The clinical significance of chromosome 1 abnormalities in newly diagnosed multiple myeloma

Some cytogenetic abnormalities frequently detected in patients with multiple myeloma (MM) can be used as a prognostic factor to predict patient outcomes; one of which is the gain of chromosome 1q (+1q). This aberration can lead to dysfunction of several genes and is associated with disease progression, from monoclonal gammopathy of undetermined significance to smoldering MM, overt MM, and relapsed disease. To date, published studies reporting on chromosome 1 abnormalities have indicated its association with a high tumor burden, high international staging system (ISS) stage, and inferior outcomes.¹ However, the literature on chromosome 1 aberrations (C1A) in MM has been inconsistent and contradictory on whether +1q is an independent predictive factor of poor prognosis that should be considered for risk stratification.

The goal of the current editorial theme on the Multiple Myeloma Hub is to provide an updated review on identifying and treating high-risk disease. After our recent overview of common cytogenetic abnormalities associated with a higher risk of relapse, we now come to discuss the latest results on C1A and their impact on clinical outcomes of novel agents.  

Incidence of chromosome 1 abnormalities in MM

A recent retrospective study by Smith Giri and colleagues was published in Blood Advances, analyzing the data available in the Flatiron Health database from patients with MM treated in the US between 2011 and 2018. In the selected cohort of patients with karyotype analysis (N = 3,578 patients), they found that in 24% of cases, C1A were present at diagnosis, resulting in a higher incidence than other traditional high-risk cytogenetic aberrations (namely del(17p), t(4;14), and t(14;16)). These patients were also more likely to have concurrent high-risk cytogenetics compared with those without C1A (27% vs 14%, p < 0.001).¹

Even when adjusting by the presence of high-risk cytogenetic abnormalities, they found C1A to be an independent predictor of worse survival, with a median overall survival (OS) of 46.7 months vs 70.1 months in patients without C1A (p < 0.001). One of the main limitations of this study, though, is that the authors were not able to analyze these results according to the subtype of C1A, i.e., del(1p), +1q, copy number variations, or size of clones.¹

The Mayo Clinic group recently conducted a large retrospective study investigating the impact of specifically the +1q subtype on patient characteristics, treatment outcomes, and OS in newly diagnosed patients with MM that were treated with novel agents, with or without autologous stem cell transplantation. Below, we summarize their findings, also published in Blood Advances.²

Outcomes of patients with +1q treated at the Mayo Clinic²

Methods

• This study included 1,376 patients diagnosed with MM between December 2005 and February 2018 at the Mayo Clinic, US.
• All patients were confirmed to have +1q by fluorescence in situ hybridization (FISH) < 6 months from the start of first-line treatment.
• +1q was defined by ≥ 3 total copies of 1q.

Results

• The +1q aberration was present in 28% of patients. It was observed frequently in older patients, and a higher proportion of the +1q group were classified as ISS stage 3 (compared to patients without +1q; 45% vs 35%). See Table 1.
• Patients with +1q
  • were diagnosed more frequently with IgA (35%), and/or λ light-chain isotype (45%) MM, but light chain MM was rarer (8%).
  • had a higher proportion of high-risk IgH translocation (25% vs 11%), monosomy 13 (48% vs 36%), and del(13q) (14% vs 7%) compared with those without +1q.
  • were less likely to have t(11;14).
  • had a higher chance of presenting with anemia, hypercalcemia, elevated lactate dehydrogenase, elevated β2-microglobulin, and/or increased bone marrow plasma cells.

Table 1. Patient characteristics¹

	Patients without +1q (n = 985)	Patients with +1q (n = 391)	p
Median age, years	64	66	0.009
≥ 70 years, %	26	33	0.009
Male, %	62	57	0.10
ISS stage, %
1	27	17
2	38	38
3	35	45	< 0.001
Standard-risk FISH abnormality, %
Trisomy	58	60	0.46
t(11;14)	23	13	< 0.001
Del(13q)	7	14	< 0.001
Monosomy 13	36	48	< 0.001
High-risk FISH abnormality, %
t(4;14)	7	16	< 0.001
t(14;16)	3	7	< 0.001
t(14;20)	1	3	0.002
Del(17p)/monosomy 17	14	11	0.32
First-line induction chemotherapy, %
PI-based	36	36
IMiD®-based	39	27
PI + IMiD-based	25	36
First-line transplantation, %	45	42
+1q, gain of chromosome 1q; ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; IMiD, immunomodulatory drug; ISS, International Staging System; PI, proteasome inhibitor.

Treatment outcomes with first-line therapy

• The responses to induction therapy (overall response rate and the rate of very good partial response or better) were not significantly different between patients with +1q and those without +1q, with either proteasome inhibitor (PI)-, immunomodulatory drug (IMiD)-, or PI + IMiD-based induction.
• For the entire analysis, time to next treatment (TTNT) following frontline treatment was briefer for patients with +1q vs patients without +1q (Table 2).
  • TTNT in patients with +1q and high-risk IgH translocation was 19.6 months (95% CI, 13.0–26.7), and in patients without +1q was 27.7 months (95% CI, 25.3–30.3).

Table 2. TTNT in patients receiving PI-, IMiD-, and PI + IMiD-based therapy²

Treatment	Patients without +1q TTNT, months	Patients with +1q TTNT, months	p value
First-line therapy	27.7	19.9	< 0.001
PI-based	22.4	15.0	0.004
IMiD-based	31.2	20.5	< 0.001
PI + IMiD-based	33.0	27.6	0.17
Frontline chemo only	13.9	8.5	0.001
Frontline chemo + SCT	37.1	29.8	0.01
+1q, gain of chromosome 1q; chemo, chemotherapy; IMiD, immunomodulatory drug; PI, proteasome inhibitor; SCT, stem cell transplantation; TTNT, time to next treatment.

 OS outcomes²

• After a median follow-up of 4.0 years, the median OS for the whole cohort was 7.4 years (95% CI, 6.5–8.5).
• Patients with +1q had a significantly shorter median OS in comparison to those without +1q (Table 3).

• The median OS was statistically significantly prolonged in patients who did not have +1q, a high-risk IgH translocation, or del(17p) (p < 0.001); in patients with +1q and a high-risk IgH translocation, the OS was 3.7 years (95% CI, 2.4–9.1).

• Having +1q (without any other high-risk mutations), or one of the other high-risk cytogenetic abnormalities (not +1q), had the same impact on worsening survival: median OS rates were 5.6 and 5.1, respectively.
• Patients with neither +1q nor a high-risk IgH translocation had a significantly prolonged OS (median OS, 9.2 years; 95% CI, 8.6–10.1 years; p < 0.001).
• In all patients who underwent stem cell transplantation (n = 842), including transplantation in the frontline setting or later as the disease progressed, the OS was shorter in patients with +1q (5.5 years; 95% CI, 4.5–7.1) vs those without +1q (8.9 years; 95% CI, 8.2–10.8; p < 0.001) (Table 3).

Table 3. Overall survival in patients receiving PI-, IMiD-, and PI + IMiD-based therapy²

Treatment	Patients without +1q OS, years	Patients with +1q OS, years	p value
Median OS	8.8	5.3	< 0.001
Frontline regimen
PI-based	8.1	5.0	< 0.001
IMiD-based	8.8	5.3	< 0.001
PI + IMiD-based	NR	6.2	0.005
Frontline chemo only	6.5	3.7	< 0.001
Frontline chemo + SCT	11.1	7.5	< 0.001
+1q, gain of chromosome 1q; chemo, chemotherapy; IMiD, immunomodulatory drug; OS, overall survival; PI, proteasome inhibitor; SCT, stem cell transplantation.

 

Conclusion

In summary, the Mayo Clinic experience analysis shows that the presence of +1q, high-risk IgH translocation, del(17p), ISS stage 3, and age ≥ 70 years were independently associated with lower OS, end-organ damage, and a higher tumor burden. These findings corroborate the work of Giri et al.¹; patients with +1q should therefore be considered to have high-risk disease at diagnosis. Adverse clinical outcomes are yet to be targeted and alleviated by currently available treatments, including transplantation, so it is urgent to design more studies to identify effective therapies for this subgroup.