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Controversies in Myeloma :
The Who , When , and Why of Treatment
Who ?
When ?
Why ?
The recent expansion of treatment options for patients with multiple myeloma ( MM ) has introduced new opportunities for redefining the goals of therapy . At the 2017 ASH Annual Meeting , several myeloma specialists convened to discuss “ Controversies in Myeloma ,” including the optimal time to start therapy , the goals of therapy , and the decision between continuous or sequential therapy .
The Value of Molecular Remission Novel combinations of newly approved agents have led to an increase in the number of patients who can achieve minimal residual disease ( MRD ) negativity . Given the new opportunities for this type of response , Faith E . Davies , MBBCh , MD , deputy director of the Myeloma Institute at the University of Arkansas for Medical Sciences in Little Rock , reconsidered the goals of MM therapy .
“ Clearly , my aspirational goal when I treat patients is achieving cure , but potentially , my everyday goal for a patient is trying to induce a long-term , disease-free survival with normal quality of life ,” Dr . Davies said . “ Within that setting , that question is , what does inducing a molecular remission add ?”
Dr . Davies reviewed recent large trials ( including IFM 2009 , Myeloma IX , POLLUX , and CASTOR ) that have confirmed the prognostic significance of MRD , as MRD negativity is associated with better survival outcomes in both transplant-eligible and -ineligible patients . The most recent data have “ put this issue to bed ,” she said . “ We can all agree that MRD negativity is associated with a better prognosis , [ but ] what does this mean for routine clinical practice , and should we use MRD testing routinely ?”
The controversies and questions about the practical use of MRD monitoring in the clinic start with a basic question about the definition of MRD negativity , Dr . Davies noted . “ When we are thinking about MRD assessment techniques , we clearly have a number of different technologies [ like flow cytometry and next-generation sequencing ], but importantly as well , we have a number of different sensitivities [ 10 -4 , 10 -5 , and 10 -6 ],” she said . “ Regardless of the technology we use , we have to know its limitations , [ which can include ] sample processing , sample quality control , and standardization across labs .”
The optimal timing and number of MRD assessments is also unknown . In the transplant setting , timepoints for monitoring are guided by the stages of therapy ; the timing is less clear for transplant-ineligible patients . Again , Dr . Davies said , the answer depends on the desired depth of response . In general , MRD assessments conducted at multiple timepoints throughout treatment can provide “ a better picture ” of a patient ’ s disease .
Defining the role of MRD monitoring and optimal sensitivity of assessment in practice depends on what clinicians want to use the results for : forming a prognosis or guiding treatment decisions . “ If we are just using MRD as a simple prognostic factor , using [ a threshold of ] 10 -4 might be okay , but to use it as a treatment decision tool , we may need to use a lower level ,” she explained . “ We shouldn ’ t be reporting MRD as a yes or no binomial ; we need to be reporting the actual level of MRD negativity .”
Also , Dr . Davies noted , the jury is still out on whether MRD detected in the bone marrow “ gives us the full picture .” The role of anatomic or functional imaging , in combination with MRD assessment , is still undefined , but research has suggested that it is possible to have low MRD per flow cytometry and have evidence of lesions on imaging , she explained . “ However , when MRD assessment is performed to a deeper sensitivity , none of those patients had active lesions ,” she added , further highlighting the importance of using the lowest possible detection level . Despite these limitations , Dr . Davies contended that MRD negativity should be the ultimate goal of treatment – and it doesn ’ t matter how that goal is achieved . “ Another controversy has been surrounding the treatment effect ,” she said . “ If you are able to achieve MRD negativity , does it matter how you get there ? Is there a difference as to whether you ’ ve taken an intensive approach to become MRD negative or not ?” Results from the IFM 2009 study that compared lenalidomide , bortezomib , and dexamethasone with and without transplant “ clearly showed that regardless of the treatment arm , those patients who were MRD negative achieved a longer progression-free survival ( PFS ),” she reported . Findings from the POLLUX and CASTOR trials , which enrolled patients with relapsed disease , also support this assertion : Patients who were treated with triplet combinations and achieved MRD negativity had better survival than those who did not .
40 Focus on Lymphoma & Myeloma