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

Sep 9, 2020

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. 1However, 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 themeon 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% vs14%, 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 vs70.1 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 Clinic 2

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 situhybridization (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% vs35%). 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% vs11%), monosomy 13 (48% vs36%), and del(13q) (14% vs7%) 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 characteristics 1

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 situhybridization; 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 vspatients 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 therapy 2

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 outcomes 2

  • 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) vsthose 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 therapy 2

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.

Expert Opinion

Multiple myeloma is a very heterogeneous disease with very different outcomes primarily driven by the underlying genetic abnormalities. Now we see multiple myeloma as a group of disorders characterized by unique sets of genetic abnormalities. Unlike the primary abnormalities, like translocations and trisomies, which remain stable during the disease course, acquisition of secondary abnormalities like chromosome 1q+ and deletion 17p continue to dynamically alter the expected trajectory of the disease based on the risk stratification at the time of diagnosis.

The prevalence of secondary abnormalities and the risk of their development during the disease course are, to some extent, determined by the primary abnormalities, as it can be derived from the associations that we see in these two studies. However, other factors, including the types of therapy that these patients receive, may influence these secondary abnormalities. Clearly, a lot more work needs to be done to understand better why patients develop secondary abnormalities and how we can prevent their development, thus altering the eventual disease outcome.

These two studies demonstrate that the presence of 1q amplification at the time of diagnosis impacts the clinical presentation and outcome of patients with myeloma. The poor prognosis mechanism is not clearly understood, but it has been hypothesized to be related to  MCL1 expression, given the presence of this gene in the amplified region. Further studies in this field will allow us to develop therapies that may be utilized explicitly for this subgroup of patients.

Along with targeted therapy for these patients, work also needs to be directed towards reducing the risk of patients developing a secondary abnormality during the disease's evolution. Whether this can be achieved by using specific treatment combinations or targeting minimal residual disease negativity with the initial therapy remains to be seen. For now, the risk stratification models for multiple myeloma need to incorporate chromosome 1 abnormalities to ensure that future clinical trials and biological studies appropriately group these patients based on their expected outcomes.

 

  1. Giri S, Huntington SF, Wang R, et al. Chromosome 1 abnormalities and survival of patients with multiple myeloma in the era of novel agents. Blood Adv.2020;4(10):2245–2253. DOI: 1182/bloodadvances.2019001425
  2. Abdallah N, Greipp P, Kapoor P, et al. Clinical characteristics and treatment outcomes of newly diagnosed multiple myeloma with chromosome 1q abnormalities. Blood Adv. 2020;4 (15):3509–3519. DOI: 1182/bloodadvances.2020002218