Another 1q bites the dust Free

In this issue of Blood, Sklavenitis-Pistofidis et al use multiple large-scale screens to identify mantle cell lymphoma 1 (MCL1) and phosphatidylinositol 3-kinase (PI3K) as specific therapeutic vulnerabilities for multiple myeloma with gain of chromosome 1q.¹ 

Outcomes in myeloma have improved significantly thanks to advances in plasma cell–directed therapy. However, precision targeted therapy based on genomic alterations has lagged, despite the presence of common translocations, copy number changes, and mutations. The one exception has been the use of BCL2 inhibitors in t(11;14) myeloma and this is due to a functional consequence of the genetic alteration and not a change in the drug target. One of the most common genetic alterations is gain (3 copies) or amplification (4 or more copies) of chromosome 1q. Gain of 1q is observed in ∼40% of patients newly diagnosed with myeloma.² This has created some controversy over the contribution of 1q to high-risk disease as this frequency is greater than that of high-risk myeloma. However, amplification of 1q has been consistently associated with worse outcomes.³ Thus, there is consensus that 1q amplification is a high-risk feature, whereas 1q gain requires the presence of an additional high-risk feature to be associated with poor outcomes. As a result, 1q has been incorporated into the high-risk definition of multiple recent risk stratification approaches, including the second revision of the International Staging System⁴ and an updated International Myeloma Working Group consensus (International Myeloma Society Meeting, 25-28 September 2024). Therefore, understanding the biology of 1q gain remains essential for this population.

The frequency of 1q gain and its association with worse outcomes have prompted a closer look at the genes on 1q that may be responsible for the observed phenotype. Genes such as MCL1, IL6R, BCL9, CKS1B, and PSMD4 regulate key pathways involved in myeloma cell survival, proliferation, and proteasome activity.⁵ However, given the large number of genes on 1q, identifying the most relevant target has proven challenging. To address the issue of targeting 1q, Sklavenitis-Pistofidis et al used CRISPR and RNAi screen data from 21 myeloma cell lines in the DepMap project, and also performed a whole genome CRISPR screen of 2 myeloma cell lines, either with 2 copies or with gain of 1q, and 2 large-scale drug screens in 4 cell lines. In all cases they selected hits that produced a stronger phenotype in 1q gain and ultimately narrowed their targets to MCL1 and PI3K. MCL1 and PI3K inhibitors individually and in combination were more effective in myeloma cell lines with gain of 1q vs those without. To examine the mechanism of action of these inhibitors, the authors performed single-cell RNA sequencing on treated gain-of-1q cell lines. Curiously, they identified a cytostatic G2M arrest with MCL1 inhibition and PI3K inhibitor–induced downregulation of both microtubule regulators and heat shock protein genes. However, previous work suggested that MCL1 is degraded by CDK1-CCNB1 and CDC20 in M phase, and thus the lower CCNB1 and CDC20 expression and enrichment of cells in G2M seen in the presence the MCL1 inhibitor may result from enrichment of cells with higher MCL1 levels.⁶ 

Inhibitors of MCL1 and the PI3K pathway have been investigated previously in multiple myeloma, although not specifically in the 1q-altered population. MCL1 in particular is a broad myeloma dependency and it was previously demonstrated that 1q gain results in increased sensitivity to MCL1 inhibitors.⁷ However, inhibitors of MCL1 have been limited by cardiotoxicity and future use of MCL1 inhibitors may require changes in pharmacokinetics or dosing schedules.⁵ Although PI3K signaling is activated by multiple survival cytokines, PI3K inhibitors have also not been successful clinically.⁸ As the authors suggest, increased dependency of 1q may allow for lower doses of the drugs that could overcome issues of tolerability.

In addition to addressing the issue of tolerability, questions for future study include: Do 1q vulnerabilities differ depending on other commonly occurring myeloma genetic backgrounds such as t(11;14), t(4;14), del(17p), and del(1p)? Perhaps some genetic backgrounds will have an even greater dependency and thus a larger therapeutic window. t(4;14) will be of particular interest for investigation given the known association of this event with 1q gain.⁹ How will clonal heterogeneity of 1q gain affect treatment response? Although gain of 1q tends to be an early event, additional subclonal gains can occur over time.⁵ How well will the MCL1/PI3K combination control 1q wild-type clones, or will it need to be further combined with traditional myeloma agents? Conversely, is there a point at which increasing amplification of MCL1 will overcome the therapeutic effect of a low-dose MCL1 inhibitor?

Targeting 1q is a critical unmet need, not only in myeloma as gains are one of the most common events in all types of cancer,¹⁰ and the work here may provide a path forward.

Conflict-of-interest disclosure: The authors declare no competing financial interests.