Novel Clonal Competition Assays Tool Can Personalize Treatment for Patients with Multiple Myeloma

Clonal competition assays (CCAs) can differentiate malignant multiple myeloma (MM) cells to determine how cell populations respond to certain agents, according to a study by the H12O-CNIO Haematological Tumours Clinical Research Unit. The novel tool may help prevent tumor drug resistance and relapse, a highly prevalent complication and characteristic of MM.

With the use of CCAs, mechanisms of resistance and progression in MM can be more thoroughly understood. Image Credit: © thekob5123 - stock.adobe.com

MM is an incurable hematological malignancy in which successive lines of therapy typically yield continuously poorer responses and outcomes. Despite various approved agents and overexpressed protein targets, relapse and resistance continue to be significant barriers to lasting remission for many patients. A common challenge involves presence of mutations, namely TP53, an established marker of high-risk, and KRAS, the most common mutation found in about 20% of patients with MM. According to prior studies, KRAS mutations are capable of giving adaptive advantages to the carrier cell, allowing them to survive treatment while other cells die.^1,2

Mechanisms of resistance in MM are extremely complex and involve various abnormal cell types that encourage progression of disease. Factors such as antigen loss, cell fitness, and mutations can interfere with the efficacy of immunomodulators, proteasome inhibitors, immunotherapies, or novel CAR T-cell therapies.³

Additionally, not all cancer cells are the same, even in a single disease state. Each cell population contain their own unique genetic errors that differ across cell types, and some can become more dominant than others to drive treatment resistance. However, through identifying and differentiating the presence, dominance, and resistances of specific tumor cells, researchers can more effectively tailor treatments and prolong remission in patients with MM.⁴

“[MM] is very heterogeneous,” said Larissa Haertle from the department of internal medicine 2 at the University Hospital Würzburg, Würzburg, Germany, in a news release. “The same tumour can contain many different genetic alterations, and we have to approach it as if it were lots of different tumours.”⁴

In the study, the research team applied CCAs based on the coculturing of fluorescence-marked isogenic MM cells with or without a genetic alterations, allowing them to study the effects of specific genetic lesions on cellular fitness and their impact under drug exposure. The data showed that mono- and biallelic alterations in TP53 and KRAS (G12A and A146T) offer a fitness advantage to the cells, revealing a potential biological rationale for the high frequency of these mutations in relapsed patients. Additionally, they discovered 3 alterations of other genes that are beneficial to tumor cells in the presence of lenalidomide (Revlimid; Bristol Myers Squibb) and bortezomib (Velcade; Millennium/Takeda and Janssen Pharmaceutical Companies), suggesting these treatments gave malignant, mutated cells an adaptive advantage.^2,4

“[CCAs] allows us to see how each population of cells in the same myeloma reacts to treatments,” she adds. “It gets much closer to understanding the heterogeneity of each patient than usual methods do. And we can see in real time how cells develop.”⁴

The findings encourage clinicians to take advantage of treatment breaks and changes during remission maintenance in the presence of mutations. With the use of CCAs, mechanisms of resistance and progression in MM can be more thoroughly understood and open doors for more effectively tailored treatment plans for patients.

REFERENCES

1. Multiple myeloma precursor diseases: advancing diagnosis and treatment for mgus and smm. Pharmacy Times. September 25, 2024. Accessed October 17, 2024. https://www.pharmacytimes.com/view/multiple-myeloma-precursor-diseases-advancing-diagnosis-and-treatment-for-mgus-and-smm

2. Haertle L, Munawar U, Hernández H, et al. Clonal competition assays identify fitness signatures in cancer progression and resistance in multiple myeloma. HemaSphere. July 11, 2024. doi:10.1002/hem3.110

3. Targeting resistance: navigating the complexity of the tumor microenvironment and car t-cell efficacy. Pharmacy Times. August 16, 2024. Accessed October 17, 2024. https://www.pharmacytimes.com/view/targeting-resistance-navigating-the-complexity-of-the-tumor-microenvironment-and-car-t-cell-efficacy

4. A new technique that makes competition between tumour cells visible can help personalise treatments for multiple myeloma. News Release. October 8, 2024. Accessed October 17, 2024. https://www.eurekalert.org/news-releases/1060576