Deep Phenotyping Reveals Distinct Immune Signatures Correlating with Prognostication, Treatment Responses, and MRD Status in Multiple Myeloma

Abstract

Despite recent advances, Multiple Myeloma (MM) remains an incurable disease with apparent heterogeneity that may explain patients’ variable clinical outcomes. While the phenotypic, (epi)genetic, and molecular characteristics of myeloma cells have been thoroughly examined, there is limited information regarding the role of the bone marrow (BM) microenvironment in the natural history of the disease. In the present study, we performed deep phenotyping of 32 distinct immune cell subsets in a cohort of 94 MM patients to reveal unique immune profiles in both BM and peripheral blood (PB) that characterize distinct prognostic groups, responses to induction treatment, and minimal residual disease (MRD) status. Our data show that PB cells do not reflect the BM microenvironment and that the two sites should be studied independently. Adverse ISS stage and high-risk cytogenetics were correlated with distinct immune profiles; most importantly, BM signatures comprised decreased tumor-associated macrophages (TAMs) and erythroblasts, whereas the unique Treg signatures in PB could discriminate those patients achieving complete remission after VRd induction therapy. Moreover, MRD negative status was correlated with a more experienced CD4- and CD8-mediated immunity phenotype in both BM and PB, thus highlighting a critical role of by-stander cells linked to MRD biology.

Minimal residual disease assessment by multiparameter flow cytometry in transplant-eligible myeloma in the EMN02/HOVON 95 MM trial

“…Nonetheless, a small proportion of persistent MRD-positive patients did not progress at the data cutoff, suggesting that an MGUS-like indolent phenotype could still be present and thus changing treatment should be contraindicated. Moreover, a precise immune profiling by flow cytometry can offer complementary information to the simple quantification of MRD levels and may contribute to identifying a subset of patients that, albeit being MRD-positive, can still experience prolonged survival due to a unique immune signature (ex: with a more prominent regeneration of mature B lymphocytes) with probably a competent immune surveillance keeping myeloma burden in repression 13 , 14 . It would be informative to evaluate the genomic profile of these residual MM cells or to monitor the trend of MRD kinetics, as previously done for other hematologic diseases 15 – 19 .…”

Aberrant Plasma Cell Contamination of Peripheral Blood Stem Cell Autografts, Assessed by Next-Generation Flow Cytometry, Is a Negative Predictor for Deep Response Post Autologous Transplantation in Multiple Myeloma; A Prospective Study in 199 Patients

“…Therefore, the elucidation of the exact molecular interactions within the BM and the identification of unique immune signatures that may have clinical utility in terms of prognostication and/or drug efficacy prediction is a very active field in MM research [40]. In this context, we recently reported on unique BM signatures that are predictive of different responses to the same VRD induction therapy [18]. Moreover, we showed that, despite the apparent innate heterogeneity in the BM subset distribution post ASCT, patients with the same MRD status (positive vs. negative) shared commonmicroenvironmental features that allowed for their efficient clustering in the two groups [18].…”

“…In this context, we recently reported on unique BM signatures that are predictive of different responses to the same VRD induction therapy [18]. Moreover, we showed that, despite the apparent innate heterogeneity in the BM subset distribution post ASCT, patients with the same MRD status (positive vs. negative) shared commonmicroenvironmental features that allowed for their efficient clustering in the two groups [18]. In order to assess whether the presence of APCs in grafts could result in a different BM profile, we evaluated the niche composition on day 100 post ASCT.…”

“…We have previously reported that the MRD status of MM patients correlates with distinct BM niche profiles [18]. To evaluate the effect of contaminated grafts on the BM reconstitution, we compared the BM signatures of con− and con+ patients who achieved CR 100 days post ASCT.…”

The Road to a Cure: Emerging Treatments for Multiple Myeloma

“…In some of these patients, laboratory or imaging techniques can identify some (minimal) residual disease (Figure 1C). Understanding of the molecular features of this minimal residual disease (MRD) and identification of new targets expressed by these MRD cells would allow us to eradicate these residual cells and offer a another option for curing this malignancy [10]. Finally, new treatment strategies are required for patients presenting a refractory disease (Figure 1D).…”