The Impact of Tumor Heterogeneity on Diagnostics and Novel Therapeutic Strategies in Multiple Myeloma

Abstract

Myeloma is characterized by extensive inter-patient genomic heterogeneity due to multiple different initiating events. A recent multi-region sequencing study demonstrated spatial differences, with progression events, such as TP53 mutations, frequently being restricted to focal lesions. In this review article, we describe the clinical impact of these two types of tumor heterogeneity. Target mutations are often dominant at one site but absent at other sites, which poses a significant challenge to personalized therapy in myeloma. The same holds true for high-risk subclones, which can be locally restricted, and as such not detectable at the iliac crest, which is the usual sampling site. Imaging can improve current risk classifiers and monitoring of residual disease, but does not allow for deciphering the molecular characteristics of tumor clones. In the era of novel immunotherapies, the clinical impact of heterogeneity certainly needs to be re-defined. Yet, preliminary observations indicate an ongoing impact of spatial heterogeneity on the efficacy of monoclonal antibodies. In conclusion, we recommend combining molecular tests with imaging to improve risk prediction and monitoring of residual disease. Overcoming intra-tumor heterogeneity is the prerequisite for curing myeloma. Novel immunotherapies are promising but research addressing their impact on the spatial clonal architecture is highly warranted.

Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab

“…Asymptomatic plasma cell dyscrasias, such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM, have a propensity to progress to symptomatic MM [19]. Cytogenetic analyses have shown that MM is a heterogenous disease, with two main primary chromosomal events: (i) hyperdiploid MM presents with several trisomies (chromosomes 3, 5, 7, 9, 11, 15, 19, and 21), and (ii) non-hyperdiploid MM is associated with primary Ig heavy-chain translocations, such as t(4;14), t (11;14), t(14;16), or t (14;20), which result in overexpression of specific oncogenes [20]. During further disease evolution, myeloma cells acquire secondary chromosomal aberrations, including (i) amplification of chromosome 1q, (ii) deletion of chromosome 1p, (iii) deletion of chromosome 17p, which includes the tumor-suppressor gene TP53, and (iv) translocations involving the MYC locus on chromosome [20][21][22].…”

“…Cytogenetic analyses have shown that MM is a heterogenous disease, with two main primary chromosomal events: (i) hyperdiploid MM presents with several trisomies (chromosomes 3, 5, 7, 9, 11, 15, 19, and 21), and (ii) non-hyperdiploid MM is associated with primary Ig heavy-chain translocations, such as t(4;14), t (11;14), t(14;16), or t (14;20), which result in overexpression of specific oncogenes [20]. During further disease evolution, myeloma cells acquire secondary chromosomal aberrations, including (i) amplification of chromosome 1q, (ii) deletion of chromosome 1p, (iii) deletion of chromosome 17p, which includes the tumor-suppressor gene TP53, and (iv) translocations involving the MYC locus on chromosome [20][21][22]. The International Myeloma Working Group (IMWG) classifies the presence of del(17p) and/or t (4;14), and/or t(14;16) as high-risk cytogenetic markers associated with reduced survival of patients with MM [23].…”

“…Since MM is a heterogeneous cancer with several subclones presenting different susceptibility to different agents, combination therapy has been a successful approach to improve clinical outcomes [20]. Based on the efficacy of CD38 antibodies, these agents are very attractive as a component of combination therapy regimens.…”

Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma

“…Arguably, this last question will be answered in the near future, thanks to the increasing use of anti-CD38 mAb combinations in early lines. These issues are particularly challenging considering the wide heterogeneity of myeloma cell populations [121]. Immunotherapy seems to be a potential strategy for targeting virtually all tumor subclones, as effector mechanisms rely on the patient immune system.…”

Therapeutic Approaches Targeting Glucose, Glutamine and Lipid Metabolism in Multiple Myeloma

“…İlerleyen süreçte klonal plazma hücrelerinin edindiği yeni moleküler değişimler hastalığın tipik bulgularının gelişmesine (anemi, böbrek yetersizliği, litik kemik lezyonları ve patolojik kırıklar, hiperkalsemi, kemik iliği yetersizliği) yol açar. MM hematolojik kanserlerle ilişkili ölümlerin %20'sinden sorumludur (7,8). Son 10 yılda immünomodülatör ilaçlar, proteozom inhibitörleri ve yakın zamanda hedefe yönelik tedavilerin geliştirilmesi ile hastalıkta önemli sağkalım avantajı elde edildiği halde halen hastaların %15 kadarında hastalık kötü seyirli olmaktadır (9).…”