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.

Keywords: clinical imaging; daratumumab; immunotherapy; minimal residual disease; multiple myeloma; risk stratification; spatial heterogeneity; targeted therapy.

Figure 1

Inter-patient heterogeneity in Multiple Myeloma. The two main pathogenetic groups hyperdiploid and non-hyperdiploid can be distinguished in myeloma. However, there are multiple different initiating events at the chromosomal level, resulting in a high level of inter-patient heterogeneity in this disease, which is also reflected in heterogeneous treatment responses and outcomes.

Figure 2

Intra-tumor heterogeneity in Multiple Myeloma. According to recent multi-region sequencing studies spatial genomic heterogeneity is a common phenomenon in myeloma. Tumor driver mutations and high-risk genomic aberrations can be restricted to one focal lesion and absent at other FLs or the iliac crest. Thus, an imaging finding with multiple FLs strongly suggests extensive intra-tumor heterogeneity.

Figure 3

Example for a mixed response to Daratumumab. At enrolment into salvage therapy, which contained Daratumumab combined with Pomalidomide and Dexamethasone, the patient presented with an M-protein of 3 g/dl and multiple focal lesions (FLs). The patient achieved an MRD-negative stringent CR but still presented with FLs. While an FL in the thoracic spine was improved (green circle), another FL in the pelvis had increased in size (red circle), highlighting a mixed response to Daratumumab.