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Minimal residual disease negativity predicts long-term survival in multiple myeloma
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Patients with multiple myeloma and negative–minimal residual disease status after treatment achieved better long-term survival outcomes than those with positive–minimal residual disease status, according to a meta-analysis of published studies.
“A substantial proportion of patients with multiple myeloma can now expect to achieve clinical complete response as a result of new therapeutic advances,” Nikhil C. Munshi, MD, professor of medicine at Harvard Medical School and director of basic and correlative science at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, and colleagues wrote. “Nevertheless, most patients who achieve complete response will eventually relapse, suggesting that a small but clinically relevant population of myeloma cells not detected by current techniques persists.”
The impact of minimal residual disease on multiple myeloma outcomes has been evaluated; however, the majority of studies have been small and varied in terms of treatment, patient population and assessment tools.
Munshi and colleagues accessed Medline to identify relevant studies published between January 1990 and January 2016. Studies reporting on minimal residual disease and PFS or OS in 20 or more patients were eligible for inclusion.
The meta-analysis included studies analyzing the impact of minimal residual disease on PFS (14 studies; n = 1,273 patients) and on OS (12 studies; n = 1,100).
Five PFS studies (n = 574) and six OS studies (n = 616) reported specifically on patients who achieved a conventional complete response.
Negative–minimal residual disease status correlated with significantly improved PFS (median, 54 months vs. 26 months; HR = 0.41; 95% CI, 0.36-0.48) and OS (median, 98 months vs. 82 months; HR = 0.57; 95% CI, 0.46-0.71).
These trends persisted in studies evaluating patients who achieved conventional complete responses in terms of improvement in PFS (HR = 0.44; 95% CI, 0.34-0.56) and OS (HR = 0.47; 95% CI, 0.33-0.67).
Heterogeneity tests showed no significant differences among studies for OS (2 = 8.81; df = 11). Heterogeneity tests were initially significant for PFS (2 = 42.1; df = 13; P < .001); however, after controlling for two studies that showed large differences, the heterogeneity test was no longer significant (2 = 10.1; df = 11).
No studies directly compared the ability of different treatment strategies to induce negative minimal residual disease status. However, five studies showed that hematopoietic stem cell transplantation increased the proportion of patients with negative status.
“The results of this large analysis showed that minimal residual disease negativity, as determined by various high-sensitivity methods, predicted better PFS and OS in patients with multiple myeloma, including those who achieved a complete response,” Munshi and colleagues wrote. “Minimal residual disease status is a marker of long-term outcomes in patients with multiple myeloma. It should, therefore, be considered a new endpoint in clinical trials and clearly has a role as a surrogate marker for OS.”
Questions remain regarding the utility of minimal residual disease as a trial endpoint, Nicole J. Gormley, MD, Ann T. Farrell, MD, and Richard Pazdur, MD, all of the FDA’s Office of Hematology and Oncology Products, wrote in a related editorial.
“Should minimal residual disease only be assessed in patients who are in complete response or those that attain a very good partial response?” Gormley, Farrell and Pazdur wrote. “Given the impact of cytogenetics on minimal residual disease, should minimal residual disease negativity in patients with high-risk cytogenetics be considered the same as minimal residual disease negativity in those with standard-risk cytogenetics? What trial design or analysis features should be implemented to address this issue? Is stratification based on cytogenetic risk sufficient? What is the appropriate timing of minimal residual disease assessment? How will novel agents, such as monoclonal antibodies, affect the minimal residual disease assessment? What is the role of imaging?”
Future research must address these questions.
“The pooled analysis by Munshi and colleagues is a considerable first step toward addressing these questions regarding minimal residual disease and its potential as a surrogate endpoint,” Gormley and colleagues wrote. “However, there are many unanswered questions that need to be resolved.” – by Cameron Kelsall
Disclosures: Munshi reports consultant roles with Celgene, Janssen, Merck and Takeda. Please see the full study for a list of all other researchers’ relevant financial disclosures. Gormley, Farrell and Pazdur report no relevant financial disclosures.
Perspective
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Saad Z. Usmani
Depth of response appears to be an important surrogate for PFS and OS in newly diagnosed multiple myeloma. Conventionally, attaining “good depth of response” would mean achieving a very good partial response or better as defined by the International Myeloma Working Group Criteria. However, it has been recognized that — even with a complete response or better — the true burden of residual disease is variable among patients with myeloma and influences outcome.
In this vein, minimal residual disease is a hot topic of debate and research in multiple myeloma nowadays. There are two minimal residual disease techniques — flow cytometry and DNA sequencing — that have reliably demonstrated their prognostic significance in newly diagnosed myeloma, in which patients who achieve minimal residual disease negativity appear to have better survival outcomes, even amongst patients who achieve complete response.
Both these techniques are being evaluated in clinical trials in newly diagnosed and early relapse settings. Accordingly, the new multiple myeloma response criteria recently added minimal residual disease negativity by flow and sequencing methods. However, minimal residual disease testing by either technique is not yet ready for prime time in clinical practice and needs to be standardized before general use.
Given the exciting era of therapeutic development in multiple myeloma, there is a dire need to adopt appropriate surrogate survival endpoints that give us clinically relevant results and also satisfy the regulatory requirements for drug approval. To this end, the meta-analysis by Munshi and colleagues demonstrates that minimal residual disease negativity may potentially serve as a surrogate prognostic marker for PFS and OS in multiple myeloma
Kumar S, et al. Lancet Oncol. 2016;doi:10.1016/S1470-2045(16)30206-6.
Paiva B, et al. Blood. 2015;doi:10.1182/blood-2014-11-568907.
Martinez-Lopez J, et al. Blood. 2014;doi:10.1182/blood-2014-01-550020.
Disclosure: Usmani reports no relevant financial disclosures.
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