Cytomegalovirus and Epstein-Barr virus infection during daratumumab treatment in patients with multiple myeloma

Figures & data

Table 1. Baseline characteristics of patients with multiple myeloma.

Characteristics	Patients treated with classical regimens without daratumumab (n = 78)	Patients treated with daratumumab-containing regimens (n = 53)	p value
Age	62 (Range: 43–76)	63 (Range: 40–87)	0.428
Sex	Male = 51, female = 27	Male = 28, female = 25	0.149
IgG	39	19	0.081
IgA	20	14
IgD	2	7
Light chain	17	13
Κ	39	26	0.916
Λ	39	27
RRMM	6	34	<0.001
ISS stage I	19	8	0.114
ISS stage II	29	18
ISS stage III	30	27
EGFR (ml/min)	81.94 (6.70–125.17)	70.50 (2.97–128.70)	0.155
Lines of therapy	1 (1–3)	2 (1–5)	<0.001
Albumin (g/L)	35.40 (21.30–49.00)	36.40 (23.00–48.10)	0.320
LDH (U/L)	166.00 (62.00–577.00)	201.00 (35.10–1346.00)	0.008
β2-MG (mg/L)	3.98 (1.44–44.54)	4.99 (1.52–26.68)	0.136
FLC ratio	30.14 (2.33–2488.89)	26.14 (1.11–1883.33)	0.701
Serum M protein (g/L)	16.70 (0.00–60.80)	7.05 (0.00–127.50)	0.086
1q21 gain	31	26	0.401
13q14 del	16	11	0.887
tp53 del	2	5	0.127
t (4; 14)	10	8	0.810
Combined agents
Pis	78	28	<0.001
IMiDs	51	23	0.013
Chemotherapeutic agents	22	12	0.476

Table 2. Baseline characteristics of patients treated with daratumumab-containing regimens.

Characteristics	Patients with EBV/CMV infection (n = 13)	Patients without EBV/CMV infection (n = 40)	P value
Age	67 (Range: 46–85)	63 (Range: 40–87)	0.534
Sex	Male = 6, female = 7	Male = 22, female = 18	0.579
IgG	3	16	0.533
IgA	4	10
IgD	3	4
Light chain	3	10
κ	6	20	0.810
λ	7	20
RRMM	8	26	0.821
ISS stage I	1	7	0.322
ISS stage II	4	14
ISS stage III	8	19
EGFR (ml/min)	89.00 (2.97–108.40)	63.90 (7.00–128.70)	0.207
Lines of therapy	2 (1–4)	2 (1–5)	0.264
Prior treatments
Bortezomib	8	30	0.349
Lenalidomide	7	21	0.933
Chemotherapeutic agents	4	19	0.349
ACST	2	7	1.000
Albumin (g/L)	29.40 (23.00–37.50)	39.05 (24.00–48.10)	<0.001
LDH (U/L)	214.00 (115.00-787.00)	198.00 (35.10–1346.00)	0.627
β2-MG (mg/L)	4.22 (2.56–25.02)	5.00 (1.52–26.68)	0.882
FLC ratio	24.16 (3.00–200.00)	27.07 (1.11–1883.33)	0.974
Serum M protein (g/L)	9.40 (0.00–21.00)	5.10 (0.00–127.50)	0.699
High-risk cytogenetic changes	9	20	0.282
1q21 gain	8	18	0.480
13q14 del	4	7	0.425
tp53 del	2	3	0.586
t (4; 14)	3	5	0.391
Hemoglobin (g/L)	90.00 (54.00–126.00)	84.50 (47.00–152.00)	0.457
ANC (10^9/L)	3.90 (0.78–8.40)	3.07 (0.83–7.30)	0.358
Lymphocytes (10^9/L)	0.68 (0.10–1.15)	1.01 (0.42–3.53)	0.002
Platelets (10^9/L)	126.00 (25.00–305.00)	133.00 (12.00–330.00)	0.992
Combined agents
Bortezomib	8	20	0.469
Lenalidomide	1	5	1.000
Pomalidomide	5	12	0.570
Chemotherapeutic agents	2	10	0.707

Table 3. Clinical characteristics of patients with EBV and/or CMV infections during daratumumab-containing regimens.

ID	Sex	Age	Isotype	DS stage	ISS stage	FISH	Scr (μmol/L)	ASCT (Time from ASCT to infection)	Prior treatment	Response evaluation	Current regimens
1	M	49	IgG, λ	IIA	II	t (4; 14), 1q21 gain	63	Yes (25 months)	VCD, IRD	Relapse	Dara + Selinexor + D
2	F	67	λ	IIIA	II	1q21 gain, 13q14 del, tp53 del	58	No	No	/	Dara + VD
3	M	85	IgG, κ	IIIA	III	1q21 gain, 13q14 del	77	No	VRD, IRD	PD	Dara + VD
4	F	69	IgA, κ	IIIA	II	Negative	48	No	No	/	Dara + VMP
5	F	68	IgA, λ	IIA	III	1q21 gain, tp53 del	64	No	VRD	Relapse	Dara + Pom + D
6	M	68	IgD, λ	IIIB	III	1q21 gain, t (11; 14)	1167	No	No	/	Dara + VD
7	F	63	IgD, λ	IB	III	1q21 gain, t (11; 14)	1057	No	No	/	Dara + VD
8	F	58	IgA, λ	IIIA	III	t (4; 14), 1q21 gain, 13q14 del	44	No	VCD, VRD	PD	Dara + Pom + D
9	F	46	IgA, κ	IIIA	III	Negative	58	No	VRD	PD	Dara + VRD
10	M	78	κ	IIA	I	Negative	80	No	VRD	PD	Dara + Pom + VD
11	F	73	κ	IIIA	II	Negative	57	No	IRD, VCD, VTD, DT-PACE	PD	Dara + Pom + D
12	M	56	IgG, κ	IIIA	III	t (4; 14), 13q14 del	57	Yes (27 months)	VAD	Relapse	Dara + Pom + D
13	M	59	IgD, λ	IIIB	III	1q21 gain	640	No	No	/	Dara + VCD

VCD: bortezomib, cyclophosphamide, dexamethasone; IRD: ixazomib, lenalidomide, dexamethasone; VRD: bortezomib, lenalidomide, dexamethasone; VMP: bortezomib, melphalan, prednisone; Pom: pomalidomide; DT-PACE: dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide; VAD: bortezomib, doxorubicin, dexamethasone.

Table 4. Characteristics, treatments, and outcomes of the EBV/CMV infections during daratumumab treatment.

ID	Types of viruses	Time of infection from the first Dara infusion	DNA loads copies/ml	Treatments	Outcomes	Viremia period /days
1	EBV	Day 20	5.62 × 10^2	IVIG: 400 mg/kg qd 5 days; 10 g biw maintenance until 1 week after DNA is undetectable.	undetectable viremia on day 95.	75
2	EBV	Day 39	1.58 × 10^3		undetectable viremia on day 69.	30
3	EBV	Day 115	1.04 × 10^4		undetectable viremia on day 253.	138
4	EBV + CMV	Day 18	EBV: 1.52 × 10^3 CMV: 4.36 × 10^3	IVIG: 400 mg/kg qd 5 days; 10 g biw maintenance until 1 week after DNA is undetectable.	undetectable viremia on day 150.	132
5	CMV	Day 24	1.12 × 10^4	Ganciclovir: 300 mg q12h ivgtt 2 weeks; 500 mg tid po until CMV-DNA turned negative on 2 consecutive measurements. IVIG: 400 mg/kg qd 5 days; 10 g biw maintenance until 1 week after DNA is undetectable.	undetectable viremia on day 36.	12
6	CMV	Day 14	1.37 × 10^4		undetectable viremia on day 34.	20
7	EBV + CMV	Day 50	EBV: 5.37 × 10^3 CMV: 4.34 × 10^3	Not treated with IVIG or ganciclovir	undetectable viremia on day 230.	180
8	EBV	Day 8	9.63 × 10^3	IVIG: 400 mg/kg qd 5 days; 10 g biw maintenance until 1 week after DNA is undetectable.	undetectable viremia on day 24.	16
9	CMV	Day 50	8.80 × 10^3	Ganciclovir: 300 mg q12h ivgtt 2 weeks; 500 mg tid po until CMV-DNA turned negative on 2 consecutive measurements. IVIG: 400 mg/kg qd 5 days; 10 g biw maintenance until 1 week after DNA is undetectable.	undetectable viremia on day 73.	23
10	CMV	Day 39	1.20 × 10^3		undetectable viremia on day 82.	43
11	CMV	Day 82	4.30 × 10^3		undetectable viremia on day 116.	34
12	CMV	Day 27	1.47 × 10^3		undetectable viremia on day 95.	68
13	CMV	Day 16	7.50 × 10^3		undetectable viremia on day 35.	19

Figure 1. Longitudinal monitoring of lymphocytes and neutrophils in MM patients treated with classical regimens or Dara-containing regimens. A) B cell depletion, NK cell depletion and T cell expansion (particularly CD8 + T cell) were observed in MM patients treated with Dara-containing regimens, which were not observed in MM patients treated with classical regimens. B) Comparison of lymphocyte subpopulations at different time points in the course of daratumumab treatment between MM patients with infections and MM patients without infections. C) The levels of ANC in MM patients in the two groups were comparable in the process of Dara treatments.

Data availability statement

The data of this study are available from the corresponding author upon reasonable request.