Two myeloma specialists weighed in on the disappointing findings of SWOG S1211: Suzanne Lentzsch, MD, PhD, Professor of Medicine at Columbia University and Director of the Multiple Myeloma and Amyloidosis Service, and Joshua Richter, MD, Assistant Professor of Medicine, Icahn School of Medicine at Mount Sinai, and Director of Myeloma at the Blavatnik Family–Chelsea Medical Center. Both emphasized the challenge of treating patients with high-risk myeloma, as effective treatments have been lacking.
Suzanne Lentzsch, MD, PhD
Joshua Richter, MD
“Despite advances in therapy, for patients with newly diagnosed myeloma and high-risk features, outcomes remain poor, and the optimal treatment needs to be defined,” said Dr. Lentzsch.
“Ultimately, we continue to fall short across the board when patients present with high-risk disease. We fall short for both the progression-free survival and overall survival standpoints,” Dr. Richter commented. “Despite the improvements we’ve seen in patients with myeloma, high-risk disease continues to represent a more complicated arena, and patients continue to suffer from worse outcomes.”
The S1211 trial sought to overcome this scenario using an elotuzumab-containing quadruplet-based induction strategy, but the study did not meet its goal.
S1211 Background
In 2011, the National Cancer Institute Multiple Myeloma Steering Committee convened a special session to develop a consensus definition for high-risk disease. The SWOG Barlogie-Salmon Myeloma Committee was charged with designing the first enrichment-designed, randomized, phase II trial to assess treatments in this group. Based on the best evidence at that time, lenalidomide plus bortezomib and dexamethasone (RVd) served as the control arm of the phase II S1211 trial. RVd plus elotuzumab, a monoclonal antibody against SLAMF7, became the experimental arm. S1211 began in October 2013 and was completed in May 2016.
“I think it is important to point out that S1211 is the first randomized study reported to date that solely focuses on high-risk myeloma,” Dr. Lentzsch said. “Unfortunately, the addition of elotuzumab to RVd induction and maintenance did not improve patient outcomes. After 53 months of median follow-up, the median progression-free survival and overall survival in both arms of the study exceeded the original statistical assumptions.”
“Those findings were unexpected, since early data with elotuzumab combinations showed similar response rates in high-risk myeloma.1,2 Furthermore, all randomized trials adding daratumumab, a monoclonal antibody against CD38, in newly diagnosed myeloma significantly improved the response rate and progression-free survival,” she said, referring to MAIA,3 ALCYONE,4 and CASSIOPEIA.5
“But analyzing the subgroup of high-risk patients in these randomized phase III trials reveals that the addition of daratumumab did not significantly improve the progression-free survival in newly diagnosed high-risk myeloma. These data suggest that, despite the impressive improvement in response, progression-free survival, and overall survival (the latter only available for ALCYONE), neither elotuzumab nor daratumumab can overcome the poor prognosis in high-risk multiple myeloma,”Dr. Lentzsch concluded.
Interestingly, however, at the ASCO20 meeting, Giri et al presented a meta-analysis of MAIA, ALCYONE, and CASSIOPEIA with a longer follow-up.6 The analysis showed the addition of daratumumab to front-line backbone regimens among patients with high-risk myeloma did lead to an improvement in progression-free survival (pooled hazard ratio = 0.67; P = .02), with little heterogeneity (Cochran’s Q P = .77; I2 = 0%).
“Of note, this benefit was seen only with longer follow-up of the MAIA trial, in which the hazard ratio decreased to 0.57, compared with 0.85, as in the original 2019 publication in The New England Journal of Medicine,”3 she said. “Therefore, this meta-analysis, using more mature data with longer follow-up, might mainly reflect the improved outcome of the biologically different high-risk myeloma group that benefits from daratumumab.”
Furthermore, in MAIA, patients in the experimental arm received continuous triplet therapy (daratumumab, lenalidomide, and dexamethasone) until disease progression, which had not been the case in prior upfront treatment trials. Most earlier trials, which focused on treating transplant-ineligible, newly diagnosed patients, used a fixed-duration combination followed by single-agent maintenance, she noted.
“Taken together, those data show that elotuzumab is not recommended for the treatment of newly diagnosed, high-risk multiple myeloma. Daratumumab showed a benefit for progression-free survival in the long-term follow-up meta-analysis and should be included in the treatment of patients with high-risk myeloma,” Dr. Lentzsch recommended, referring providers to the mSMART Mayo Clinic Guidelines.7
Dr. Richter suggested that a better understanding of risk could lead to improvements in management. “It may be that we need to consider a risk-adapted approach, not only in the induction phase of treatment of high-risk myeloma nor in the consolidation phase, but also in the maintenance phase,” he said. “Ongoing work is needed to standardize and better classify patients in terms of their risk stratification…. Better definitions will allow us to cross-compare trials and make true analyses about how to treat these patients.”
DISCLOSURE: Dr. Lentzsch has served as a consultant or advisor for Caelum Bioscience, Sorrento, Celularity, and Janssen; owns stock and holds royalties/patents in Caelum Bioscience; and has received research support from Karyopharm and Sanofi. Dr. Richter has served as a consultant or advisor for Adaptive Biotechnologies, Amgen, Antengene, Celgene, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and X4 Pharmaceuticals and has served on speakers bureaus for Bristol-Myers Squibb, Celgene, and Janssen.
REFERENCES
1. Jakubowiak AJ, Benson DM, Bensinger W, et al: Phase I trial of anti-CS1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/refractory multiple myeloma. J Clin Oncol 30:1960-1965, 2012.
2. Lonial S, Vij R, Harousseau JL, et al: Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol 30:1953-1959, 2012.
3. Facon T, Kumar S, Plesner T, et al: Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med 380:2104-2115, 2019.
4. Mateos MV, Dimopoulos MA, Cavo M, et al: Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med 378:518-528, 2018.
5. 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 394:29-38, 2019.
6. Giri S, Grimshaw A, Bal S, et al: Efficacy of daratumumab in the treatment of multiple myeloma with high-risk cytogenetics: Meta-analysis of a randomized phase III trial. ASCO20 Virtual Scientific Program. Abstract 8540.
7. Mayo Clinic: mSMART (Mayo Stratification for Myeloma And Risk-adapted Therapy): Newly diagnosed myeloma. Available at https://static1.squarespace.com/static/5b44f08ac258b493a25098a3/t/5ebc6d998b1aa05753cfb3fe/1589407130047/Treatment-of-Newly-Diagnosed-Myelomav17_May+20FINAL.pdf. Accessed June 18, 2020.
