“Ask yourself at every moment, ‘Is this necessary?’”
—Marcus Aurelius
To complement The ASCO Post’s extensive coverage of the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition, here are two important abstracts selected from the meeting proceedings focusing on induction and consolidation regimens used in conjunction with autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma. For full details of the study abstracts, visit www.hematology.org/meetings/annual-meeting/abstracts.
PERSEUS Trial
Abstract LBA-1: Primary results of a phase III randomized study of daratumumab plus bortezomib, lenalidomide, and dexamethasone (D-VRd; n = 355) vs bortezomib, lenalidomide, and dexamethasone (VRd; n = 354) in patients aged 18 to 70 with newly diagnosed multiple myeloma who are eligible for ASCT.1
Background: Daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) quadruplet therapy has shown clinical benefit vs bortezomib, thalidomide, and dexamethasone (VTd) alone and is approved for transplant-eligible patients with newly diagnosed multiple myeloma. VRd induction followed by ASCT, VRd consolidation, and lenalidomide maintenance is also considered a standard of care for transplant-eligible newly diagnosed multiple myeloma. In the phase II GRIFFIN study, D-VRd induction/consolidation followed by daratumumab and lenalidomide maintenance improved the depth of response and progression-free survival vs VRd induction and consolidation and lenalidomide maintenance in transplant-eligible patients with newly diagnosed multiple myeloma after more than 4 years of follow-up.2
Syed A. Abutalib, MD
Saad Z. Usmani, MD, MBA, FACP, FASCO
Method: All patients received up to six 28-day cycles (four pre-ASCT induction, two post-ASCT consolidation) of VRd (bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11; lenalidomide at 25 mg on days 1–21; dexamethasone at 40 mg on days 1–4 and 9–12) followed by lenalidomide maintenance therapy (10 mg on days 1–28 until progressive disease). Patients in the D-VRd arm also received subcutaneous daratumumab (1,800 mg) weekly in cycles 1 to 2, every 2 weeks in cycles 3 to 6, and every 4 weeks during maintenance until progressive disease.
Results: The primary endpoint of the study is progression-free survival.
Efficacy: At a median follow-up of 47.5 months, progression-free survival was significantly improved with D-VRd vs VRd (hazard ratio = 0.42; 95% confidence interval = 0.30–0.59; P < .0001 [crossing the prespecified stopping boundary of 0.0126]). Median progression-free survival was not reached in either arm; estimated 48-month progression-free survival rate was 84.3% for D-VRd vs 67.7% for VRd.
Prespecified subgroup analyses showed a consistent progression-free survival improvement with D-VRd vs VRd across clinically relevant subgroups, including patients with International Staging System stage III disease and patients with high cytogenetic risk (t[4;14], t[14;16], or del[17p]). Overall rates of complete response or better (87.9% vs 70.1%; P < .0001) and undetectable MRD (75.2% vs 47.5%; P < .0001) were significantly higher with D-VRd vs VRd.
Safety: For D-VRd and VRd, serious treatment-emergent adverse events occurred in 57.0% vs 49.3% of patients, and treatment-emergent adverse events leading to treatment discontinuation occurred in 8.8% vs 21.3% of patients, respectively.
Clinical Implications: D-VRd in transplant-eligible patients with newly diagnosed multiple myeloma significantly improved progression-free survival and increased the depth of response (complete response or better and undetectable MRD), with a consistent progression-free survival benefit across clinically relevant subgroups. The safety profile was consistent with the known safety profiles for D-VRd.
These data, together with results from the phase II GRIFFIN study, demonstrate the consistent and clinically meaningful benefit of quadruplet therapy followed by daratumumab and lenalidomide maintenance vs triplet VRd followed by lenalidomide maintenance and support the combination of D-VRd followed by daratumumab and lenalidomide maintenance as a new standard of care for transplant-eligible patients with newly diagnosed multiple myeloma.
IsKia Trial
Abstract 4: Results of a phase III randomized study using isatuximab, carfilzomib, lenalidomide, and dexamethasone (IsaKRd; n = 151) vs carfilzomib, lenalidomide, and dexamethasone (KRd; n = 151) as pre-ASCT induction and posttransplant consolidation in patients with newly diagnosed multiple myeloma.3
Background: The current standard treatment of transplant-eligible patients with newly diagnosed multiple myeloma consists of quadruplet induction with proteasome inhibitors, immunomodulatory agents, dexamethasone, and an anti-CD38 monoclonal antibody followed by high-dose melphalan and ASCT, with subsequent consolidation. The phase III IsKia trial assessed efficacy and safety of a different anti-CD38 antibody and proteasome inhibitor, compared with the PERSEUS study, in patients younger than age 70.
Method: IsaKRd group received four 28-day cycles of isatuximab at 10 mg/kg intravenously (IV) on days 1, 8, 15, and 22 of cycle 1, followed by 10 mg/kg on days 1 and 15 of cycles 2 to 4; carfilzomib at 20 mg/m2 IV on day 1 of cycle 1, followed by 56 mg/m2 IV on days 8 and 15 of cycle 1 and days 1, 8, and 15 of cycles 2 to 4; lenalidomide at 25 mg daily on days 1 to 21; dexamethasone at 40 mg orally on days 1, 8, 15, and 22; melphalan at 200 mg/m2 followed by ASCT; and four consolidation cycles with IsaKRd at the same schedule. The KRd group received four KRd induction cycles; melphalan at 200 mg/m2 followed by ASCT; and four KRd consolidation cycles (with carfilzomib, lenalidomide, and dexamethasone at the same schedule as in the IsaKRd arm).
Results: The primary endpoint was the rate of undetectable MRD by next-generation sequencing (10–5) after consolidation in the intention-to-treat population. MRD was tested in all patients who achieved a very good partial response or better.
MRD and Efficacy: In intention-to-treat analysis, the rate of undetectable MRD at the 10−5 cutoff by next-generation sequencing after consolidation was 77% vs 67% (odds ratio = 1.67; P = .049) with IsaKRd vs KRd. At the current follow-up (median = 20 months, interquartile range = 18–23 months), there was no difference in progression-free survival (95% at 1 year in both arms).
Safety: The rate of discontinuation of treatment for toxicity was 6% in the IsaKRd arm vs 5% in the KRd arm; there were four treatment-related deaths with IsaKRd (two from COVID-19, one from pneumonia, and one from pulmonary embolism) and one treatment-related death with KRd (from septic shock).
Clinical Implications: The addition of isatuximab to KRd induction and consolidation significantly increased undetectable MRD rates compared with KRd alone even in high-risk cytogenetic (t[4;14], t[14;16], or del[17p]) myeloma, with no new safety concerns. After consolidation, the rates of stringent complete response, complete response or better, and very good partial response or better were comparable in both arms, with no difference in progression-free survival at 12 months. The IsKia study highlights the value of undetectable MRD as an endpoint to distinguish the efficacy of different front-line strategies especially for high-risk multiple myeloma; however, longer follow-up for sustained undetectable MRD and progression-free survival would be more important before considering any change in clinical practice.
DISCLOSURE: Dr. Abutalib has reported a financial relationship with AstraZeneca. Dr. Usmani has received research funding and/or consulting fees from AbbVie, Amgen, BMS, Celgene, Edo Pharma, Genentech, Gilead Sciences, GSK, Janssen, Oncopeptides, Sanofi, Seattle Genetics, Secura Bio, SkylineDx, Takeda, and TeneoBio.
REFERENCES
1. Sonneveld P, Dimopoulos MA, Boccadoro M, et al: Phase 3 randomized study of daratumumab + bortezomib, lenalidomide, and dexamethasone (VRd) versus VRd alone in patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplantation: Primary results of the PERSEUS trial. 2023 ASH Annual Meeting & Exposition. Abstract LBA-1. Presented December 12, 2023.
2. Voorhees PM, Sborov DW, Laubach J, et al: Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): Final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol 10:E825-E837, 2023.
3. Gay F, Roeloffzen W, Dimopoulos MA, et al: Results of the phase III randomized IsKia trial: Isatuximab-carfilzomib-lenalidomide-dexamethasone vs carfilzomib-lenalidomide-dexamethasone as pre-transplant induction and post-transplant consolidation in newly diagnosed multiple myeloma patients. 2023 ASH Annual Meeting & Exposition. Abstract 4. Presented December 10, 2023.
Dr. Abutalib is Director of the Malignant Hematology and Transplantation & Cellular Therapy Programs at the Advocate/Aurora St. Luke’s Medical Center, Milwaukee, and Associate Professor at Rosalind Franklin University of Medicine and Science, Chicago. Dr. Usmani is Professor of Medicine and Chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center, New York.
