Effect of ECOG performance status on real-life outcomes of patients with relapsed/refractory multiple myeloma treated with daratumumab

The Eastern Cooperative Oncology Group performance status (ECOG PS) is widely used as an inclusion criterion in oncologic clinical trials. Eligibility is usually limited to patients with an ECOG PS between 0–2, on a scale of 0–5. In the real world, therapies might be used for patients with more advanced disease (a higher ECOG PS) and a higher dependency on others for daily activities, and this population is often excluded from registry trials.¹ With this in mind, and added to the lack of real-life data from patients with relapsed/refractory multiple myeloma(R/R MM), Gabriel Afram et al. retrospectively analyzed the outcomes of patients treated with single-agent daratumumab, with a especial focus on ECOG PS before starting the treatment. The results were recently published in the European Journal of Haematology.²

Daratumumab, an anti-CD38 monoclonal antibody, was approved for use as a single-agent by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2016 and 2017, respectively, for patients with R/R MM. The MM Hub monthly theme is currently “Novel monoclonal antibodies in multiple myeloma”. Read the introductory review article here.

Study design

This was a retrospective study conducted at the Karolinska University Hospital, SE, where 156 patients with MM were treated with single-agent daratumumab after at least one prior line of therapy. The median patient age was 71 (62–75) years, and after a median of 2.9 (1–5) prior lines of treatment, 87% of patients were refractory to at least one therapy, with 52% being triple refractory to proteasome inhibitors (PIs) and/or immunomodulatory drugs (IMiDs®) and/or alkylating agents. Despite being a heavily pre-treated population, at baseline, 7% and 61% of patients had an ECOG PS of 0 and 1, respectively; 20% had an ECOG PS of 2, and 3% had an ECOG PS of 3.

Results

 Patient survival outcomes were the primary objective of the study. The authors analyzed median progression-free survival (PFS), and overall survival (OS) results according to ECOG PS and refractory status. Eventually, almost all patients (N = 105) relapsed while on daratumumab treatment, but 56% achieved at least a partial response (≥ PR), regardless of the refractory status (Table 1).

Table 1. Responses to daratumumab by refractory status

PR, partial response; VGPR, very good partial response
Refractory status	< PR, n (%)	PR, n (%)	≥ VGPR, n (%)
Non (n = 20)	9 (45)	2 (10)	9 (45)
Single/double (n = 54)	18 (33)	10 (19)	26 (48)
Triple (n = 82)	42 (51)	12 (15)	28 (34)

Factors found to be associated with an inferior PFS and OS in univariate analysis were (Tables 2 and 3):

• Higher ECOG status (0 vs 1 vs 2 vs 3), p < 0.001
• Higher refractory status (non vs single/double vs triple), p < 0.001
• Increasing lines of treatment prior to daratumumab (1 vs 2 vs 3 vs ≥ 4): p < 0.001
• Additionally, estimated glomerular filtration rate (eGFR) was significantly associated with OS (p = 0.003) but not PFS (p = 0.375)
• Cytogenetic risk did not significantly impact PFS or OS

Table 2. Outcomes by refractory status

NR, not reached; PFS, progression-free survival; OS, overall survival
Refractory status	Median PFS, months	Median OS, months	36-months OS, %
Non	NR	NR	58
Single/double	11.4	NR	73
Triple	7.2	20	34

 Table 3. Outcomes by ECOG PS

NR, not reached; PFS, progression-free survival; OS, overall survival
ECOG PS score	Median PFS, months	Median OS, months	36-month OS, %
0	18.5	NR	100
1	10.2	NR	53
2	3.7	13	26
3	1.3	2	0

Multivariate analysis

In the multivariate analysis, when comparing outcomes by ECOG PS ≥ 2 vs ECOG PS < 2, differences in PFS and OS were statistically significant with patients with an ECOG PS score of  ≥ 2 being at a higher risk of earlier progression (Hazard ratio [HR] 2.12, 95% CI, 1.26–3.57, p = 0.005) and death (HR 2.71, 95% CI, 1.37–5.36, p = 0.004).

Response to daratumumab (≤ PR vs ≥ VGPR) was also significantly associated with an increased risk of earlier progression (HR 0.27, 95% CI, 0.16–0.44, p < 0.001) and death (HR 0.43, 95% CI, 0.22–0.83, p = 0.011).

Conclusions

These results confirm the efficacy and safety of single agent daratumumab in patients with R/R MM, regardless of their refractory status (to PIs and/or IMiDs and/or alkylating agents). Although outcomes were poorer, the authors consider daratumumab as a viable option for patients with higher ECOG PS, who are usually excluded from clinical trials.

The impact of ECOG PS on OS in patients with R/R MM could be more critical than previously reported and needs to be addressed in additional real-life studies, which should include patients in various stages of the disease.