Whole Bone Marrow (BM) Immunophenotypic Profiling for the Identification of Newly Diagnosed Symptomatic Multiple Myeloma (MM) Patients with an MGUS-Like Signature Associated with Long-Term Disease Control (LTDC)
Authors: Paiva Bruno , Vidriales María-Belén , Perez Jose J. , Montalbán María-Angeles , Gutierrez Norma , Rosiñol Laura , Martínez-López Joaquín , Mateos María-Victoria , Cordon Lourdes , Oriol Albert , Terol Maria Jose , Echeveste Maria Asuncion , Paz Raquel , de Arriba Felipe , Palomera Luis , De La Rubia Javier , Díaz-Mediavilla Joaquín , Sureda Anna , Gorosquieta Ana , Alegre Adrian , Martín Alejandro , Orfao Alberto , Lahuerta Juan-Jose , Blade Joan , Miguel Jesus F. San 
Published: October 2019

Abstract
Abstract 3949
Although in MM an optimal response to front-line therapy is a surrogate for extended survival, two class of patients fall outside this paradigm: those that after treatment show unsustained complete remission (CR) and those that not achieving CR, return into an MGUS-like signature and experience nevertheless long term disease control (LTDC). The prospective identification of the later group remains to be accomplished.
Herein, we hypothesized that whole BM immunophenotypic profiling by multiparameter flow cytometry (MFC) would help to identify upfront, symptomatic MM patients with an occult MGUS-like signature (from here on named MGUS-like-MM). For this purpose, the relative frequency of plasma cells (plus the balance between clonal and normal PC), precursor and mature B-cells, T- and NK-cells, erythroblasts, monocytes, neutrophils and eosinophils was determined in 698 newly diagnosed, transplant eligible MM patients included in two consecutive GEM/PETHEMA trials: GEM2000 (VBMCP/VBAD; n=486) and GEM2005<65y (randomized induction with the same chemotherapy plus bortezomib in the last two cycles or thalidomide/dexamethasone or bortezomib/thalidomide/dexamethasone followed by HDT/ASCT; n=212). In addition, we extended this analysis to 114 high-risk smoldering MM patients included in the Quiredex trial. Median follow-up was 63 months for symptomatic MM patients. Unsupervised hierarchical cluster analysis was used on the log2 transformed values of the 11 variables described above.
Whole BM immunophenotypic profiling identified a cluster of 176 (25%) symptomatic MM patients “assigned as MGUS-like-MM” based on the following phenotypic features: significantly decreased median numbers of myelomatous PC together with a significant increment of eosinophils, neutrophils, monocytes, T- and NK -cells, mature B-cells and particularly normal PC. This subgroup was characterized by a favorable clinical presentation with increased (P<.005) frequency of ISS stage I or II (88%), high baseline hemoglobin (116 g/L) and albumin (3.8 g/dL) values. MGUS-like-MM patients showed an increased frequency of hyperdiploid DNA content (63%; P=.001) and a lower incidence of t(4;14) (3%; P=.05). When compared to the overall population, MGUS-like-MM patients showed a markedly superior median TTP (88 vs 40 months; P<.001) and OS (141 vs 61 months; P<.001). Moreover, the MGUS-like signature was a strong predictor for LTDC, with 16% of these patients being disease-free at 10 years as compared to 3.5% in the overall MM population (P<.001). Interestingly, while the depth of response achieved after HDT/ASCT translated into superior TTP (P=.032) and OS (P=.005) in the overall population, MGUS-like-MM patients failing to achieve CR showed non significantly different median TTP (80m vs 105m; P=.167) and OS (not reached vs 141m; P=.438) as compared to those attaining CR, respectively.
Finally, it should be pointed out that this MGUS-like signature was not restricted to symptomatic MM, since we have also found a subset of high-risk smoldering MM patients with the same signature. These later patients showed a significantly lower risk of progression into symptomatic MM as compared to the rest of high-risk smoldering MM patients (data not shown).
In summary, whole BM immunophenotypic profiling by MFC is capable to identify a subset of symptomatic MM patients with an occult MGUS-like signature associated with prolonged survival. Given that in this subgroup of patients the value of CR is not as important as in the rest of MM patients, the prospective identification of this signature may contribute to discriminate a sub-optimal response that require additional treatment from a residual “MGUS-like component” that may remain stable without further treatment.

Disclosures:
Paiva: Celgene: Honoraria; Miellenium: Honoraria; Janssen: Honoraria. Martínez-López:Celgene: Honoraria. Mateos:Celgene: Honoraria; Miellenium: Honoraria; Janssen: Honoraria. De La Rubia:Celgene, Janssen: Consultancy, Speakers Bureau. Lahuerta:Celgene: Honoraria; Millenium: Honoraria. Blade:Celgene: Honoraria; Millenium: Honoraria; Janssen: Honoraria. San Miguel:Celgene: Honoraria; Millenium: Honoraria; Janssen: Honoraria.