Predicting ultrahigh risk multiple myeloma by molecular profiling: an analysis of newly diagnosed transplant eligible myeloma XI trial patients

The prognosis for newly diagnosed multiple myeloma (NDMM) has improved with the advent of new agents, but outcome in some patients remains very poor. Identifying patients with high-risk disease early opens up the prospect of strati ﬁ ed treatment [1 – 3]. Biomarkers including chromosomal and t(14;20) translocations, gain of 1q and deletion 17p, by ﬂ


Statistical analyses
Statistical analyses were performed in R (version 3.5.1) using sub-routines survival, metaphor and base R functions. Progression-free survival (PFS) was defined as time from induction or maintenance randomization or time of transplant to progression or death and overall survival (OS) as time from induction or maintenance randomization or time of transplant to death. Cox proportional hazards regression was used to estimate univariate and multivariable hazard ratios (HRs) and 95% confidence intervals (CI). Kaplan-Meier survival curves were generated and homogeneity between groups was assessed using the log-rank test. Association between categorical variables was examined using Fishers exact test and between continuous variables using the Wilcoxon signed-rank test or t-test for normally distributed variables. Correlation between continuous variables was calculated using Pearson product-moment correlation. A two-sided P-value of ≤0.05 was considered statistically significant.

DATA-SHARING STATEMENT
Gene expression data has been deposited under EGA accession EGAS00001004183; requests will be reviewed by the data access committee. Only non-commercial requests will be considered. De-identified participant data will be made available when all primary and secondary endpoints have been met. Requests for trial data and supporting material (data dictionary, protocol, and statistical-analysis plan) will be reviewed by the trial-management group in the first instance. Only requests that have a methodologically sound proposal and whose proposed use of the data has been approved by the independent trial steering committee will be considered. Proposals should be directed to the corresponding author in the first instance; to gain access, data requestors will need to sign a data access agreement.

Supplementary Figure 1
Kaplan-Meier plot of the analyzed representative NCRI Myeloma XI trial patients (n=329) in context of SKY92 risk profiling results for A) PFS, B) OS from induction randomization. Log-rank P-values displayed.
A) B)

Supplementary Figure 2
Kaplan-Meier plots for groups defined by presence or absence of SKY92 GEP risk status in patients randomised (ITT) to induction with CTD (A, B) or CRD (C, D).

A) B)
C) D)

Supplementary Figure 3
Kaplan-Meier plots for PFS and OS for double-hit (A,B,E,F,I,J) or SKY92 (C,D,G,H,K,L) high-risk absent vs landmarked from induction randomization (A,B,C,D), post high dose melphalan and autologous stem cell transplant (E,F,G,H) and randomization to lenalidomide maintenance (subset to only patients randomized to lenalidomide monotherapy)(I,J,K,L).

Double-hit vs other SKY92 High-Risk vs other
Landmarked post induction randomisation Landmarked from lenalidomide randomization (subset to patients who were randomized to receive lenalidomide)

Supplementary Figure 4
Kaplan-Meier plots of subset of 161 patients with no chromosomal high-risk markers in context of presence or absence of SKY92 high-risk status A) PFS B) OS.

Supplementary Figure 5
Kaplan-Meier plots of molecular risk groups defined by absence of any high-risk marker, presence of a single genetic marker, presence of either double-hit or SKY92 high-risk or combined double-hit and SKY92 high-risk for A) PFS B) OS landmarked from HDMEL+ASCT consolidation.

Supplementary Figure 6
Kaplan-Meier plots of molecular risk groups defined by absence of any high-risk marker, presence of a single genetic marker, presence of either double-hit or SKY92 high-risk or combined double-hit and SKY92 high-risk for A) PFS B) OS from maintenance randomization. Kaplan-Meier plots for molecular risk groups of patients that underwent maintenance lenalidomide or observation only. Landmarked analysis from Lenalidomide maintenance randomization, showing lenalidomide vs. observation for sub-groups with C) no genetic or gene expression high-risk marker D) single genetic high-risk marker E) double-hit or SKY92 high-risk F) double-hit and SKY92 high-risk. Proportion of patients with ISS status for groups with A) no, single or double-hit genetics and patients with B) absence or presence of SKY92 high risk. LDH values at presentation for patients with C) no, single or double-hit genetics and patients with D) absence or presence of SKY92 high risk. EMC92 quantitative score plotted for groups with A) normal, gained or amplified chromosome 1q B) normal, heterozygous or homozygous deletion 17p.
A) B)