[BLOOD] del(1p32) is a poor prognosis for NDMM, and biallele censoring is ultra-risky

del(1p32)

For multiple myeloma (MM), cytogenetic abnormalities (CA) of malignant plasma cells have a strong prognostic impact, with del(17p) known to be the most unfavorable, affecting approximately 8% of patients
with newly diagnosed multiple myeloma (NDMM).

In fact, del(1p32) also accounts for a high proportion of NDMM (11%), and studies have clearly confirmed its negative effects
on patients.
In addition, Perrot et al.
reported in JCO in 2019 that del(1p32) is the second most adverse abnormality in myeloma, and the adverse effect is second only to del(17p), which has a significant impact
on prognosis.

In order to confirm the effect of del(1p32) on the prognosis of the NDMM patient cohort in a large sample of patients, Professor Jill Corre et al.
of France analyzed the data of 2551 NDMM patients in the French Myeloma Collaboration Group (IFM), confirming the adverse effects of del(1p32) in MM, and the copy number of del(1p32) is also important
.
The results of the study were recently published in BLOOD
.

Study results

The authors analyzed 2551 patients with NDMM at IFM-related hospitals who died or progressed
within 36 months of follow-up ≥ or within 36 months of treatment.
Bone marrow samples were collected at baseline and FISH were analyzed, including gain(1q), del(1p32), del(17p), and t(4; 14)
。

Patient characteristics are shown in Table 1
.
The median follow-up was 67.
4 months
.
No significant differences
in protocol allocation between patients were found based on del(1p32) status.

11.
1% of patients carried del (1p32), and patients with del(1p32) had significantly inferior OS than those without del(1p32) (median OS 49.
1 and 123.
9 months, p< 0.
0001) (Figure 1A) and PFS was significantly shortened (median PFS 17.
7 and 29.
2 months, p< 0.
0001) (Figure 1B).

。 Similar outcomes (median PFS 24.
9 vs.
36.
8 months, p< 0.
0001, median OS 66.
9 vs.
127.
4 months, P = 0.
0009, P = 0.
0009) with del (1p32) versus no del (1p32) were also observed when focusing on patients receiving intensive therapy (transplant candidates) (n=1258) (Figure 1C and 1D).

The authors then hypothesized that the biallele del(1p32) should have a higher prognostic effect than monoallele loss
.
The 1p32 copy number was available in 281 of the 282 del(1p32) patients, which the authors divided into "biallele del(1p32)" (0 copies) and "monoallele del(1p32)" (1 copy).

。 Patients with the biallele del(1p32) had significantly shorter OSs than those with the single allele del(1p32) (median OS 24.
6 and 60.
4 months, p< 0.
0001), respectively) (Figure 2A), and PFS was similar (median PFS 9.
6 and 19.
6, P< 0.
0001) (Figure 2B).

These data suggest that a single allele deletion of 1p32 still has a detrimental effect on prognosis, even if it is slightly better than a double allele deletion
.
In addition, there was no difference in del(17p) frequency between the double allele and the single allele del(1p32) (27.
6% vs.
21.
3%, p=0.
49), thus excluding possible bias
due to coexistence with del(17p).

The authors then went back to the entire del(1p32) cohort and found that 25% of patients carrying del(1p32) also carried del(17p), twice as many as
the general NDMM population 。 To assess whether low survival is due to this higher level of correlation, the authors also looked at survival based on del(17p) status, and the outcomes were comparable to those for the entire cohort in patients without del(17p): del(1p32) patients had significantly lower PFS and OS compared with patients without del(1p32) (median PFS 18.
3 vs.
30.
4 months, p< 0.
0001; median OS 66.
3 months vs.
.
126.
0 months, P<0.
0001) (Figure 3).

To assess whether low survival is due to a high level of correlation with known adverse cytogenetics, the authors focused on del(1p32) patients without major high-risk cytogenetic abnormalities (HR CA), defined as the presence of del(17p), t(4; 14) and/or gain(1q).

PFS and OS remained low in patients without HR CA with del(1p32) (median PFS 23.
0 vs.
34.
9 months without del(1p32), p=0.
0003; median OS 80.
6 vs.
136.
1 months, P=0.
0002).

Cumulative HR CA worsens prognosis, so the authors assessed the effect
of additional HR CA on prognosis in patients with del(1p32).
Results When del(1p32) was present in combination with other HR CAs, the median OS of del(1p32) patients was significantly reduced: 80.
6 months for del(1p32) alone, 42.
2 months for 1 HR CA del (1p32) and 30.
8 months for 2 HR CAs ≥ pooled, p=0.
0001) (Figure 4).

In univariate analysis, patients carrying del(1p32), del(17p), gain(1q), or t(4;14) had an increased
risk of progression and death.
Similarly, the risk is significantly higher
when comparing patients with stage II ISS with stage I and stage III with stage ISS with stage I.
In multivariate analysis, del(1p32) appears to be a poor prognostic factor
.
After adjusting for age and type of treatment, patients carrying del(1p32) had a 1.
3-fold higher risk of progression (p=0.
0065) and a 1.
9-fold higher risk of death (p< 0.
0001) (Table 2).

discuss

This was the largest sample study (n=282) in patients with del(1p32) NDMM, up from 85 and 34 previously reported, confirming the adverse effects
of del(1p32).
This study is also the first time to compare biallele deletion and monoallele deletion at locus 1p32, indicating that biallele deletion at 1p32 significantly worsens prognosis
.

This study also confirms the cumulative risk of del(1p32) combined with multiple cytogenetic abnormalities, and del(17p), t(4;14) and gain(1q) all worsen the prognosis
of patients with del(1p32).

Treatment of multiple myeloma is rapidly evolving, and while this study confirms the adverse effects of del(1p32) in transplant-friendly and unsuitable patients (mostly triple therapy), there are insufficient data to explore the effects of second-generation IMiD and proteasome inhibitors, including immunotherapies
such as CD38.

Despite evidence of a poor prognosis, there are no official guidelines recommending systematic evaluation of del(1p32) at diagnosis and its inclusion in
R2-ISS or MASS.

In conclusion, this study reaffirms the importance of detecting del(1p32) at the time of diagnosis, as it has a huge impact
on prognosis.
In addition, the del(1p32) copy number is also important, and the prognosis of patients with double hit is significantly poor
.
And in this era of risk-stratified treatment strategies, we should look directly at the discouraging prognosis of del(1p32) patients, and therefore advocate systematic detection of del(1p32) at the time of diagnosis for risk assessment
.

References

Schavgoulidze A, Talbot A,Perrot A,et al.
Biallelic deletion of 1p32 defines ultra-high-risk myeloma, but monoallelic del(1p32) remains a strong prognostic factor.
Blood .
2022 Nov 14; blood.
2022017863.
doi: 10.
1182/blood.
2022017863.

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