Frontline Therapy and MRD: Exciting New Data from France

A recent study illustrates just how useful minimal residual disease (MRD) testing by flow cytometry is to predict excellent outcomes with new highly active combination therapies. A phase II study from the Intergroupe Francophone du Myelome (IFM) is reported in the July 14^th issue of the Journal of Clinical Oncology. This study served as a pilot protocol for the ongoing IFM/Dana-Farber Cancer Institute 2009 phase II study assessing lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone frontline with or without autologous stem cell transplantation (ASCT). In the phase II study reported in the JCO, 31 patients with newly diagnosed symptomatic myeloma all received RVD followed by ASCT plus RVD consolidation and one year of Revlimid maintenance.

The results with this protocol were extremely good. Very good partial response (VGPR) or better was achieved in 58%, 70%, and 87% of patients after RVD induction, ASCT, and RVD consolidation, respectively. What was especially exciting is that 68% of patients achieved MRD-negative status as measured by flow cytometry. MRD negative by flow is an extremely helpful category as a one-time test measured at the point of maximum response. When MRD negativity is confirmed by subsequent serial testing (i.e. sustained MRD-negativity) and supported by additional testing, such as a negative pet/CT scan and normal HevyLite test, one can use MRD-Zero as a new category indicative of potential cure status.

With a median follow-up of over 3 years (39 months), patients achieving MRD-flow negative status are still in remission. The overall survival is obviously 100% at over 3 years. Thus, as we await the results of the phase III comparison study, the impact of induction, ASCT, consolidation, and maintenance is quite impressive, especially with regard to the MRD-negative status and stable remission status of the patients.

These findings strongly validate the key principle of the IMF's Black Swan Research Initiative. Monitoring with sensitive MRD testing at very low levels of disease both predicts exceptionally good outcomes and can be the basis for additional treatment decisions to achieve the sustained deep responses noted above, which can translate into cure.

It is important to emphasize that these new data support considerable prior data, for example utilizing Velcade plus thalidomide rather than Revlimid with dexamethasone (VTd) for induction, followed by transplant, consolidation, and maintenance. The new RVD results are clearly more promising, but the pattern of benefit throughout the four treatment phases is comparable. For the RVD regimen, it was notable that 13% of patients achieved MRD-negative status during the maintenance period.

The clinical benefit of achieving MRD-negative status documented using the Spanish flow methodology has been recognized for more than 10 years. Two sequential studies by the Spanish team in 2008 and 2012, and one from the UK team have shown that patients achieving MRD-negative status by flow have longer remissions and overall survival. What is remarkable about the new data is the sustained value of the deep responses in the IFM trial: no relapses after more than 3 years.

Thus, with the even more sensitive and standardized new flow method now available and use of increasingly effective novel combinations of therapy, it seems very likely that it will be easily feasible to reliably predict unusually good outcomes and define a patient population potentially curable with comprehensive frontline treatment. This new IFM study thus points the way to incorporation of MRD testing by flow cytometry into tailored approaches to achieve the very best results with therapy throughout the course of disease.

As always, stay tuned for further exciting developments! 

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