According to results of a study published in the Journal of Clinical Oncology, favorable outcomes were observed for patients with newly diagnosed, transplant-eligible multiple myeloma who achieved minimal residual disease (MRD)-negative status as assessed by next-generation flow cytometry — irrespective of disease cytogenetics or the timing of the assessment of MRD negativity.1
The depth of response as measured by MRD — which is the presence of residual myeloma cells not detected by conventional morphological methods — has been shown to correlate with risk of disease relapse in patients with multiple myeloma achieving complete remission. However, the use of lower-sensitivity methods for MRD detection (ie, through older flow cytometry technologies), only showed a 60% reduction in the risk of disease progression or death when patients with multiple myeloma who were characterized as having MRD-negative vs MRD-positive disease were compared.
Newer, more sensitive methods for evaluating MRD status in the setting of multiple myeloma are evolving, and include next-generation sequencing for the detection of clonal immunoglobulin VDJ gene rearrangements, and next-generation flow cytometry.
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The latter method, used in this study, is a 2-tube assay involving 8-color antibody panels that evaluate surface antigens on, as well as light-chain expression within, plasma cells.2
Positron emission tomography/computed tomography (PET/CT) imaging are other tests used for detection of MRD in multiple myeloma.
This study utilized longitudinal data on patient MRD status, assessed using next-generation flow cytometry, that were prospectively collected during the open-label, phase 3 PETHEMA/GEM2012MENOS65 clinical trial (ClinicalTrials.gov Identifier: NCT01916252), in which 458 patients with newly diagnosed, transplant-eligible multiple myeloma were randomly assigned to receive (following induction therapy) 6 cycles of bortezomib/lenalidomide/dexamethasone (VRD) to receive busulfan plus melphalan or high-dose melphalan, which was then followed by autologous transplantation and 2 consolidation cycles of VRD.
And, 28%, 42%, and 45% of patients in the intent-to-treat population patients were classified as MRD-negative following induction therapy, autologous transplantation, and consolidation therapy, respectively. Sixty-one patients stopped treatment following induction therapy and though there was no MRD data on them, they were considered to be MRD-positive for intent-to-treat analysis.
For those achieving undetectable MRD status, the hazard ratio for risk of disease progression or death was 0.18 (95% CI, 0.11-0.30; P <.001) and risk of death was 0.12 (95% CI, 0.05-0.29; P <.001) compared with those patients classified as MRD-positive.
Of the 7% of patients (14 individuals) with MRD-negative status who experienced disease progression during a median study follow-up of 40 months, approximately half had extraosseous plasmacytomas at diagnosis and were determined to have progressive disease on the basis of new plasmacytomas without detectable M-protein or disease infiltration in the bone marrow.
“Thus, it appears that these were true false-negative MRD results, reinforcing the need to combine next-generation flow cytometry or next-generation sequencing with PET/CT to monitor treatment efficacy, particularly in patients presenting with extramedullary or macrofocal disease as well as elevated lactate dehydrogenase levels,” the study authors noted.
Other key findings of this study included the following:
- The median limit of detection of MRD using next-generation flow cytometry was determined to be 2.9 × 10-6
- Patients achieving undetectable MRD status before or after autologous transplantation/consolidation therapy had similar survival
- Patients
with high-risk and lower-risk cytogenetics who achieved MRD-negative status had
similar survival
- Conversely, patients with MRD-positive disease had poor survival rates, irrespective of high- or lower-risk cytogenetics
In commenting on the findings from this study, the study authors stated that “these are unprecedented results that identify new outcomes for transplant-eligible patients and establish undetectable MRD as the new treatment end point for multiple myeloma.”
Disclosure: Some of the authors of the original study reported financial relationships with pharmaceutical companies and patent ownership of related products. For a full list of disclosures, please refer to the original study.
References
- Pavia B, Puig N, Cedena MT, et al. Measurable residual disease by next-generation flow cytometry in multiple myeloma [published online November 26, 2019]. J Clin Oncol. doi: 10.1200/JCO.19.01231
- Flores-Montero J, Sanoja-Flores L, Paiva B, et al. Next generation flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma. Leukemia.2017;31:2094-2103.
