Monoclonal Gammopathies and the Bone Marrow Microenvironment: From Bench to Bedside and Then Back Again
Abstract
:1. Introduction
2. Multiple Myeloma and Other Monoclonal Gammopathies: A Multistep Disease
Genomic Aspects
3. The Cellular and Humoral Compartment of the Bone Marrow Niche
3.1. Non-Immune Compartment
3.1.1. Stromal Cells
3.1.2. Bone Remodeling: Osteoblasts, Osteoclasts and Osteocytes
3.2. The Immune Compartment
3.2.1. Myeloid Cells
3.2.2. Lymphoid Cells
3.3. Soluble Factors Promoting Tumor Evolution
4. Bone Marrow Modulating Agents: Clinical Applications
4.1. Carfilzomib, Lenalidomide, Desametasone
4.2. Zoledronate
4.3. Curcumin
5. Targeting MM Cells to Activate the Immune System: Monoclonal Antibodies and Vaccines
5.1. Daratumumab and Isatuximab (Anti-CD38)
5.2. Vaccines
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Plasma Cell Disorder | Diagnosis | Note |
---|---|---|
Non-IgM MGUS (IgG, IgA, IgD) | Serum monoclonal protein < 3 g/dL) Clonal plasma cells in the bone marrow < 10% * Absence of end-organ damage (CRAB symptoms) or amyloidosis that can be attributed to the plasma cell proliferative disorder | Up to 85% of MGUS cases Annual risk of progression of 1% * Bone marrow can be deferred in patients with low-risk MGUS (IgG type, M protein < 15 gm/L, normal free light chain ratio) in whom there are no clinical features concerning myeloma |
IgM MGUS | Serum IgM monoclonal protein < 3 g/dL) Clonal plasma cells in the bone marrow < 10% No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, hepatosplenomegaly, or other end-organ damage that can be attributed to the plasma cell proliferative disorder | 15% of MGUS cases |
Light chain MGUS | Abnormal FCL ratio Increased level of involved FLC No immunoglobulin heavy chain expression on immunofissation Absence of CRAB symptoms or amyloidosis that can be attributed to the plasma cell proliferative disorder Clonal plasma cells in the bone marrow < 10% Urinary monoclonal protein < 500 mg/24 h | |
Monoclonal gammopathy of renal significance (MGRS) | One or more renal lesions related to the monoclonal immunoglobulin produced The underlying B-cell or plasma cell clone neither causes tumor complications nor meets any current hematologic criteria for specific therapy The diagnosis of MGRS can only be established with renal biopsy | Based on consensus report of the International Kidney and Monoclonal Gammopathy Research Group [6] |
Monoclonal gammopathy of neurologic significance (MGNS) | Chronic neuropathy with sensory ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes The diagnosis of MGNS is one of exclusion | |
Smoldering Multiple Myeloma | Serum monoclonal protein (IgM or IgA) ≥ 3 g/dL) or urinary monoclonal protein ≥ 500 mg/24 h Clonal plasma cells in the bone marrow 10–60% Absence of MDE or amyloidosis | Based on Mayo 2018 criteria [7] there are three groups of patients:
|
Cellular Component | Function | References |
---|---|---|
MDSCs | Hamper the anti-tumor immune response by multiple mechanisms dependent on:
Induce Treg development Differentiate into osteoclasts, contributing to the formation of osteolytic lesions | [27,28,29,30,31,32] |
BMSCs | Generate premetastatic niche:
| [8,33,34,35,36] |
Osteoclasts | Create an immunosuppressive microenvironment:
| [37,38,39] |
Dendritic cells | Immunosuppressive and tumor-promoting actions:
| [40,41] |
TAMs | Support MM cells proliferation and survival through activation of the IL-6/JAK/STAT3 pathway. Decrease T cell proliferation and activation through the downregulation of IFN-γ, IL-2, and TNF-α secretion. Immune suppressive activity mediated by their secretion of IL-6, IL-10, activating Tregs and M2 macrophages, and TGF-β, inhibiting both cytotoxic T-cells and NK cells Angiogenic and vasculogenic activities:
| [25,42] |
Neutrophils | Overexpress IFN-γ, resulting in increased autophagy flux and JAK-2/STAT3 pathway activation, which supports their promotion of pro-inflammatory and survival signals within MM niches. Produce arginase that inhibits T cell activation and proliferation. Reduced lysozyme activity and increased secretion of the amino acid degrading enzyme. | [9,43] |
T cells | Th17 cells:
| [44,45] |
Clinical Trial | Phase | Therapeutic Regimen | Patients | Follow-Up and Results | |
---|---|---|---|---|---|
Lenalidomide-Based Treatments | QuiRedex- NCT00480363 | III | RD +/− R maintenance for 2 years | 119 High-risk SMM | Median FU: 10.8 years HR OS: 46% HR PFS: 73% median TTP: 9.0 years (treatment arm) vs. 2.1 years (control arm) median OS: not reached (treatment arm) vs. 7.8 years (control arm) |
ECOG E3A06-NCT01169337 | III | R | 182 Intermediate/high-risk SMM | Median FU: 35 months HR PFS: 72% 3 years PFS: 91% (treatment arm) vs. 66% (control group) | |
Proteasome Inhibitor-Based Treatments | NCT01572480 | II | KRd + R maintenance | 18 High-Risk SMM | Median FU: 43.3 months MRD-negative: 63% Estimated 4 years PFS: 71% Estimated 4 years OS: 100% |
GEM-CESARNCT02415413 | II | KRd + high-dose Melphalan and ASCT + Rd maintenance for up to 2 years | 90 High/ultra high-risk SMM | Median FU: 32 months OS: 98% PFS: 93% biochemical relapses: 5 patients ORR after induction: 98% ORR after ASCT: 98% ORR after consolidation: 100% CR: 68.6% (55% of them achieving MRD negativity) | |
NCT02916771 | II | IxRd + IxR mainteinance | 26 (56 planned) High-risk SMM | ORR: 89% (after at least 3 cycles of treatment) CR: 19.2% No progression to active MM. | |
Monoclonal antibody-Based Treatments | CENTAURUS NCT02316106 | II | Dara (three different treatment schedules: extended intense, extended intermediate and short dosing) | 123 Intermediate/high-risk SMM | Median FU: 26 months CR: 4.9%, 9.8%, 0% (respectively, in the three treatment schedules) 2 years PFS: 89.9%, 82%, 75,3% (respectively, in the three treatment schedules) |
NCT03236428 | II | Dara | 28 Lower-risk SMM | PR: 53% VGPR: 20% | |
NCT02960555 | II | Isatuximab | 24 High-risk SMM | PR: 42% VGPR:17% CR with MRD negativity: 5% | |
NCT01441973 | II | Elo | 31 | FU > 28 months Modest activity of Elo monotherapy. ORR: 10% 2-year PFS: 69% | |
NCT02279394 | II | EloRd + EloR | 50 High-risk SMM | PR: 84% No progression to active MM. | |
NCT02603887 | Pilot study | Pembrolizumab | 13 Intermediate/high-risk SMM | After a median of 8 cycles: 85% CR, 15% progressed to active MM, 8% MRD negativity (for up 27 months) | |
NCT01484275 | Pilot study | Siltuximab | 85 High-risk SMM | Median FU: 29.2 months 1-year PFS: 84.5% (siltuximab) vs. 74.4% (placebo) median PFS: not reached (siltuximab) vs. 23.5 months (placebo) OS: not reached in both arms | |
Vaccines | NCT01718899 | I/IIa | PVX410 +/− R | 20 Intermediate/high-risk SMM | progressions: 3 (PVX-410-alone) vs. 1 (PVX-410 + R) median TTP: 36 weeks (PVX-410-alone) vs. not reached (PVX-410 + R) |
Ibrutinib | NCT02943473 | II | Ibrutinib | 9 High-risk SMM | poor efficacy unfavorable risk/benefit ratio |
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Plano, F.; Corsale, A.M.; Gigliotta, E.; Camarda, G.; Vullo, C.; Di Simone, M.; Shekarkar Azgomi, M.; Speciale, M.; Carlisi, M.; Caccamo, N.; et al. Monoclonal Gammopathies and the Bone Marrow Microenvironment: From Bench to Bedside and Then Back Again. Hematol. Rep. 2023, 15, 23-49. https://doi.org/10.3390/hematolrep15010004
Plano F, Corsale AM, Gigliotta E, Camarda G, Vullo C, Di Simone M, Shekarkar Azgomi M, Speciale M, Carlisi M, Caccamo N, et al. Monoclonal Gammopathies and the Bone Marrow Microenvironment: From Bench to Bedside and Then Back Again. Hematology Reports. 2023; 15(1):23-49. https://doi.org/10.3390/hematolrep15010004
Chicago/Turabian StylePlano, Federica, Anna Maria Corsale, Emilia Gigliotta, Giulia Camarda, Candida Vullo, Marta Di Simone, Mojtaba Shekarkar Azgomi, Maria Speciale, Melania Carlisi, Nadia Caccamo, and et al. 2023. "Monoclonal Gammopathies and the Bone Marrow Microenvironment: From Bench to Bedside and Then Back Again" Hematology Reports 15, no. 1: 23-49. https://doi.org/10.3390/hematolrep15010004