A simple new prognostic stratification system can effectively predict the prognosis of newly diagnosed multiple myeloma patients

Multiple myeloma (MM) is the second most common hematological malignancy, accounting for approximately 2% of all cancer deaths in the United States
.

With the advent of novel therapeutic agents and combination regimens, the survival outcomes of patients with MM have improved significantly
.

Despite these therapeutic advances, there is still a high degree of heterogeneity in survival outcomes even within uniformly treated clinical trial populations
.

This suggests that risk stratification at diagnosis is important for MM prognosis and patient selection for clinical trials
.

Several risk stratification systems have been proposed based on clinical features, laboratory markers, bone marrow cytogenetics, and gene expression profiles; among them, the International Staging System (ISS) and the Revised ISS (R-ISS) have been tested in clinical practice.
the test of time
.

In clinical practice, ISS remains a common choice for risk stratification due to its simplicity (although its ability to discriminate low-risk patients is limited in the era of novel treatments)
.

FISH testing identifies high-risk patients independent of ISS stage based on abnormalities such as t(4;14), t(14;16), and del(17p)
.

Introduced in 2015, R-ISS includes these cytogenetic abnormalities as well as elevated lactate dehydrogenase (LDH) as a high-risk marker
.

R-ISS was subsequently validated in several studies and is currently used to risk stratify newly diagnosed MM patients
.

Recent studies have found that other cytogenetic abnormalities not included in R-ISS are also associated with poor survival outcomes in MM patients, including monosomy 13, 1q21 amplification, and rearrangements involving the MYC gene
.

Although the presence of high-risk laboratory and cytogenetic features has been incorporated into R-ISS, the additive effect of multiple co-occurring high-risk disease features has not been explained
.

Furthermore, unlike ISS, which had a similar proportion of patients in each of the three stages, most patients in the R-ISS stage were classified as intermediate-risk
.

Based on the identification of additional cytogenetic risk factors and a better understanding of the prognostic significance of multiple-hit disease, investigators conducted a new study to evaluate a new simple staging system for the prognosis of patients with newly diagnosed MM (NDMM)
.

Methods We included all patients with MM ≥18 years of age who presented to the Mayo Clinic in Rochester, Minnesota between February 2004 and June 2019, who passed the Cytogenetic analysis was performed by FISH
.

The researchers extracted data on FISH results, standard serum and urine tests, bone marrow biopsy results, first-line therapy, transplant status, and date of death or last follow-up
.

To build the model, the investigators included 1327 Mayo Clinic patients with concurrent data on all prognostic high-risk abnormalities identified by multivariate analysis; the validation population included 502 patients enrolled in the MMRF CoMMpass study (MMRF)
.

We updated the R-ISS system so that the definition of HR cytogenetic abnormalities included all FISH abnormalities found to be significantly associated with OS in the final multivariate model of this study; a simpler approach was explored that combined all independent prognostic factors and group patients according to the number of risk factors
.

Results Patient Baseline Characteristics The Mayo Clinic cohort included 2556 patients diagnosed with MM between February 2004 and June 2019
.

The median age was 64 years, and 62% were male
.

The clinical characteristics and first-line treatment of the patients are detailed in Table 1
.

Of all patients, 143 (6%) had no abnormality in FISH using the probes tested
.

Trisomy of at least one chromosome was found in 55% of patients tested
.

IgH translocation was most common with t(11;14), accounting for 21%; t(4;14) and t(14;16) accounted for 10% and 4%, respectively
.

Amplification of ≥1 copy of chromosome 1q was detected in 31% of patients, and a rearrangement involving the MYC gene was found in 9% of patients
.

Monosomy 13 was seen in 37% of patients, and chromosome 17 abnormality [del(17p)/monosome 17] was seen in 13% (Table 2)
.

Table 1: Patient Baseline Characteristics Table 2: Patient Cytogenetic Abnormalities Results from Univariate and Multivariate Survival Analysis The median follow-up for the entire cohort was 6.
2 years (95% CI: 5.
9-6.
5 years), and the median OS was 7.
5 years (95%CI: 7.
0-8.
1 years)
.

In multivariate analysis (including all FISH abnormalities significantly associated with OS in univariate analysis), monosomy 13 and trisomy were no longer prognostic factors for OS
.

In univariate analysis, both ISS stage III and elevated LDH were associated with increased risk of death in patients and were therefore included in the final multivariate with high-risk IgH translocation, MYC rearrangement, 1q amplification, and chromosome 17 abnormality in the model
.

In the final multivariate model, HR IgH translocation, 1q amplification, chromosome 17 abnormality, ISS stage III, and elevated LDH were all independently associated with decreased OS
.

MYC rearrangement was associated with a lower OS rate, but not statistically (see Table 3 for details)
.

Table 3: Results of univariate and multivariate analysis of patients R-ISS was updated based on updated PFS and OS of R-ISS, in addition to high-risk IgH translocation and chromosome 17 abnormality, 1q amplification was included in high-risk cytogenetics in the definition of academic anomalies
.

Based on this definition, there were 193 (11%), 1130 (66%), and 396 (23%) patients with stage I, II, and III stages, respectively; the median PFS of the three groups was 60.
0 months and 44.
0 months, respectively.
and 28.
1 months (P < 0.
001) (Fig.
1a); the median OS of patients in the three groups was 9.
4 years, 7.
5 years, and 3.
9 years, respectively (P < 0.
001) (Fig.
1b)
.

Figure 1: Development of a Simpler Risk Stratification System Based on Updated PFS and OS in R-ISS Patients - MASS in all 1327 patients included in the study with the following data simultaneously: high-risk IgH translocation, 1q amplification, 17 Chromosomal abnormalities, ISS staging, and LDH
.

Baseline characteristics of patients did not differ significantly between evaluable patients and the rest of the cohort
.

Among the evaluable patients, 476 (36%) had no high-risk factors (stage I), 442 (33%) had one high-risk factor (stage II), and ≥2 high-risk factors (stage III) were 409 patients (31%); the median PFS of the 3 groups were 63.
1, 44.
0, and 28.
6 months, respectively (Fig.
2a); the median OS of the 3 groups of patients was 11.
0, 7.
0, and 4.
5 years, respectively (Fig.
2b) (Table 4 )
.

Figure 2: MASS-based patient PFS and OS using the Mayo Clinic cohort Table 4: Subgroup analysis by age and engraftment status of the MASS–Mayo cohort to assess the prognostic power of this staging system according to age group and engraftment status
.

Among patients <65 years, median OS was 12.
8, 9.
3, and 5.
5 years for stage I, II, and III patients, respectively (P < 0.
001) (Fig.
3a)
.

Among patients ≥65 years old, the median OS was 8.
3, 6.
4, and 3.
7 years in the 3 groups (P<0.
001) (Fig.
3b)
.

Among patients who did not receive transplantation, the median OS was 9.
1, 5.
8, and 3.
0 years in the 3 groups (P<0.
001) (Fig.
4a)
.

Among patients who received transplantation, the median OS was 11.
3, 9.
7, and 6.
1 years in the 3 groups (P < 0.
001) (Fig.
4b)
.

Figure 3: OS of different patients based on MASS stage by ageFigure 4: OS of different patients based on MASS stage by transplant status Restaging using MASS Among all patients, 1269 patients obtained both R-ISS stage and MASS stage data, including 244 (18%) R-ISS I patients, 791 (62%) R-ISS II patients, and 234 (18%) R-ISS III patients; overall, when MASS was used for risk stratification 469 (37%) patients had stage migration (Fig.
5)
.

Among R-ISS I patients, 21% were reclassified as stage II using the MASS system; among R-ISS II patients, 32% and 21% were classified as stage I and III using the MASS system; Among R-ISS III patients, all patients were classified as stage III using the MASS system
.

147 cases of double-hit MM patients were divided into 71 cases (48%) of stage II and 76 cases (52%) of stage III by R-ISS
.

Among the 17 patients with triple-hit MM, 4 (24%) were in R-ISS stage II, and 13 (76%) were in R-ISS stage III
.

By definition, all patients with double- and triple-hit MM were classified as stage III using the MASS system
.

Figure 5: Stage migration between R-ISS and MASS and between ISS and MASS was validated using the MMRF cohort.
The MMRF cohort included 502 patients with a median age of 63 years
.

The median follow-up time was 4.
4 years
.

According to the MASS system, there were 172 cases (34%), 181 cases (36%), and 149 cases (30%) of stage I, II, and III patients, respectively; the median PFS was 65.
2, 38.
0, and 22.
6 months, respectively (P＜ 0.
001) (Fig.
6a); median OS was 7.
8, 6.
0, and 4.
3 years, respectively (P < 0.
001) (Fig.
6b)
.

Figure 6: Conclusions of the MASS-based PFS and OS study in the MMRF cohort.
The study developed and validated a simple, additive, 5-factor, 3-tier NDMM risk model in two diverse patient populations that is easily Implemented in clinical practice, it can play an important role in patient selection for clinical trials
.

References: Nadine H Abdallah , Moritz Binder , S Vincent Rajkumar, et al.
A simple additive staging system for newly diagnosed multiple myeloma.
Blood Cancer J.
2022 Jan 31;12(1):21.
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