Revised international staging system allocation in the ICARIA‐MM study: Practical challenges and impact on outcome

1 Jerome LipperMultipleMyeloma Center, Department ofMedical Oncology, HarvardMedical School, Dana-Farber Cancer Institute, Boston, Massachusetts, USA 2 CHU de Toulouse, IUCT-O, UPS, Service d’Hématologie, Université de Toulouse, Toulouse, France 3 Department of Hematology, Faculty ofMedicine, Pharmaceutical and Health Sciences/Faculty of Transdisciplinary Sciences, Institute ofMedical, Institute of Transdisciplinary Sciences, KanazawaUniversity, Kanazawa, Japan


Dear Editor
The aim of the ICARIA-MM Phase 3 study (ClinicalTrials.gov, number NCT02990338) was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone alone in patients with relapsed and refractory multiple myeloma [1]. Results from this study demonstrated that the addition of isatuximab to pomalidomide and dexamethasone provides a significant benefit for progression-free survival over pomalidomide and dexamethasone alone. Additionally, results showed a positive treatment effect in all subgroups, including revised international staging system (R-ISS) stage at study entry [1].
The R-ISS, as defined by the international myeloma working group (IMWG), combines the original ISS (beta-2 microglobulin and albumin) with chromosomal abnormalities (del[17p] and/or t [4;14] and/or t[14;16]; determined by fluorescence in situ hybridization) and lactate dehydrogenase (LDH) results [2]. Like the ISS, the R-ISS is based on three stages; patients with beta-2 microglobulin <3.5 mg/L and albumin ≥3.5 g/dL, standard-risk for cytogenetics abnormalities and normal LDH (≤upper limit of normal) are allocated as stage I; patients with beta-2 microglobulin of ≥5.5 mg/L and either high-risk for cytogenetics abnormalities or high LDH (>upper limit of normal) are allocated to stage III; and patients who do not meet criteria for stage I or stage III are allocated to stage II.
In the original analysis of the ICARIA-MM study results, the inter- Among patients for whom the cytogenetic abnormalities status was unknown, but other variables were available and allowed the R-ISS status to be determined, 19 patients were allocated as R-ISS stage I and nine patients as R-ISS stage II. In addition, six patients with missing beta-2 microglobulin were allocated as R-ISS stage II, following the R-ISS definition that suggests this stage when a patient does not meet criteria to be allocated as stage I or stage III (Table 1).
A more conservative way of allocating the R-ISS status would be to separate the patients with unknown cytogenetic abnormalities and missing beta-2 microglobulin at baseline into a fourth category named 'unclassified' . In the ICARIA-MM study, a total of 34 patients (19 R-ISS stage I and 15 R-ISS stage II according to the original allocation) would have been allocated to 'unclassified' ( Table 2).
To further investigate if this alternative R-ISS allocation approach would lead to different conclusions about the ICARIA-MM study, the authors conducted a post hoc analysis to assess the progressionfree survival benefit using the alternative R-ISS staging allocation in which the 34 patients with unknown cytogenetics and missing beta-2 microglobulin at baseline were allocated to an 'unclassified' R-ISS stage at study entry. A comparison of the results from this post hoc analysis is shown in Table 3. The hazard ratios for progressionfree survival remain in favour of isatuximab plus pomalidomide and TA B L E 1 R-ISS stage at study entry according to beta-2 microglobulin, albumin, LDH and cytogenetic abnormalities results measured at baseline (original allocation used in ICARIA-MM), intent-to-treat population  It is important to note that with the original R-ISS allocation method used in the ICARIA-MM study, patients with R-ISS stage III were not inappropriately allocated to either stage II or stage I. Additionally, the number of patients in each unclassifiable cohort in the alternative R-ISS allocation approach, that is, n = 16 for isatuximab plus pomalidomide and dexamethasone and n = 18 for the pomalidomide and dexamethasone, is low. Assuming that a truly random population of patients is part of these cohorts, it is also likely that only a significant randomization error could produce a real difference in outcome, such as having all patients in stage I in one cohort and stage III in another.
Since this is an unlikely event, the alternative R-ISS allocation approach  use of these different methodologies and the data derived as part of the broader conclusions from this Phase 3, approval-finding study [4].