Presenter: Annemiek Broijl, PhD
Session: 654. Multiple Myeloma: Pharmacologic Therapies: Optimizing Therapy in Newly Diagnosed Myeloma and Beyond
Date & Time: Sunday, December 8, 2024 5:15 PM–5:30 PM
Location: Pacific Ballroom Salons 21-22 (Marriott Marquis San Diego Marina)
Keywords: Lenalidomide, Carfilzomib, CD38, MRD, CD19, lenalidomide, dexamethasone, carfilzomib, HR-SMM
Abstract Summary:
- The KRd regimen (carfilzomib, lenalidomide, dexamethasone) significantly improved MRD negativity rates (57% vs. 5%) and progression-free survival (PFS) compared to Rd (lenalidomide, dexamethasone) in high-risk smoldering multiple myeloma (HR-SMM) patients.
- The 3-year PFS was markedly higher in the KRd arm (94%) compared to the Rd arm (40%), with a hazard ratio of 0.08, indicating a substantial reduction in the risk of progression or death.
- Although MRD negativity after 4 induction cycles was not significantly different between the groups, the overall depth of response and overall response rate favored the KRd regimen.
- The KRd treatment was associated with a higher incidence of grade 3-4 adverse events (74% vs. 53%) and a higher discontinuation rate due to toxicity (26% vs. 9%) compared to Rd.
- No treatment-related deaths occurred, and the KRd regimen was deemed feasible and safe, offering a significant therapeutic advantage in HR-SMM.
Abstract
Background. Standard treatment for smoldering multiple myeloma (SMM) consists of active surveillance according to international guidelines, yet some current guidelines advise lenalidomide with or without dexamethasone for high-risk SMM (HR-SMM)(1). This is based on two randomized phase 2 trials comparing lenalidomide with/without dexamethasone in comparison to active surveillance (2,3). Both trials have shown benefit in terms of time to progression (TTP) to MM, and in one trial also on overall survival (OS)(3). Adding a third agent, carfilzomib, to lenalidomide and dexamethasone (KRd), generated deep responses, high percentages of minimal residual disease (MRD) negativity and progression-free survival (PFS) in a single arm phase 2 trial (4). This phase 2, international, multi-center, randomized, open label, superiority EMN15/HOVON147 study assessed efficacy and safety of KRd versus lenalidomide-dexamethasone (Rd) in patients with HR-SMM.
Methods This trial, which was developed in 2017, used MAYO and/or PETHEMA criteria to identify patients with HR-SMM. MAYO HR-SMM criteria include bone marrow plasma cells ≥10 %, serum M-protein ≥ 3 g/dl, and serum free light-chain ratio <0.125 or >8 (5). PETHEMA HR-SMM criteria include the following: of the plasma cell population, presence of ≥95% abnormal plasma cells (presence or absence of CD38, CD56, CD19 and/or CD45), and immunoparesis, defined as a reduction (below the lower normal limit) in the levels of 1 or 2 of the uninvolved immunoglobulins (6).
HR-SMM patients were randomized 2:1 to KRd (Cycles 1-9 carfilzomib 20/56 mg/m2, lenalidomide 25 mg, dexamethasone 20 mg cycles 1-4 and 10 mg cycles 5-9) or Rd (Cycles 1-9 lenalidomide 25 mg, dexamethasone 20 mg cycles 1-4 and 10 mg cycles 5-9); followed by extended lenalidomide dosing (10 mg days 1-21 of a 28-day cycle for 24 cycles).
The primary endpoint was the rate of MRD negativity by next generation flowcytometry (NGF) (10-5) after induction treatment. Among the secondary endpoints were rate of NGF MRD negativity (10-5) after 4 induction cycles and PFS. MRD rates were evaluated based on modified intention-to-treat (m-ITT) analysis, patients with missing MRD data were considered as positive. PFS was defined as time from randomization to biochemical progression (according to IMWG 2016 criteria for multiple myeloma)(7) or death, whichever comes first. Data cut-off for the analysis was July 11, 2024.
Results. A total of 58 patients were included in the trial, 23 in arm A (Rd) and 35 in arm B (KRd); 1 patient from arm A has been considered ineligible in hindsight and was excluded from all analysis according to protocol. Two patients, one in each arm, went off-protocol by decision before starting treatment. Patient characteristics in the Rd and KRd arms were well balanced: median age was 63 and 61 years, respectively. 14% and 9% of patients had HR-SMM based on Mayo criteria, while 96% and 94% of patients fulfilled both PETHEMA high-risk criteria, respectively.
Median follow-up in the trial was 34 months, inter-quartile range (IQR) 21-48. Median number of cycles of total treatment was 16 in arm A, and 27 in arm B.
Rates of m-ITT MRD negativity at 10-5 cut-off after induction were 57% versus 5% in the KRd versus Rd arm (odds ratio (OR)=0.04, 95% confidence interval (CI) = 0.00-0.28; P < 0.001). Furthermore, a statistically significant benefit in PFS was observed with KRd versus Rd, with an estimated hazard ratio (HR) of 0.08 (95% CI = 0.02-0.35; P < 0.001). 3-years PFS was 94% versus 40% in the KRd and Rd arm, respectively. MRD negativity after 4 induction cycles was not significantly better in the KRd arm, 37% versus 14% (OR=0.27, 95% CI 0.06-1.12; P = 0.07).- DoR and ORR showed a statistically significant benefit in favor of the KRd arm, for PFS2 and OS no formal test was performed due to lack of events and longer follow up is required.
At least one grade 3-4 (non)-hematologic AE’s occurred in 74% versus 53% of KRD versus Rd treated patients. Less patients went off protocol due to progression in the KRd arm, 6% versus 36% in the Rd arm. Rate of discontinuation for toxicity was 26% versus 9% in the KRd versus Rd arm. No treatment-related deaths occurred, two deaths occurred in the Rd arm, after disease progression.
Conclusions. Treatment with KRd was observed to be feasible and safe in patient with HR-SMM. 9 cycles of KRd treatment significantly increased flow MRD negativity rates (10-5) as compared to Rd, which translated into a significantly higher PFS.
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