https://orcid.org/0000-0002-8619-412X
In this issue of Blood, Perrot et al1 reported preliminary results of the MIDAS study showing that roughly two-thirds of patients with newly diagnosed multiple myeloma (NDMM) can achieve measurable residual disease (MRD) negativity after a quadruplet induction with isatuximab, carfilzomib, lenalidomide, and dexamethasone (IsaKRd). These results represent the premises for the second portion of the study where treatment deintensification (IsaKRd consolidation vs autologous stem-cell transplant [ASCT]) will be tested in MRD− patients and treatment intensification (single vs tandem ASCT) will be evaluated in MRD+ ones.
The current initial treatment for transplant-eligible patients with multiple myeloma (MM) is a straight path that goes from induction therapy through transplant and maintenance. This therapeutic approach does not account for the impact that the response obtained during each treatment phase has on individual patient prognosis, including MRD status, which is probably the most important prognostic factors in MM.2 The MIDAS study aims at individualizing treatment of patients with NDMM according to their response to initial treatment and to define individual patient risk in a purely dynamic fashion rather than according to baseline biological characteristics. A personalized treatment can maximize efficacy while sparing unnecessary toxicity, quality-of-life impairment, and financial toxicity. It requires (1) an early end point that is a reliable predictor for long-term disease remission and survival; (2) an appropriate time point suitable for treatment decision; (3) an antimyeloma regimen that is able to meet such an early end point in a significant proportion of patients; and (4) alternative strategies according to the initial response to treatment. MRD stands out as an ideal tool for treatment tailoring; MRD negativity is associated to prolonged progression-free survival and overall survival in patients with MM,2 and its early achievement has been correlated to sustained negativity over time.3,4
The authors demonstrated that using MRD, assessed by next-generation sequencing at a sensitivity of 10−5, to establish subsequent therapy after the induction phase is feasible in the vast majority of patients (>99%). The results reported by Perrot et al also build on the existing literature supporting the role of carfilzomib-based quadruplets as induction therapy for patients with transplant-eligible (TE) MM.5,6 Indeed, the high post-induction MRD negativity rates displayed by regimens incorporating anti-CD38 monoclonal antibodies and KRd, along with a safety profile characterized by a limited cardiovascular toxicity (cardiac events, 6%; hypertension, 13%) and very low rates of peripheral neuropathy (13%),5,6 do support the use of carfilzomib-based quadruplets as an alternative to bortezomib-based ones in young, transplant-eligible patients. In this scenario, the postinduction MRD negativity rates (63%) observed in the MIDAS study are the highest ever reported in a phase 3 study. Cross-trial comparisons should be performed with caution; nevertheless, a prolonged induction with 6 vs the standard 4 cycles may have resulted in higher MRD negativity rates. The duration of induction might not be so relevant in the context of a treatment strategy that includes ASCT and posttransplant consolidation; on the contrary, in a response-driven treatment strategy, defining the optimal number of induction cycles becomes crucial to identify 2 numerically and clinically meaningful groups of patients in whom exploring different randomized strategies.
Subgroup analyses performed by Perrot et al, despite limited sample size in some groups, are of great interest, particularly in a study that has the ambitious goal of evaluating MRD as the key determinant of patient outcomes, replacing baseline biological parameters. Among traditionally defined high-risk patients, 81% of t(4;14)-positive patients achieved MRD negativity, and only 48% of those carrying del17p did so; a surprisingly low rate of MRD negativity (40%) was observed in patients carrying t(11;14), a population conventionally defined at standard risk in which, however, a lower sensitivity to novel agents, including proteasome inhibitors, and a longer time to response have been previously observed.7 A response-driven strategy that does not take into consideration the disease biology is indeed an intriguing yet risky concept, particularly when response is assessed at a single time point only. Previous studies showed that, despite similar MRD negativity rates in patients with conventionally defined standard or high-risk disease,8 the latter have a higher risk of MRD resurgence and relapse, suggesting a role for disease biology even in the context of MRD negativity.3,4 This is particularly important considering that sustained MRD negativity is undoubtedly a more powerful prognostic factor than a single MRD evaluation. The MIDAS study, with longer follow-up and data on the efficacy of the different treatment approaches, will shed light on the validity of such a biology-agnostic approach purely based on MRD.
Another important issue when using MRD for treatment tailoring is the optimal sensitivity cutoff to adopt, as MRD negativity at 10−6 has been proven to be more powerful than 10−5 in predicting long-term outcomes. In this light, balancing the prediction power and the feasibility of the assessment is crucial; potentially, different cutoffs at different time points may be considered in the context of a prolonged treatment with various options for treatment intensification and deescalation.
In conclusion, preliminary results from the MIDAS study demonstrated that a prolonged, highly effective, carfilzomib-based quadruplet induction such as IsaKRd identifies 2 distinct patient populations with a different “dynamic risk” and that an MRD-driven approach is feasible. As king Midas turned everything he touched into gold, in the future the MIDAS study may establish MRD-driven treatment as the new gold standard in TE NDMM.
Conflict-of-interest disclosure: F.G. reported receiving honoraria from Amgen, Janssen, Takeda, Pfizer, Sanofi, Bristol Myers Squibb/Celgene, AbbVie, and GlaxoSmithKline and serving on the advisory boards for Amgen, Janssen, Takeda, Pfizer, Sanofi, Bristol Myers Squibb/Celgene, Oncopeptides, Roche, AbbVie, AstraZeneca, and GlaxoSmithKline. R.M. reported receiving honoraria from Janssen, Celgene, Takeda, and Amgen; serving on the advisory boards for Janssen, Celgene, Takeda, Bristol Myers Squibb, Amgen, and Pfizer; and receiving consultancy fees from Janssen, Takeda, and Sanofi.
