Immunofixation (IF) in Urine Is Really Necessary to Define Complete Remission in Multiple Myeloma (MM)? a Subanalysis from the Pethema/GEM2012MENOS65 Phase III Clinical Trial

Background: The international criteria for definition CR, requires, among other parametres, a negative IF both in serum and urine; however, urine IF is not always performed. In the belief that this lack could bias the comparison between trials, the First Trial Independent Response Adjudication Committee (FTIRAC) recommended that patients who met all CR criteria except the availability of a urine IF should be classified as VGPR (Blood 2014; 124 [abstract 3460]) but this criteria is not always applied which may translate into differences in CR rates between trials. However, it is unknown (1) if this conversion has a real clinical basis, (2) if urine IF results alter the clinical meaning of CR, or (3) on the contrary, if patients in CR with and those without a documented negative urine IF have a similar prognosis, in which case this rule would underestimate the CR rates, increasing the biases and magnifying the problem that was intended to improve.

Aim: To determine the value of urine negative IF in the definition of CR.

Methods: 459 patients were enrolled into the GEM2012MENOS65phase3 trial and treated with 6 induction cycles of bortezomib, lenalidomide, and dexamethasone, HDT/ASCT and 2 consolidation courses. Evaluable patients were enrolled in a maintenance trail (NCT02406144). Excluding 6 patients who discontinued early, 453 were evaluable. At diagnosis, the M-component was detected exclusively in serum in 173 of these patients and in serum and urine in 212 patients; 68 patients had pure Bence-Jones M-protein (BJMM). The protein studies were performed in each cycle. At the time of negative IF, bone marrow aspirates were analysed for count of PCs and monitoring minimal residual disease (MRD) following EuroFlow SOPs (median limit of detection of 3x10^-6).The response classifications were made according to the IMWG criteria, but we applied the FTIRAC criteria, and, patients with <5% BM PCs and negative serum IF but with unavailable urine IF (or vice versa for patients with BJMM) were classified as VGPR. For the purpose of this study, we called these uncertain CR (uCR). Stringent Complete Responses were classified as CR.Median follow-up was 40 months.

Results: Overall, 3774 protein evolution studieswere performed: 691 (18%) in CR, 802 (21%) in uCR and 868 (23%)in VGPR.In all patients with M-component exclusively in serum at diagnosis butwith negative serum IF after treatment, and available urine IF (174 patients, 1476 protein studies), the urine paraprotein IF detection rate was 0%. In patients with a positive M-component in both serum and urine at diagnosis, but with negative serum IF after treatment, and available urine IF (212patients, 1763 protein assessment), 11 protein evaluations in 6 patients (2.8%) tested positive in urine; in other words: in 97,2% of the patients a negative serum IF predicts for negative urine.Since MRD is a robust subrogate of depth of responses (J ClinOncol. 2017;35:2900-10), we compared MRD^-verates in patients achieving CR, uCR and VGPR. Interestingly, there were no significant differences in the post-consolidation MRD^-verates among patients in CR vsthose in uCR (68% vs 77%, P=.1), whereas significant differences were seen when comparing CR and uCRvs VGPR (23% in the latter; P≤.0001). Accordingly, a landmark analysis performed at HDT/ASCT, - time pointselected to improve the PFS observation time- , showed 2-year PFS rates of 88%, 87% and 77% inpatients in CR, uCR and VGPR, no differences in 2-year PFS rates between patients in CR vsuCR (P=.6) while patients in VGPR showed inferior PFS compared with those in uCR (P=.04). With this landmark, the MRD-negativity ratios are similar to those described after consolidation.

Conclusions: In MM patients with M-component exclusively in serum at diagnosis, urine IF follow-up is unnecessary, while in patients with paraprotein in both serum and urine,a negative serum IF response is accompanied by a negative urinary IF in 97.8% of patients. Moreover, patients with CR but without available IF in urine display similar MRD^-veand PFS rates compared withthose in CR. By contrast, MRD^-veand PFS values in these patients are significantly superior to those in VGPR. Thus, our results suggest that, except for those with pure BJMM, patients fulfilling CR criteria but with unavailable urine IF should be classified as CR instead of VGPR. This data discourages the application of the FTIRAC conversion criteria. Also, the IMWG criteria for CR should be reviewed.

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