Minimal Residual Disease After Autologous Stem-Cell Transplant for Patients With Myeloma: Prognostic Significance and the Impact of Lenalidomide Maintenance and Molecular Risk

Abstract

PURPOSE Minimal residual disease (MRD) can predict outcomes in patients with multiple myeloma, but limited data are available on the prognostic impact of MRD when assessed at serial time points in the context of maintenance therapy after autologous stem-cell transplant (ASCT) and the interaction between MRD and molecular risk. METHODS Data from a large phase III trial (Myeloma XI) were examined to determine the relationship between MRD status, progression-free survival (PFS), and overall survival (OS) in post-ASCT patients randomly assigned to lenalidomide maintenance or no maintenance at 3 months after ASCT. MRD status was assessed by flow cytometry (median sensitivity 0.004%) before maintenance random assignment (ASCT + 3) and 6 months later (ASCT + 9). RESULTS At ASCT + 3, 475 of 750 (63.3%) patients were MRD-negative and 275 (36.7%) were MRD-positive. MRD-negative status was associated with improved PFS (hazard ratio [HR] = 0.47; 95% CI, 0.37 to 0.58 P < .001) and OS (HR = 0.59; 95% CI, 0.40 to 0.85; P = .0046). At ASCT + 9, 214 of 326 (65.6%) were MRD-negative and 112 (34.4%) were MRD-positive. MRD-negative status was associated with improved PFS (HR = 0.20; 95% CI, 0.13 to 0.31; P < .0001) and OS (HR = 0.33; 95% CI, 0.15 to 0.75; P = .0077). The findings were very similar when restricted to patients with complete response/near complete response. Sustained MRD negativity from ASCT + 3 to ASCT + 9 or the conversion to MRD negativity by ASCT + 9 was associated with the longest PFS/OS. Patients randomly assigned to lenalidomide maintenance were more likely to convert from being MRD-positive before maintenance random assignment to MRD-negative 6 months later (lenalidomide 30%, observation 17%). High-risk molecular features had an adverse effect on PFS and OS even for those patients achieving MRD-negative status. On multivariable analysis of MRD status, maintenance therapy and molecular risk maintained prognostic impact at both ASCT + 3 and ASCT + 9. CONCLUSION In patients with multiple myeloma, MRD status at both ASCT + 3 and ASCT + 9 is a powerful predictor of PFS and OS.

Modern Myeloma Therapy + Sustained Minimal Residual Disease–Negative = (Functional) Cure!

“…In their study, in accord with prior meta-analyses focusing on MRD status and clinical outcomes in patients with newly diagnosed multiple myeloma, [6][7][8] de Tute et al 10 found MRD negativity to be associated with improved PFS (HR 5 0.21; P , .0001) and OS (HR 5 0.33; P 5 .0077). Their findings were very similar when restricted to those patients in complete response or near complete response.…”

“…9 To our knowledge, the Myeloma XI trial is one of the largest studies conducted to date (N 5 2,568) focusing on transplant-eligible patients with newly diagnosed multiple myeloma. 10 In the current paper, the authors examined data from Myeloma XI to determine the relationship between MRD status, PFS, and OS in post-HDM-ASCT patients randomly assigned to lenalidomide maintenance or no maintenance at 3 months after HDM-ASCT (N 5 1,248; Fig 1). 10 MRD status was assessed by flow cytometry (median sensitivity 0.004%) before maintenance random assignment (HDM-ASCT 1 3) and 6 months later (HDM-ASCT 1 9).…”

MRD dynamics during maintenance for improved prognostication of 1280 patients with myeloma in the TOURMALINE-MM3 and -MM4 trials

“…1,2 Persistent MRD in the setting of continuous therapy for transplant-ineligible 3,4 and relapsed patients, 5 as well as after induction and intensification in transplant-eligible patients, [6][7][8] is significantly associated with inferior survival. There are promising, yet scarce, data on the clinical value of MRD assessment during continuous [8][9][10] or fixed-duration 6 maintenance therapy. In contrast, there is virtually no information on patients' MRD status during observation.…”

“…In contrast, there is virtually no information on patients' MRD status during observation. 10 Paradoxically, maintenance and observation are the disease settings where MRD status is anticipated to help tailor treatment duration. 11,12 Historically, MRD has been evaluated at specific single time points during therapy.…”

“…As noted above, existing data on serial MRD assessments during maintenance are limited to a few studies in relatively small samples of patients, 6,8,9 or to a 6-month interval in the large Myeloma XI trial. 10 Because current treatment paradigms are based on continuous treatment until progressive disease (PD), there is very limited information on the prognostic value of MRD kinetics in patients not receiving active treatment, with only 1 reported analysis to date. 10 Ixazomib has been investigated as maintenance therapy in MM, both in transplant-eligible (TOURMALINE-MM3; clinicaltrials.gov number NCT02181413) 14 and transplant-ineligible (TOURMALINE-MM4; NCT02312258) patients.…”