized trials using carfilzomib-based triplets—daratumumab, carfilzomib, and dexamethasone in CANDOR9 and isatuximab, carfilzomib, and dexamethasone in IKEMA10—have shown striking efficacy in this patient population. Both these regimens appeared to have comparable efficacy, with a median progression-free survival not reached with either at the time of analysis and likely to exceed 2 years. However, the numbers cannot be directly compared with those seen with the pomalidomide-based triplets, given the differences in the patients enrolled onto these trials.
Choosing Among Treatment Options at Initial Relapse
This leaves us with an important question for which no randomized comparisons exist—Should we use daratumumab or isatuximab in combination with pomalidomide or with carfilzomib at the time of initial relapse? Without a direct comparison, the decision will have to be based on other clinical factors, namely lenalidomide refractoriness, prior exposure to proteasome inhibitors, prior toxicity with immunomodulatory agents, presence of comorbidities such as cardiovascular problems, logistics of administration (intravenous vs oral), required frequency of hospital visits, and need for vascular access, among others. Although we may not have definitive evidence on which regimen to go with, the results of these clinical trials nevertheless open a wide set of choices for clinicians and patients to choose from, a luxury that was not available less than a decade ago.
Without a doubt, these paradigms will continue to evolve with the introduction of newer therapies, especially treatments utilizing T-cell redirection, such as chimeric antigen receptor T-cell therapies and bispecific antibodies. The advances will no doubt continue to improve the survival outcomes of patients with myeloma, with the first-line approaches providing a median progression-free survival of 4 to 5 years and the second-line therapies adding an additional progression-free survival of 2 to 3 years—with many more options still available at the time of second relapse. However, we may run out of catchy names for the clinical trials!
Dr. Kumar is Professor of Medicine at the Mayo Clinic College of Medicine and Consultant in the Division of Hematology at the Mayo Clinic Cancer Center in Rochester, Minnesota.
DISCLOSURE: Dr. Kumar has received honoraria from BeiGene; has served as a consultant or advisor to Cellectar Biosciences; has served as an institutional consultant or advisor to AbbVie, Amgen, Bluebird Bio, Celgene, GeneCentrix, Genentech/Roche, Janssen Oncology, Kite Pharma, Merck, Molecular Partners, Oncopeptides, and Takeda; and has received institutional research funding from AbbVie, Carsgen Therapeutics, Celgene, Janssen Oncology, Kite Pharma, MedImmune, Merck, Novartis, Roche/Genentech, Sanofi, Takeda, and TeneoBio.
REFERENCES
1. Kumar SK, Rajkumar SV: The multiple myelomas: Current concepts in cytogenetic classification and therapy. Nat Rev Clin Oncol 15:409-421, 2018.
2. Dimopoulos MA, Jakubowiak AJ, McCarthy PL, et al: Developments in continuous therapy and maintenance treatment approaches for patients with newly diagnosed multiple myeloma. Blood Cancer J 10:17, 2020.
3. Kumar SK: Monoclonal antibodies for myeloma: Make it easy! J Oncol Pract 14:423-424, 2018.
4. Dimopoulos MA, Oriol A, Nahi H, et al: Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 375:1319-1331, 2016.
5. Palumbo A, Chanan-Khan A, Weisel K, et al: Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 375:754-766, 2016.
6. Dimopoulos MA, Terpos E, Boccadoro M, et al: Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): An open-label, randomised, phase 3 trial. Lancet Oncol 22:801-812, 2021.
7. Chari A, Suvannasankha A, Fay JW, et al: Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood 130:974-981, 2017.
8. Attal M, Richardson PG, Rajkumar SV, et al: Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): A randomised, multicentre, open-label, phase 3 study. Lancet 394:2096-2107, 2019.
9. Dimopoulos M, Quach H, Mateos MV, et al: Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): Results from a randomised, multicentre, open-label, phase 3 study. Lancet 396:186-197, 2020.
10. Moreau P, Dimopoulos MA, Mikhael J, et al: Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): A multicentre, open-label, randomised phase 3 trial. Lancet 397:2361-2371, 2021.
