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Page 10 of 15 Sabol et al. J Cancer Metastasis Treat 2021;7:20 https://dx.doi.org/10.20517/2394-4722.2021.35

To this date, no Notch inhibitors are approved for the treatment of MM. In fact, only 2 trials have tested
Notch inhibition in MM patients. The effects of the GSI inhibitor RO4929097 were tested in MM patients
after autologous stem cell transplantation (NCT01251172). Unfortunately, although no severe side-effects
were reported in this study, the clinical trial was withdrawn due to the termination of drug development by
the company. Recently, interest in Notch inhibitors has increased due to the observation that the γ-secretase
complex cleaves BCMA from the membrane of MM cells, decreasing the amount of available target for
chimeric antigen receptor (CAR) T cells specific for BCMA . The anti-MM efficacy of BCMA-specific
[113]
CAR T-cells in combination with GSI JSMD194 in relapsed or persistent MM patients is currently being
tested in clinical trial NCT03502577. In this line, several companies have announced the testing of their
GSIs (i.e., Nirogacestat and AL102) in combination with BCMA-specific CAR T-cells in MM patient
populations.

Given its multifunctional role in MM, Notch still remains an attractive therapeutic target. However, Notch-
related therapies have not gathered momentum due to the toxicities seen with current therapeutic strategies
and the difficulty of targeting multiple Notch ligand-receptor interactions. Our group has taken a new
[105]
direction to improve the therapeutic index of GSIs for the treatment of MM . We have developed a novel
bone-targeted GSI to bypass Notch inhibition in other tissues, particularly the gut. Preclinical results in
animal models of human and murine MM showed that our bone-targeted GSI approach results in specific
inhibition of Notch in skeletal tissues and decreases MM growth and bone destruction, without inducing
gut toxicity. Ongoing pharmacokinetic and pharmacodynamics studies, as well as a full assessment of the
safety profile, should provide a better picture of the potential of this new approach for the clinic.

CONCLUSION
Progress in medical research has improved our understanding of tumor biology and defined the impact of
the microenvironment on cancer pathogenesis. This is particularly true for MM, where the bone/marrow
niche plays a critical role in its onset and progression. MM cells locate in specialized niches in the marrow
where they interact with stromal cells, endothelial cells, immune cells, osteoblasts, osteoclasts, adipocytes,
and osteocytes. These interactions transform the marrow niche into an ideal environment for MM
progression and the development of bone disease. Further, the marrow niche provides protection to drug-
resistant MM cells, which can repopulate the marrow and induce disease relapse. Accumulating evidence
supports that transmission of near-range signals via Notch between MM cells and marrow cells shapes the
microenvironment and transforms it into a niche conducive to MM cell proliferation and survival,
promoting drug resistance, and bone destruction [Figure 2].

Yet, several aspects of Notch signaling and its pleiotropic role of in MM remain to be resolved. A clear
understanding of the specific role of each Notch component, the receptor-ligand specificity for homotypic
and heterotypic interactions, and potential redundancies in receptor and ligand functions is required to
identify effective and safer strategies to inhibit this pathway. It is expected that with the inclusion of next-
generation RNA and DNA sequencing approaches in clinical practice, more information regarding the
changes in expression and actionable mutations in Notch components will be available in the coming years.
Particular attention should be paid to the changes during the progression from MGUS to MM to PCL in
patients, as well as in the recurrence of the disease. Although Notch1 and 2 receptors are highly expressed in
[40]
medullary and extramedullary MM cells , whether Notch signaling plays a role in MM migration and
extramedullary growth remains to be determined. Pharmacological inhibition of Notch with GSIs in
preclinical models of MM shows promising dual strong anti-myeloma and anti-resorptive efficacy.
Moreover, recent evidence shows that GSIs can enhance BCMA-directed CAR T-cell therapy by increasing
the amount of surface BCMA target . Unfortunately, the severe side-effects associated with the systemic
[113]