Bortezomib in patients with renal impairment

Figures & data

Table 1. Patients’ characteristics

	eGFR (ml/minute)
	⩾90	60–89	30–59	<30	⩾60	<60	Total
No. of patients (% of total)	17 (30·4)	15 (26·9)	10 (17·9)	14 (25)	32 (57·3)	24 (42·9)	56 (100)
Male (%)	11 (64·7)	6 (40·0)	6 (60·0)	10 (71·4)	17 (53·1)	16 (66·7)	33 (58·9)
Age (mean±SEM) (years)	50·65±2·53	58·00±2·04	62·30±2·30	55·07±3·30	54·09±1·75	58·08±2·24	55·80±1·40
Myeloma type (%)
IgG	52·9	50·0	30·0	35·7	51·6	33·3	43·6
IgA	35·3	21·4	30·0	14·3	29·0	20·8	25·5
LC	11·8	28·6	40·0	50·0	19·4	45·8	30·9
Serum creatinine
Mean±SEM (mg/dl)	0·68±0·05	0·95±0·05	1·63±0·12	3·63±0·24	0·82±0·04	2·79±0·25	1·75±0·18
>2 mg/dl (%)	0	0	10·0	100	0	62·5	29·4
Range of creatinine clearance (ml/minute)	97–62	64–9	32–59	13–29	64–162	13–59	13–162
Beta2-microglobuline
Median (ng/ml)	3301	3600	10 263	8407	3494	10 093	5600
Range	1952–7800	1488–14 300	2647–20 000	5770–20 000	1488–14 300	2647–20 000	1488–20 000
>4000 ng/ml (%)	16·7	36·4	87·5	100	26·1	95·0	58·1
Median calcium (range) (mg/dl)	8·80 (7·9–12·1)	8·80 (7·7–11·9)	8·90 (7·5–9·7)	9·10 (6·7–10·3)	8·80 (7·7–12·1)	8·95 (6·7–10·3)	8·9 (6·7–12·1)
Median hemoglobin (range) (g/dl)	11·10 (4·2–14·6)	10·80 (5·8–13·6)	9·05 (7·3–15·3)	8·70 (6·5–11·6)	11·10 (4·2–14·6)	8·70 (6·5–15·3)	9·5 (4·2–15·3)
Platelet count (mean±SEM) (10^9/l)	231·24±22·41	196·23±24·15	213·85±38·12	231·00±38·12	216·07±16·49	224·86±29·70	218·86±14·50
Median no. of prior therapies (range)	2 (1–3)	1 (1–2)	1 (1–4)	2 (1–3)	1 (1–3)	2 (1–4)	2 (1–4)
Median no. of bortezomib cycles (range)	6 (2–10)	4 (2–12)	5·5 (2–10)	4 (1–13)	5 (2–12)	5 (1–13)	5 (1–13)
Bortezomib use in combination (%)	64·7	35·7	70·0	50·0	51·6	58·3	54·5
ISS stage (%)
I	41·7	25·0	0·0	0·0	33·3	0·0	17·4
II	50·0	50·0	20·0	0·0	50·0	9·1	30·4
III	8·3	25·0	80·0	100	16·7	90·9	52·2

Note: eGFR, estimated glomerular filtration rate; SEM, standard error of mean; LC, light chain; ISS, the International Staging System.

Table 2. Efficacy data

	eGFR (ml/minute)
	⩾90	60–89	30–59	<30	⩾60	<60	Total	P1, P2
Response rates
No. of patients (% of total)	16 (31·4)	14 (27·4)	10 (19·6)	11 (21·6)	30 (58·8)	21 (41·2)	51 (100)
Overall response (%)	11 (68·8)	12 (85·7)	8 (80·0)	8 (72·7)	23 (76·7)	16 (76·2)	39 (76·5)	0·7
								1·0
CR+VGPR (%)	7 (43·8)	11 (78·6)	8 (80·0)	7 (63·6)	18 (60·0)	15 (66·4)	33 (64·7)	0·2
								0·2
CR (%)	6 (37·5)	2 (14·3)	7 (70·0)	5 (45·5)	8 (26·7)	12 (52·1)	20 (39·2)
VGPR (%)	1 (6·3)	9 (64·3)	1 (10·0)	2 (18·2)	10 (33·3)	3 (14·3)	13 (25·5)
PR (%)	4 (25·0)	1 (7·1)	0	1 (9·1)	5 (16·7)	1 (4·8)	6 (11·8)
SD (%)	5 (31·3)	1 (7·1)	1 (10·0)	1 (9·1)	6 (20·0)	2 (9·5)	8 (15·7)
PD (%)	0	1 (7·1)	1 (10·0)	2 (18·2)	1 (3·3)	3 (14·3)	4 (7·8)	0·008
								0·06
Overall survival rates
No. of patients (% of total)	17 (30·4)	15 (26·8)	10 (17·9)	14 (25·0)	32 (57·2)	24 (42·9)	56 (100)
Median (months)	Not reached	Not reached	31	20	Not reached	31	Not reached	0·1
								0·1
95% CI (lower and upper bound)	NE	NE	22·99–39·01	11·54–28·46	NE	14·40–44·60	NE

Note: eGFR, estimated glomerular filtration rate; CR, complete response; VGPR, very good partial response; PR, partial response; SD, stable disease; PD, progressive disease; 95% CI, 95% confidential interval. P₁, level of statistical significance for difference between groups of ⩾90, 60–89, 30–59, and <30 ml/minute; P₂, level of statistical significance for difference between groups of ⩾60 and <60 ml/minute; NE, not estimable.

Figure 1. Kaplan–Meier curves for patients with normal renal functions and renal impairment. eGFR, estimated glomerular filtration rate; OS, overall survival; HR, hazard ratio.

Figure 2. Kaplan–Meier curves for patients with eGFRs of ⩾90, 60–89, 30–59, and <30 ml/minute. eGFR, estimated glomerular filtration rate; OS, overall survival.

Table 3. Adverse events

Adverse events (AEs)	eGFR (ml/minute)
	⩾90	60–89	30–59	<30	⩾60	<60	Total	P1, P2
	(n = 17)	(n = 15)	(n = 10)	(n = 14)	(n = 32)	(n = 24)	(n = 56)
All grades	9	14	8	20	23	28	51
AE rate (per patient)	0·53	0·93	0·80	1·43	0·72	1·17	0·91	0·04
95% CI (lower–upper bound)	0·21–0·85	0·44–1·42	0·24–1·36	0·89–1·97	0·44–1·00	0·78–1·55	0·68–1·14	0·06
Presyncope (% pts)	0	0	1 (10)	0	0	1 (4·2)	1 (1·8)
Neuropathy (% pts)	5 (29·4)	6 (40·0)	2 (20·0)	6 (42·9)	11 (34·4)	8 (33·3)	19 (33·9)
Hemorrhagic conjunctivitis (% pts)	1 (5·9)	0	0	0	1 (3·1)	0	1 (1·8)	0·2
								0·2
Dizziness (% pts)	1 (5·9)	0	0	0	1 (3·1)	0	1 (1·8)
Rash (% pts)	0	1 (6·7)	0	0	1 (3·1)	0	1 (1·8)
Thrombocytopenia (% pts)	0	3 (20·0)	5 (50·0)	5 (35·7)	3 (9·4)	10 (41·7)	13 (23·2)
Acute renal failure (% pts)	0	0	0	2 (14·3)	0	2 (8·3)	2 (3·6)	0·08
Zona (% pts)	2 (11·8)	1 (6·7)	0	0	3 (9·4)	0	3 (5·4)	0·04
Anemia (% pts)	0	2 (13·3)	0	1 (7·1)	2 (6·3)	1 (4·2)	3 (5·4)	0·04
Diarrhea (% pts)	0	1 (6·7)	0	6 (42·9)	1 (3·1)	6 (25·0)	7 (12·5)	0·04
Grade III–IV	1	5	2	10	6	12	18
AE rate (per patient)	0·06	0·33	0·20	0·71	0·19	0·50	0·32	0·01
95% CI (lower–upper bound)	0–0·18	0–0·68	0–0·50	0·29–1·13	0·02–0·36	0·22–0·78	0·17–0·48	0·03
Neuropathy (% pts)	1 (5·9)	1 (6·7)	0	2 (14·3)	2 (6·3)	2 (8·3)	4 (7·1)	0·6
								1·0
Thrombocytopenia (% pts)	0	2 (13·3)	2 (20·0)	2 (14·3)	2 (6·3)	4 (16·7)	6 (10·7)	0·4
								0·4
Diarrhea (% pts)	0	1 (6·7)	0	6 (42·9)	1 (3·1)	6 (25·0)	7 (12·5)	0·001
								0·04
Anemia (% pts)	0	1 (6·7)	0	0	1 (3·1)	0	1 (1·8)	0·4
								1·0
AEs leading to dose modification	1	0	5	4	1	9	10
AE rate (per patient)	0·06		0·50	0·29	0·03	0·38	0·18	0·03
95% CI (lower–upper bound)	0–0·18	0	0–1·00	0–0·64	0–0·10	0·10–0·65	0·05–0·30	0·006
Presyncope (% pts)	0	0	1 (10·0)	0	0	1 (4·2)	1 (1·8)
Neuropathy (% pts)	1 (5·9)	0	1 (10·0)	0	1 (3·1)	1 (4·2)	2 (3·6)	0·06
Diarrhea (% pts)	0	0	0	2 (14·3)	0	2 (8·3)	2 (3·6)	0·06
Thrombocytopenia (% pts)	0	0	3 (30·0)	2 (14·3)	0	5 (20·8)	5 (8·9)	0·08
								0·03
AEs leading to treatment discontinuation	0	0	1	4	0	5	5
AE rate (per patient)			0·10	0·29		0·21	0·09	0·08
95% CI (lower–upper bound)	0	0	0–0·33	0–0·64	0	0–0·42	0–0·18	0·006
Presyncope (% pts)	0	0	1 (10·0)	0	0	1 (4·2)	1 (1·8)
Neuropathy (% pts)	0	0	0	1 (7·1)	0	1 (4·2)	1 (1·8)	0·1
Diarrhea (% pts)	0	0	0	2 (14·3)	0	2 (8·3)	2 (3·6)	0·1
Acute renal failure (% pts)	0	0	0	1 (7·1)	0	1 (4·2)	1 (1·8)	0·3
								0·2

Note: eGFR, estimated glomerular filtration rate; pts, patients, 95% CI, 95% confidence interval. P₁, level of statistical significance for difference between groups with eGFRs of ⩾90, 60–89, 30–59, and <30 ml/minute; P₂, level of statistical significance for difference between groups with eGFRs of ⩾60 and <60 ml/minute.

Table 4. Patients with diarrhea

Pts	Sex	Age (year)	eGFR (ml/minute)	Type of MM	Stage of MM	Dexa	Time of diarrhea	Duration of diarrhea	Response to bortezomib	Extra AEs	Current status
1	M	50	17	IgA, lambda	III	+	C1D11	4 days	N/A	None	Alive
2	M	48	29	IgG, lambda	III	—	C2D11	2 months	VGPR	N, T	Alive
3	M	50	28	LC, kappa	III	—	C1D4	7 days	CR	ARF	Alive
4	F	49	22	LC, lambda	III	—	C1D4	2 weeks	N/A	ARF	Died
5	F	44	15	LC, kappa	III	—	C5D11	2 weeks	CR	N	Alive
6	F	67	76	LC, kappa	I	+	C1D4	NR	VGPR	None	Died
7	M	71	18	IgG, lambda	III	—	C3D11	1 months	CR	N, T	Alive

Note: Pts, patients; M, male; F, female; eGFR, estimated glomerular filtration rate; MM, multiple myeloma; Dexa, dexamethasone; C, cycle; D, day; NR, not reported; N/A, not applicable; VGPR, very good partial response; CR, complete response; N, neuropathy; T, thrombocytopenia; ARF, acute renal failure; AE, adverse event.