Prognostic significance of CD56 expression in patients with multiple myeloma: a meta-analysis

Figures & data

Figure 1. Flow chart depicting the selection process of included studies.

Table 1. Characteristics of the 14 included studies.

Study	Region	Patients	Age	CD56 Expression	Therapy	Detection method	Survival analysis	Cut-off value	Endpoint	NOS
Miyazaki et al. (2015) [26]	Japan	215	65 (29–88)	155	NR	FCM	UVA	50%	OS	7
Kraj et al. (2008) [24]	England	204	63 (32–89)	135	VAD (NR) MP (NR) ASCT (6)	FCM	UVA	20%	OS	7
Sahara et al. (2002) [17]	Japan	70	68 (41–91)	55	MP (21) VMMD (19) VMMD-IFN (24) Others (6)	FCM	UVA	NR	OS	7
Okura et al. (2020) [22]	Japan	49	72 (36–88)	36	Bortezomib-based or Lenalidomide-based (49)	FCM	UVA	20%	OS	7
Pan et al. (2015) [18]	China	50	63 (41–79)	37	Thalidomide + Bortezomib-based (15) Thalidomide + VAD-based (29) Thalidomide + Others (6)	FCM	MVA	NR	OS	8
Wang et al. (2018) [29]	Japan	80	62 (24–80)	56	Bortezomib and thalidomide (80)	FCM	UVA	20%	OS、PFS	8
Shi et al. (2019) [20]	China	108	65 (41–85)	70	Bortezomib-based (108)	FCM	MVA	20%	OS	8
Ngo et al. (2009) [5]	England	93	59 (34–72)	68	Conventional chemotherapy + ASCT (93)	IHC	MVA	10%	OS	7
Hundemer et al. (2007) [25]	Germany	99	57 (37–72)	71	High-dose chemotherapy (99)	FCM	MVA	NR	PFS	7
Chang et al . (2006) [23]	Canada	107	54 (32–71)	76	Melphalan-based high-dose chemotherapy + ASCT (107)	IHC	UVA	50%	OS、PFS	7
Iriyama et al. (2017) [28]	Japan	46	65 (36–83)	33	Bortezomib-based (46)	FCM	UVA	20%	OS	7
Skerget et al. (2018) [21]	Slovenia	55	NR	39	Bortezomib-based (55)	FCM	UVA	NR	PFS	8
QIU et al. (2016) [19]	China	84	60 (25–90)	48	Bortezomib-based or Lenalidomide-based (84)	FCM	UVA	20%	OS、PFS	7
FAN et al. (2016) [27]	China	105	NR	80	Bortezomib-based (105)	FCM	UVA	NR	OS、PFS	7

NR: not reported; ASCT: autologous stem cell transplantation; VAD: vincristine, adriamycin and dexamethasone; MP: melphalan and prednisone; VMMD: vincristine, ranimustine, dexamethasone and melphalan; IFN: interferon; OS: overall survival; PFS: progression-free survival; IHC: immunohistochemistry; FCM: flow cytometry; NOS: Newcastle–Ottawa Scale.

Figure 2. Forest plots of HR and 95%CI for CD56 and OS in patients with MM.

Table 2. Results of subgroup analysis for OS and PFS.

Factors	Studies	Patients	Test for association		Test for heterogeneity
			Pooled HR (95% CI)	P-value	I^2 (%)	P-value
Overall survival (OS)	12	1211	1.83 (1.29–2.60)	0.001	70.5%	0.000
Treatment Novel drugs ASCT
	6	472	2.03 (1.56–2.65)	0.000	44.9%	0.106
	2	200	1.19 (0.64–2.21)	0.583	0.0%	0.774
Analytic method Univariate Multivariate
	9	960	1.77 (1.18–2.65)	0.006	74.4%	0.000
	3	251	2.14 (0.96–4.76)	0.061	58.4%	0.090
Detection method FCM IHC
	10	1011	1.99 (1.33–2.96)	0.001	75.4%	0.000
	2	200	1.19 (0.64–2.21)	0.583	0.0%	0.774
Study region Asia Non-Asia
	9	807	2.20 (1.40–3.45)	0.001	74.6%	0.000
	3	404	1.11 (0.81–1.52)	0.526	0.0%	0.927
Cut-off value 20%
	6	571	1.83 (1.18–2.85)	0 .007	69.6%	0.006
Progress-free survival (PFS)	6	530	1.57 (1.27–1.95)	0.000	31.9%	0.196
Treatment Novel drugs
	3	244	1.91 (1.44–2.54)	0.000	0.0%	0.849
Analytic method Univariate
	5	431	1.65 (1.32–2.06)	0.000	19.3%	0.292
Detection method FCM
	5	423	1.59 (1.24–2.04)	0.000	45.3%	0.120
Study region Asia Non-Asia
	3	269	1.54 (0.97–2.44)	0.067	56.5%	0.100
	3	261	1.49 (1.08–2.05)	0.016	21.2%	0.281
Cut-off value
20%	2	164	1.41 (0.62–3.20)	0.413	78.2%	0.032

CI: confidence interval; HR = hazard ratio; ASCT: autologous stem cell transplantation; IHC: immunohistochemistry; FCM: flow cytometry.

Figure 3. Forest plots for subgroup analysis of treatment regimen.

Figure 4. Forest plots of HR and 95%CI for CD56 and PFS in patients with MM.

Table 3. The association between CD56 and clinicopathological characteristics of MM.

Clinicopathological parameters	Studies	Patients	Pooled OR (95% CI)	P value	Heterogeneity
					I^2	P value	Model
Age (≥60 vs. <60)	2	158	1.02 (0.51–2.05)	0.959	0.0%	0.761	Fixed
Sex (Male vs. Female)	8	937	0.87 (0.66–1.15)	0.335	18.1%	0.287	Fixed
Stage (I–II vs. III)	7	722	1.06 (0.76–1.48)	0.718	0.0%	0.712	Fixed
Serum calcium (>2.75 mmol/L vs. ≤2.75 mmol/L)	4	432	0.57 (0.31–1.06)	0.073	0.0%	0.771	Fixed
Scr (>176.8 μmol/L vs. ≤176.8 μmol/L)	3	228	1.79 (0.64–5.00)	0.264	57.7%	0.094	Random
Beta2 microglobulin (>5.5 mg/dL vs. ≤5.5 mg/dL)	3	228	1.48 (0.40–5.57)	0.559	76.6%	0.014	Random
Bone lesions (YES vs. NO)	6	638	0.50 (0.34–0.74)	0.001	15.4%	0.315	Fixed
Presence of extramedullary disease (YES vs. NO)	3	381	1.46 (0.22–9.71)	0.698	84.0%	0.002	Random
Bone marrow plasma cells (≥30% vs.<30%)	2	158	0.57 (0.16–1.97)	0. 374	60.6%	0.111	Random

95% CI: 95% confidence interval; Scr: Serum creatinine; OR: odds ratio.

Figure 5. Sensitivity analysis on the relationship of CD56 and OS.

Figure 6. Begg’s funnel plot for publication bias analysis.

Miyazaki K, Suzuki K. Clinical and laboratory significance of CD56 (a neural cell adhesion molecule) positivity in multiple myeloma and AL amyloidosis. Int J Myelom. 2015;50(3):30–35.

 Google Scholar

Kraj M, Sokołowska U, Kopeć-Szlezak J, et al. Clinicopathological correlates of plasma cell CD56 (NCAM) expression in multiple myeloma. Leuk Lymphoma. 2008;49(2):298–305.

 PubMed Web of Science ®Google Scholar

Sahara N, Takeshita A, Shigeno K, et al. Clinicopathological and prognostic characteristics of CD56-negative multiple myeloma. Br J Haematol. 2002;117(4):882–885.

 PubMed Web of Science ®Google Scholar

Okura M, Ida N, Yamauchi T. The clinical significance of CD49e and CD56 for multiple myeloma in the novel agents era. Med Oncol. 2020;37(11):103.

 PubMed Web of Science ®Google Scholar

Pan Y, Wang H, Tao Q, et al. Absence of both CD56 and CD117 expression on malignant plasma cells is related with a poor prognosis in patients with newly diagnosed multiple myeloma. Leuk Res. 2016;40:77–82.

 PubMed Web of Science ®Google Scholar

Wang H, Zhou X, Zhu JW, et al. Association of CD117 and HLA-DR expression with shorter overall survival and/or progression-free survival in patients with multiple myeloma treated with bortezomib and thalidomide combination treatment without transplantation. Oncol Lett. 2018;16(5):5655–5666.

 PubMed Web of Science ®Google Scholar

Shi J, Sun K, Zhu ZM, et al. Prognostic significance of CD56 and CD117 expression in patients with newly diagnosed multiple myeloma treated with bortezomib-based first-line therapy. Zhonghua Xue Ye Xue Za Zhi. 2019;40(8):693–696.

 PubMedGoogle Scholar

Ngo NT, Brodie C, Giles C, et al. The significance of tumour cell immunophenotype in myeloma and its impact on clinical outcome. J Clin Pathol. 2009;62(11):1009–1015.

 PubMed Web of Science ®Google Scholar

Hundemer M, Klein U, Hose D, et al. Lack of CD56 expression on myeloma cells is not a marker for poor prognosis in patients treated by high-dose chemotherapy and is associated with translocation t(11;14). Bone Marrow Transpl. 2007;40(11):1033–1037.

 PubMed Web of Science ®Google Scholar

Chang H, Samiee S, Yi QL. Prognostic relevance of CD56 expression in multiple myeloma: a study including 107 cases treated with high-dose melphalan-based chemotherapy and autologous stem cell transplant. Leuk Lymphoma. 2006;47(1):43–47.

 PubMed Web of Science ®Google Scholar

Iriyama N, Miura K, Hatta Y, et al. Clinical effect of immunophenotyping on the prognosis of multiple myeloma patients treated with bortezomib. Oncol Lett. 2017;13(5):3803–3808.

 PubMed Web of Science ®Google Scholar

Skerget M, Skopec B, Zadnik V, et al. CD56 expression is an important prognostic factor in multiple myeloma even with Bortezomib induction. Acta Haematol. 2018;139(4):228–234.

 PubMed Web of Science ®Google Scholar

Qiu Q, Zhu P, Wang MJ, et al. Expression of CD56 and CD19 in patients with newly diagnosed multiple myeloma and their relationship with karyotypes and prognosis. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2016;24(4):1071–1078.

 PubMedGoogle Scholar

Fan QY, Wang Y, Mi JQ. Study on the efficacy of bortezomib on CD56 negative multiple myeloma patients. J Shanghai Jiaotong Univ. 2016;36(10):1445–1450.

 Google Scholar