Sarah A. Holstein, MD, PhD
An updated analysis of the phase III CANDOR study—recently reported by Usmani et al and summarized in this issue of The ASCO Post—confirmed a significant progression-free survival benefit for the combination of daratumumab, carfilzomib, and dexamethasone (KdD) over carfilzomib and dexamethasone (Kd) in patients with one to three prior lines of therapy for multiple myeloma.1 To date, a total of six randomized phase III studies have been performed in which a doublet has been compared with the doublet plus anti-CD38 monoclonal antibody therapy in the relapsed or refractory setting. Four of these studies involved daratumumab (POLLUX, CASTOR, CANDOR, APOLLO), and two involved isatuximab (ICARIA and IKEMA) as the anti-CD38 monoclonal antibody. It is not surprising, given the single-agent activity of both daratumumab and isatuximab, that all six of these studies have demonstrated substantial progression-free survival benefit for the triplets over the doublets.
Are All Combinations Created Equal?
These studies, coupled with multiple other phase III studies performed in this space (eg, TOURMALINE-MM1, ELOQUENT-2, ASPIRE, OPTIMISMM, BOSTON) present both physicians and patients with what seems like an overwhelming number of options. However, are all combinations created equally, and is there rationale to select one combination over another for specific patient populations?
I would argue that understanding U.S. treatment practices, particularly in the induction setting, can help us navigate through the large number of options available at first relapse. The current U.S. practice involves the widespread use of upfront lenalidomide in both the transplant-eligible and -ineligible settings, often continued until disease progression. In that context, the studies that evaluated lenalidomide-containing salvage regimens (TOURMALINE-MM1, ELOQUENT-2, ASPIRE, POLLUX) become less relevant, as these studies primarily enrolled lenalidomide-naive patients. This then leaves bortezomib-, carfilzomib-, or pomalidomide-containing regimens to consider. Many patients will not be refractory to bortezomib at first relapse, but it can be difficult to continue bortezomib treatment indefinitely because of the development of neuropathy or exacerbation of preexisting neuropathy.
Notably, the only study of an anti-CD38 monoclonal antibody that did not include treatment until disease progression was the CASTOR trial. In this study, the bortezomib/dexamethasone backbone was discontinued in both arms, leaving the control arm on observation and the experimental arm on single-agent daratumumab.2 Thus, carfilzomib- or pomalidomide-containing regimens are often considered for patients whose disease has become refractory to lenalidomide.
CANDOR and IKEMA: Progression-Free Survival Benefit
One of the notable aspects of the CANDOR study is the marked progression-free survival benefit observed in the subgroup of patients with lenalidomide-refractory disease (hazard ratio [HR] = 0.46, 95% confidence interval [CI] = 0.28–0.73).1 The median progression-free survival for this subgroup in the triplet arm was 28.1 months (compared with 28.6 months for the entire population in the triplet arm). Although only a small number of patients were refractory to lenalidomide in the front-line setting (19 patients in the triplet arm were refractory to lenalidomide and had one previous line of therapy; 6 in the control arm), the median progression-free survival for this subgroup was 25 months for KdD.1 The IKEMA study, which had a similar design of anti-CD38 monoclonal antibody therapy (in this case, isatuximab) plus Kd vs Kd demonstrated a trend toward superior progression-free survival in patients refractory to lenalidomide (HR = 0.60, 95% CI = 0.34–1.06), with median progression-free survival values not yet reported.3
“Understanding U.S. treatment practices, particularly in the induction setting, can help us navigate through the large number of options available at first relapse.”— Sarah A. Holstein, MD, PhD
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Overall, these two studies reported impressive progression-free survival benefits for the anti-CD38 monoclonal antibody/Kd arms for their entire enrolled populations: hazard ratios of 0.59 (95% CI = 0.45–0.78) in CANDOR and 0.53 (95% CI = 0.32–0.89) in IKEMA. Interestingly, there is little in the translational/preclinical literature discussing potential mechanisms for synergy between anti-CD38 monoclonal antibodies and proteasome inhibitors. Whether it is simply a matter of two very effective classes of agents being used in combination or whether there are additional immunomodulatory effects at play needs further investigation.
Turning to APOLLO and ICARIA
The final options to discuss are the combinations of an anti-CD38 monoclonal antibody, pomalidomide, and dexamethasone, studied in the APOLLO (daratumumab) and ICARIA (isatuximab) trials. Cross-trial comparisons become even more difficult, as unlike the CANDOR or IKEMA studies that enrolled patients with one to three prior lines of therapy, the APOLLO study included all patients who had received at least one line of therapy with both lenalidomide and a proteasome inhibitor. If patients had received only one prior line of therapy, they had to be refractory to lenalidomide. Overall, 80% of the enrolled subjects were refractory to lenalidomide, with approximately 60% refractory to lenalidomide as the most recent line of therapy.4 In that context, the combination of daratumumab plus pomalidomide/dexamethasone (Pd) did prove superior to Pd alone for the overall study population (median progression-free survival = 12.4 vs 6.9 months, HR = 0.63, 95% CI = 0.47–0.85), as well as in the lenalidomide-refractory subgroup (median = 9.9 vs 6.5 months, HR = 0.66, 95% CI= 0.49–0.90).4
In contrast, the ICARIA study enrolled patients who had received at least two prior lines of therapy and had not responded to therapy with lenalidomide and a proteasome inhibitor. Approximately 93% of patients were considered refractory to lenalidomide, with approximately 59% receiving lenalidomide as the last line of therapy.
The median progression-free survival for the entire population was 11.5 months with isatuximab/Pd vs 6.5 months with Pd alone (HR = 0.60, 95% CI = 0.44–0.81), whereas similar benefits were observed in the lenalidomide-refractory subgroup (HR = 0.59, 95% CI = 0.43–0.82) and the subgroup given lenalidomide as the last line of therapy (HR = 0.50, 95% CI = 0.34–0.76).5 The median progression-free survival values for these isatuximab/Pd subgroups have subsequently been published, with 11.4 months for the subgroup of overall lenalidomide-refractory patients and 11.6 months for the subgroup that was refractory to lenalidomide at the last line.6 Thus, recognizing the dangers of cross-trial comparisons involving different patient populations, it is still tempting to conclude that to date, the longest median progression-free survival reported in a lenalidomide-refractory patient population was in the context of KdD in the CANDOR trial.
CANDOR: Overall Survival and Toxicity
The overall survival data for the CANDOR study have not yet been reported, as they were not mature at the time of the current analysis data cutoff.1 Presumably, the impressive progression-free survival benefit observed in this study will translate to superior overall survival for the triplet combination. However, the overall survival data will also be influenced by access to active subsequent salvage therapies. It is notable that only 18% of patients in the control arm received an anti-CD38 monoclonal antibody–containing regimen as the next line of therapy and overall only 21% received such a regimen with any subsequent therapy.1 This is most likely reflective of the majority of subjects being from European or Asian countries, where access to daratumumab or isatuximab is much more limited than in the United States.
“It is not unreasonable to proclaim this combination [daratumumab, carfilzomib, and dexamethasone] as a standard of care in the relapsed or refractory setting, particularly in lenalidomide-refractory disease.”— Sarah A. Holstein, MD, PhD
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No new safety signals were reported in the updated CANDOR analysis, including no new treatment-related deaths. It is interesting to note there were two cases of COVID-19 pneumonia reported: one grade 4 event in the KdD arm and one grade 5 event in the Kd arm.1 There has been long-standing concern about vaccine responsiveness in the context of proteasome inhibitors. More recent data in the era of COVID-19 vaccinations have suggested suboptimal antibody responses in those receiving anti-CD38 monoclonal antibody therapy.7 Thus, patients receiving KdD salvage therapy are likely to be at higher risk of breakthrough COVID-19 infections, and aggressive support with booster doses and monoclonal antibody therapy is warranted.
Closing Thoughts
Given the activity of KdD, which was demonstrated regardless of prior lines of therapy, refractoriness to prior therapies, and cytogenetic risk, it is not unreasonable to proclaim this combination as a standard of care in the relapsed or refractory setting, particularly in lenalidomide-refractory disease. As noted, this combination is a particularly attractive option for those patients who are experiencing disease progression on lenalidomide in the front-line setting.
However, it should also be noted that standards of care in the front-line setting are evolving rapidly. In the transplant-ineligible setting, a current standard of care is daratumumab, lenalidomide, and dexamethasone, as per the MAIA study; the study has shown an unprecedented progression-free survival duration (median not yet reached at 60 months).8
In the transplant-eligible setting, quadruplet combinations such as daratumumab plus lenalidomide, bortezomib, and dexamethasone (VRd) or isatuximab plus VRd appear poised to become a new standard of care, should phase III studies demonstrate a progression-free survival benefit. The ongoing PERSEUS and GMMG-HD7 studies as well as several other randomized phase III studies, such as SWOG S1803 and MMY3021 (AURIGA), are all exploring maintenance strategies including an anti-CD38 monoclonal antibody plus lenalidomide. Furthermore, there is likely to be an increased use of carfilzomib-containing induction and maintenance strategies, based on the strength of the results from the FORTE trial.9 Thus, the utility of salvage KdD in the context of patients with significant exposure to anti-CD38 monoclonal antibody or carfilzomib therapy in the induction and maintenance settings will need to be determined.
Dr. Holstein is Associate Professor, Internal Medicine, Division of Oncology & Hematology, University of Nebraska Medical Center, Omaha.
DISCLOSURE: Dr. Holstein has served as a consultant for or received honoraria from BMS/Celgene, Genentech, GSK, Janssen, Oncopeptides, Sanofi, SecuraBio, and Takeda; and has received research funding from Oncopeptides.
REFERENCES
1. Usmani SZ, Quach H, Mateos MV, et al: Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): Updated outcomes from a randomised, multicentre, open-label, phase 3 study. Lancet Oncol 23:65-76, 2022.
2. Palumbo A, Chanan-Khan A, Weisel K, et al: Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 375:754-766, 2016.
3. 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.
4. 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.
5. 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.
6. Richardson PG, Harrison SJ, Bringhen S, et al: Isatuximab for relapsed/refractory multiple myeloma: Review of key subgroup analyses from the phase III ICARIA-MM study. Future Oncol 17:4797-4812, 2021.
7. Van Oekelen O, Gleason CR, Agte S, et al: Highly variable SARS-CoV-2 spike antibody responses to two doses of COVID-19 RNA vaccination in patients with multiple myeloma. Cancer Cell 39:1028-1030, 2021.
8. 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 22:1582-1596, 2021.
9. 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 22:1705-1720, 2021.
