According to results of a study comparing CD38-positive tumor cells of patients with newly diagnosed multiple myeloma, a high-risk status determined by either a validated gene-expression profiling assay or the presence of specific chromosomal abnormalities was independently predictive of poor outcome. These findings were published in Leukemia.1

Because survival rates of patients with newly diagnosed multiple myeloma can vary widely, it is important to identify those with high-risk disease characterized by a more aggressive clinical course who may require a new therapeutic approach.

Chromosomal aberrations known to be associated with more aggressive disease include translocations t(4;16), t(14;16), and t(14;20), as well as the presence of 4 or more copies of the 1q chromosome, as well as deletion of both copies of chromosome 17p. In particular, previous studies of patients with multiple myeloma have shown low survival rates in those with disease characterized by the presence of 2 or more of these genetic features (ie, a double hit). In addition, other methods that have been validated for the prediction of outcome in patients with multiple myeloma include gene-expression assays, such as the SKY92 MMproflier (SKY92), and the International Staging System (ISS), as well as the combination of these 2 methods.2

In this study, the presence or absence of chromosomal aberrations, as well as SKY92 expression profiles of 92 genes, were evaluated in CD38-postive tumor cells from a cohort of 329 patients with newly diagnosed multiple myeloma receiving intensive therapy in the NCRI Myeloma XI trial.


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A comparison of the 81 patients in this cohort with disease characterized by a high-risk gene-expression profile showed median overall survival (OS) was significantly shorter (36.7 months) compared with the subgroup with disease that lacked this gene-expression signature (median OS not reached; hazard ratio HR, 3.9; 95% CI, 2.7-5.7; P =2.5 x 10-13).

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On multivariable analyses, a high-risk SKY92 profile (HR, 2.7; 95% CI, 1.8–4.2; P =4.4 × 10−6), high-risk chromosomal translocations (HR 1.8; 95% CI, 1.2–2.9; P =.007), and deletion of the 17p chromosome (HR; 2.5, 95% CI, 1.5–4.1; P =.0007) were all found to be independently associated with worse OS compared with patients without these markers of high-risk disease.

Furthermore, high-risk SKY92 and double-hit were independently prognostic by multivariable analysis, with HRs for OS of 2.9 (95% CI, 1.9–4.2; P =2.6 × 107) and 2.3

(95% CI, 1.5–3.6; P =.0002) compared with subgroups without these markers.

Percentages of the 3 subgroups defined by a high-risk SKY92 profile and/or high-risk chromosomal marker(s), and the hazard ratios for OS for these subgroups compared with the subgroup without these disease markers, were as follows:

  1. Double-hit and SKY92 (9.7%; HR, 11.0; 95% CI, 6.3–19.1; P <2.2 × 1016)
  2. Double-hit or SKY92 (23.4%; HR, 3.8; 95% CI, 2.3–6.3; P =2 × 107)
  3. Single-hit (24.0%; HR, 1.9; 95% CI, 1.1–3.3; P =.03)

Of note, these findings were validated in a separate cohort of 116 patients enrolled in the transplant arm of MRC Myeloma IX study of newly diagnosed patients with multiple myeloma.

The study authors stated that these results “highlight the molecular diversity of [multiple myeloma] and demonstrate that single time point combined GEP and chromosomal profiling at diagnosis can predict clinical outcome with significant precision…”

References

  1. Shah V, Sherbone AL, Johnson DC, et al. Predicting ultrahigh risk multiple myeloma by molecular profiling: An analysis of newly diagnosed transplant eligible Myeloma XI Trial patients [published online March 11, 2020]. Leukemia. 10.1038/s41375-020-0750-z
  2. van Beers EH, van Vliet MH, Kuiper R, et al. Prognostic validation of SKY92 and its combination with ISS in an independent cohort of patients with multiple myeloma. Clin Lymphoma Myeloma Leuk. 2017;17:555-562.