Evidence-Based Minireview: Does achieving MRD negativity after initial therapy improve prognosis for high-risk myeloma patients?

Multiple myeloma (MM) patients with high-risk (HR) fluorescence in situ hybridization (FISH) abnormalities [t(4;14), t(14;16), t(14;20), and deletion 17p] or HR gene expression profiling have inferior outcomes. Amplification (≥4 copies) of CKS1B (1q21) also portends a poor prognosis. Although survival has improved for patients with HR myeloma, outcomes still remain inferior compared with those of patients who have standard-risk (SR) disease.¹  Achievement of bone marrow minimal residual disease (MRD) negativity results in improved progression-free survival (PFS) and overall survival (OS) in MM.²  It remains unclear whether the benefit of achieving MRD negativity extends to HR patients and if it mitigates the adverse impact of HR cytogenetics. Here, we review data on the rates of MRD negativity in patients with HR MM and the impact of MRD status on prognosis in this population. Table 1 describes data from recent studies evaluating outcomes with MRD negativity in patients with HR cytogenetics.

The commonly used techniques for MRD assessment in MM are multiparametric flow cytometry, including next generation flow cytometry (NGF) and next generation sequencing (NGS).³  The sensitivity of MRD detection can vary and should be carefully considered when interpreting the results of MRD studies in MM. Each method also has its advantages and disadvantages. NGS requires a baseline sample to determine the clonotype (tumor-specific sequences), which may not be identifiable in all cases. The advantages of NGS are that it is generally more sensitive (10⁻⁶) than flow cytometry, is less user dependent, requires fewer cells than NGF, and does not require a fresh sample. However, flow cytometry, including NGF, does not require a baseline sample. It is generally less sensitive (NGF usual sensitivity: 10⁻⁵) than NGS, although higher sensitivity with NGF (10⁻⁶) can be achieved with the analysis of more cells. It requires a fresh sample. Efforts to streamline NGF with EuroFlow have resulted in standardization of this technique to reduce interuser variability.³ 

As shown in Table 1, the proportion of HR patients achieving MRD negativity was similar to that of SR patients in several large prospective studies, including the Intergroupe Francophone du Myélome (IFM) 2009 trial (HR: 31% and SR: 26%; 10⁻⁶) and the Medical Research Council (MRC) IX trial (HR: 61.5% and SR: 59.8%; 10⁻⁴).^4-6  However, this was not consistent across all studies. Paiva et al⁷  reported that MRD negativity was seen in 27% of HR patients and 38% of SR patients in the GEM2010MAS65 trial, and Hu et al⁸  observed MRD negativity rates (sensitivity: 10⁻⁴) of 42% in HR patients vs 69% in SR patients (P = .014) in a retrospective analysis. Data on MRD negativity for individual HR abnormalities are more limited and suggest that, although patients with t(4;14) have similar rates of MRD negativity as SR patients, MRD negativity may be lower in patients with 17p deletion.^9-11  In the IFM 2009 study, MRD negativity rates by NGS (sensitivity: 10⁻⁶) in patients with 17p deletion, t(4;14), and SR cytogenetics were 11%, 40%, and 26%, respectively. Using NGF (sensitivity: 10⁻⁵ to 10⁻⁶), Goicoechea et al¹¹  reported MRD negativity rates of 24%, 43%, 60%, and 50% in 17p deletion, t(4;14), t(14;16), and SR, respectively, among patients treated in the GEM2012MENOS65 trial. In a retrospective study, posttransplant MRD negativity by flow cytometry (sensitivity: 10⁻⁴) was seen in 48% and 60% of patients with 17p deletion and t(4;14), respectively.⁹ 

Achievement of MRD negativity has been associated with improved PFS in patients with HR cytogenetics in most studies described in Table 1,^4-8,10-12  and a meta-analysis reported by Munshi et al.²  Conversely, a retrospective analysis using flow cytometry evaluation (10⁻⁵) did not show any difference in PFS among MRD-negative vs MRD-positive HR patients.¹³  Data on outcomes with specific HR abnormalities are more limited. In patients with t(4;14), the achievement of MRD negativity has been associated with improved PFS.^9,11  In patients with deletion 17p, variable results have been seen across studies. Goicoechea et al¹¹  reported improved PFS with MRD-negative vs MRD-positive disease (PFS: not reached vs 14 months), but Chakraborty et al⁹  did not observe any difference based on MRD status in patients with 17p deletion (PFS: 22.5 vs 20 months, P = .464) or ≥2 HR abnormalities (PFS: 12 vs 14 months, P = .293). Although there is some variation in the outcomes of MRD-negative HR patients as described above, data consistently show that MRD-positive HR patients have dismal outcomes, even those who are in complete remission (Table 1).

In the IFM 2009 trial, there was no difference in the PFS of HR and SR patients achieving MRD negativity at the end of maintenance therapy, with adjusted hazard ratio (covariates: MRD, treatment, and international staging system stage) of 1.08 (0.61-1.91; P = .785). In this trial, PFS in HR patients was inferior based on MRD results at the start of maintenance therapy, with adjusted hazard ratio of 1.69 (1.14-2.48; P = .008).⁴  Paiva et al⁷  demonstrated that there was no difference in the PFS of elderly patients in the GEM2010MAS65 trial with HR and SR disease who achieved MRD negativity (P = .70). Other studies demonstrate that, although patients with HR MRD-negative disease have better outcomes than HR MRD-positive patients, HR cytogenetics still remains an independent prognostic factor for PFS and OS.^2,6,12,14  Some of the differences observed across studies may be attributed to the timing of MRD evaluation as well as the sensitivity of the MRD assay. Future studies are needed to definitively answer this question.

Interpretation of MRD status and its impact on outcomes in HR disease is limited by the heterogeneity of studies, which include both prospective and retrospective studies and different evaluation time points as well as different techniques used for MRD assessment with varying sensitivity (10⁻⁴ to 10⁻⁶). It is well described that survival improves with every log reduction in MRD in MM.⁷  It is unclear whether there is a threshold effect in HR patients. Future studies with high-sensitivity MRD techniques (≥10⁻⁵) and those that concurrently evaluate resolution of extramedullary disease (which is more common in HR patients and can impact outcomes in MRD-negative patients¹⁵ ) are needed to provide additional clarification. Studies are also needed to evaluate the achievement of sustained MRD negativity (MRD negative in bone marrow and by imaging on 2 occasions at least 1 year apart)³  and its impact on outcomes in patients with HR MM. One would expect that HR patients with sustained MRD negativity would have superior outcomes than HR patients who achieve but do not sustain MRD negativity. However, whether sustained MRD negativity can overcome the impact of HR cytogenetics entirely remains to be determined.

In conclusion, there is high-quality evidence based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach suggesting that achievement of MRD negativity after initial therapy in HR MM is associated with improved PFS, with some studies also demonstrating longer OS in HR MRD-negative patients. The GRADE approach is a comprehensive system to rate the quality of evidence. High-quality evidence implies that additional research is very unlikely to change confidence in the estimate of effect. The question of whether MRD negativity abrogates HR is still unanswered, with some studies indicating that MRD-negative HR patients have similar outcomes as MRD-negative SR patients and others indicating that outcomes in HR MRD-negative patients may be similar or even inferior to those of SR MRD-positive patients. Based on available data, we can conclude that achievement of MRD negativity may partially abrogate the adverse prognosis of HR cytogenetics. HR patients with MRD-positive disease have poor outcomes, suggesting that eradicating MRD should remain the goal of treatment in HR patients.

Based on the data available to date, achievement of MRD negativity and resolution of all fluorodeoxyglucose avid disease are favorable prognostic factors for this patient. There is insufficient evidence to determine whether this completely mitigates his adverse risk attributable to the HR cytogenetic abnormality [t(4;14)] noted at diagnosis.

Surbhi Sidana, Stanford University, 300 Pasteur Dr, Room H0101, Stanford, CA 94305-5623; e-mail: surbhi.sidana@stanford.edu.