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As the treatment landscape for multiple myeloma (MM) evolves, regular reviews are required to monitor the long-term effects on patient outcomes. Concomitant with improved treatment options and patient outcomes, the therapeutic aim has changed, with a greater emphasis on maximizing the depth of response to delay relapse and control the disease in the long term. Additionally, achieving MRD-negativity and sustained long-term disease control, referred to as “functional” or “operational” cures, may be more likely with the combination of novel agents and autologous stem cell transplant (auto-SCT). This is in contrast with the previous goal of “eradication” cure.
Auto-SCT is considered a crucial component of MM therapy and postulated to have a curative potential based on the graft-versus-myeloma effect.2 To assess the improvements in long-term survival and rates of functional cures attained after a total therapy (TT) approach using induction therapy, auto-SCT, consolidation, and maintenance, in combination with novel agents, Katherine K. Nishimura, Cancer Research and Biostatistics, Seattle, US, and colleagues conducted a retrospective study.1
Table 1. Patient characteristics with significant differences by year of first ASCT1
Auto-SCT, autologous stem cell transplant; GEP, Gene Expressing Profiling; ISS, International Staging System; TC6, translocation cyclin D; TT, total therapy; *p value connotates statistical significance |
|||||||
|
Year of first auto-SCT |
||||||
---|---|---|---|---|---|---|---|
|
All patients |
< 1997 |
1998–2003 |
2004–2008 |
2009–2013 |
≥ 2014 |
p* |
Sample size |
4,329 |
661 |
1,002 |
1,294 |
837 |
535 |
|
Median follow-up time, y |
10.5 |
21.5 |
15.3 |
11.0 |
6.5 |
2.5 |
— |
Age, y |
|
|
|
|
|
|
< 0.0001
|
Median (range) |
58.9 (17.4–84.8) |
53.0 (27.1–77.0) |
57.4 (25.1–84.8) |
59.7 (30.3–84.5) |
61.7 (17.4–82.5) |
63.0 (32.9–79.3) |
|
< 65, % |
72.1 |
90.6 |
77.2 |
70.3 |
63.7 |
57.6 |
|
≥ 65, % |
27.9 |
9.4 |
22.9 |
29.7 |
36.3 |
42.4 |
|
On a TT clinical trial, % |
|
|
|
|
|
|
< 0.0001
|
Yes |
43.0 |
30.9 |
51.6 |
43.1 |
55.3 |
22.2 |
|
No |
57.0 |
69.1 |
48.4 |
56.9 |
44.7 |
77.8 |
|
GEP70, % |
|
|
|
|
|
|
< 0.0001
|
Low risk |
42.5 |
0 |
23.0 |
54.6 |
70.6 |
58.1 |
|
High risk |
9.2 |
0 |
3.3 |
13.1 |
14.8 |
13.3 |
|
No data |
48.3 |
100 |
73.8 |
32.3 |
14.6 |
28.6 |
|
Any chromosomal abnormality, % |
|
|
|
|
|
|
< 0.0001
|
Yes |
37.9 |
68.2 |
62.9 |
64.5 |
52.6 |
53.8 |
|
No |
61.1 |
28.6 |
36.0 |
34.9 |
47.1 |
46.0 |
|
No data |
1.0 |
3.2 |
1.1 |
0.7 |
0.4 |
0.2 |
|
Tandem transplant, % |
|
|
|
|
|
|
< 0.0001
|
No |
38.1 |
37.4 |
39.1 |
25.9 |
46.1 |
53.8 |
|
Yes |
61.9 |
62.6 |
60.9 |
74.1 |
53.9 |
46.2 |
|
Race/ethnicity, % |
|
|
|
|
|
|
|
White |
86.0 |
92.3 |
98.2 |
85.6 |
81.2 |
80.6 |
< 0.0001
|
African American |
10.2 |
6.1 |
8.1 |
9.9 |
13.8 |
13.8 |
|
Other |
3.8 |
1.7 |
2.7 |
4.5 |
4.8 |
5.6 |
|
TC6 classification |
|
|
|
|
|
|
< 0.0001
|
CCND1 |
10.0 |
0.0 |
3.3 |
13.4 |
17.9 |
14.2 |
|
CCND3 |
1.0 |
0.0 |
0.5 |
0.9 |
2.3 |
1.3 |
|
D1 |
15.0 |
0.0 |
5.6 |
19.7 |
26.4 |
22.1 |
|
D2 |
14.0 |
0.0 |
4.8 |
19.0 |
22.2 |
22.2 |
|
MAF/MAFB |
3.6 |
0.0 |
0.6 |
5.3 |
5.3 |
7.1 |
|
MMSET |
6.3 |
0.0 |
2.9 |
8.7 |
11.0 |
7.7 |
|
No data |
50.0 |
100 |
82.3 |
32.8 |
14.2 |
25.4 |
|
ISS |
|
|
|
|
|
|
< 0.0001
|
I |
42.6 |
43.9 |
54.1 |
40.4 |
32.3 |
39.0 |
|
II |
33.6 |
28.3 |
26.1 |
37.6 |
40.6 |
34.1 |
|
III |
18.3 |
11.0 |
18.6 |
20.3 |
24.4 |
12.2 |
|
No data |
5.5 |
16.8 |
1.3 |
1.6 |
1.6 |
14.7 |
With each successive time period and the integration of novel therapies, patients with MM that were treated with auto-SCT had an improved long-term survival. However, the elderly population (≥ 65 years old) and patients with high-risk disease still had a poor prognosis and survival.
Table 2. Cox proportional hazard model with covariates of statistical significance1
CI, confidence interval; HR, hazard ratio; TT, total therapy |
|||
Covariate |
HR |
95% CI |
p value |
Year of transplant < 1997 1998–2003 2004–2008 2009–2013 ≥ 2014 |
Reference 0.08 0.69 0.68 0.35 |
— 0.72–0.89 0.62–0.77 0.59–0.78 0.27–0.45 |
— < 0.001 < 0.001 < 0.001 < 0.001 |
Age, years < 65 ≥ 65 |
(reference) 1.65 |
— 1.51–1.81 |
— < 0.001 |
Clinical trial Non-TT TT participant |
(reference) 0.59 |
— 0.54–0.64 |
— < 0.001 |
In summary, this study was able to cumulate substantial patient data and enabled comparisons of different treatment eras to assess the efficacy of auto-SCT in combination with novel agents used during induction, consolidation, and maintenance. The results demonstrate the combination of auto-SCT and novel agents were able to prolong OS and PFS whilst decreasing early mortality. It also highlights that high-risk patients did not significantly benefit in survival outcome. However, further periodic follow-up is warranted to be able to adequately test for improvements in longer-term survival, particularly in the > 2014 group that were assessed.
The introduction of thalidomide and bortezomib into standard clinical treatment significantly improved the outcomes of patients who receive auto-SCT. However, following an institute-wide shift from lenalidomide to thalidomide as standard therapy in the subsequent years, the authors were not able to replicate these findings and deduce a significant improvement. In more recent time periods, OS and PFS were superior for low-risk and older patients.
Although younger patients have better outcomes compared to older patients, both the Kaplan-Meier and Cox models show a promising improvement in outcomes of older patients in each consecutive year, with an increase in the 5-year survival rate from 35% to 63% and a reduction in mortality. This may be attributed to an earlier initiation of treatment based on improved detection or a more aggressive disease management approach.
The authors reported a high rate of early mortality and worse statistical cure fraction in patients with high-risk GEP70. Therefore, future research that focuses on both the short-term and long-term survival in patients with high-risk disease is warranted.
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