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. 2021 Mar 25;22(7):3389. doi: 10.3390/ijms22073389

Table 2.

Novel agents under investigation.

Molecular Target Mechanism Use in MM/Therapeutic Implication
Increased OC Activity
Inhibition of miR-21 [41]

  1. Expression of miR-21 reduces OPG expression and secretion.

  2. MicroRNA (miR-21) overexpression induced by MM–BMSCs interaction antagonizes the physiologic RANKL/OPG balance. OCL activity is dependent on BMSC miRNA-network perturbation.

  3. Antagonizing miR-21 may reduce STAT3 signaling mediated by PIAS3 upregulation.

  1. The combination of miR-21 antagonism with conventional drugs might improve the clinical outcome of MM patients.
CCL-3 (MIP-1α) [7,79,80]

  1. CCL3 inhibits OB function and contributes to OB/OC imbalance by inhibiting OB differentiation and function in MBD.

  2. OCs secrete high levels of CCL3, which triggers MM cell migration.

  1. CCL3 antibody partially restores OB activity through the upregulation of the OCN, Runx2, and Osx.

  2. MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of MM cells and OCs by inhibiting Akt signaling and abrogates MM cell-to-OC adhesion to inhibit MM cell survival and proliferation.
Activin A [81,82]

  1. Activin A is produced in MM-related osteolysis.

  2. Lenalidomide acts directly on BMSCs via an Akt-mediated increase in the c-Jun N-terminal kinase-dependent signaling, resulting in activin A secretion, with the consequent inhibition of osteoblastogenesis.

  1. Lenalidomide + Activin A inhibitor. Phase 1 clinical trial.

  2. Sotatercept (ACE-011) (ligand trap fusion receptor) is a recombinant activin receptor type IIA IgC-Fc fusion protein to prevent continued loss of bone. It causes an increase in hemoglobin, hematocrit, and red blood cell counts in patients with myeloma. Phase 2 clinical trial completed showing that sotatercept increased BMD in MM patients.
IL-6 [83]

  1. In the bone marrow microenvironment, IL-6 is produced by BMSCs, mediating MM cell growth and preventing apoptotic cell death.

  2. IL-6 triggers at least three major signaling pathways: Ras/MEK/ERK cascade, JAK2/signal transducer and activator of transcription (STAT-3) cascade, and PI3K/Akt cascade.

  3. IL-6 protects against apoptotic cell death induced by a variety of agents, including dexamethasone.

  4. IL-6 controls the expression of various other key growth and survival mechanisms in myeloma.

  1. Anti-IL-6 moAb exhibits anti-MM activity in clinical trials.
IL-17 [84,85]

  1. IL-17 is significantly elevated in blood and bone marrow in MM, and IL-17A promotes MM cell growth via the expression of IL-17 receptor and induces IL-6 production.

  1. AIN457, anti-human IL-17A human moAb in MM significantly inhibited MM cell growth OC cell differentiation.
Suppressed OB Activity
Wnt pathway [37,86]

  1. Wnt3a signaling within bone inhibits MBD and tumor growth.

  1. Treatment of myelomamatous SCID-hu mice with recombinant Wnt3a-stimulated bone formation and attenuated MM growth.

  2. LGR4 expression allows MMs to respond to (pre)OB-derived R-spondins (RSPOs), resulting in stabilization of the Wnt receptors and markedly enhances sensitivity to auto and paracrine Wnt ligands.

  3. These results provide further support regarding the potential anabolic effect of the targeting of proximal Wnt signaling in MM.
Scl [15,33,87,88]

  1. Scl, an osteocyte-derived inhibitor of Wnt/β-catenin signaling, is elevated in MM patient sera and increased in osteocytes in MM-bearing mice.

  1. Administration of anti-Scl antibody (Scl-Ab) increased bone mass and decreased osteolysis in immune-competent mice with established MM. Sost/Scl inhibition increased OB numbers, stimulated new bone formation, and decreased OC number in MM-colonized bone.

  2. Romosozumab is an anti-Scl moAb for benign bone disorders.
DKK1 [31,89,90]

  1. DKK1 is another antagonist of the Wnt signaling pathway secreted by MM cells.

  2. By binding to LRP6, it inhibits osteoblastogenesis and new bone formation. DKK1 is also responsible for enhanced Scl secretion in the bone microenvironment, as Scl is released by immature OBs in the presence of MM-derived DKK1.

  1. BHQ880, a DKK1 neutralizing Ab, increased bone anabolic activity in a phase 2 clinical trial.
EphrinB2/EphB4 signaling pathway [44]

  1. Bidirectional signaling between the cell surface ligand ephrinB2 and its receptor, EphB4, is involved in the coupling of osteoblastogenesis and osteoclastogenesis and in angiogenesis.

  1. The ephrinB2/EphB4 axis is dysregulated in osteoprogenitors from myeloma patients. Its activation affects myeloma bone disease and tumor growth.
Adiponectin [91]

  1. Patients who subsequently progressed to myeloma have a lower serum adiponectin concentration.

  2. The apolipoprotein peptide, mimetic L-4F, was used for the pharmacologic enhancement of adiponectin.

  3. L-4F reduced tumor burden, increased the survival of myeloma-bearing mice and prevented myeloma bone disease.

  1. A novel mechanism results in a decrease in host-derived adiponectin and promotes myeloma tumor growth and osteolysis.

  2. Increasing adiponectin may have potential therapeutic benefits for the treatment of myeloma and the associated bone disease.

BM, bone marrow; BMSC, bone marrow stromal cell; CCL3, chemokine C-C motif ligand 3; DKK1, Dickkopf-1; IL-6, Interleukin-6; IL-17, Interleukins 17; IL-17A, Interleukins 17A; mAb, monoclonal antibody; MBD, myeloma bone disease; MM, multiple myeloma; OB, osteoblast; OC, osteoclast; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor-kappa B ligand; Scl, sclerostin; Wnt, Wingless-type6.