Bortezomib-cyclophosphamide-dexamethasone induction/consolidation and bortezomib maintenance for transplant-eligible newly diagnosed multiple myeloma: phase 2 multicenter trial

Figures & data

Figure 1. Scheme of the protocol. NDMM: newly diagnosed multiple myeloma, BM: bone marrow, VCD: bortezomib-cyclophosphamide-dexamethasone, s.c.: subcutaneous, p.o.: per os, SD: stable disease, G-CSF: granulocyte colony-stimulating factor, ASCT: autologous stem cell transplantation.

Table 1. Characteristics of the patients.

Variable		Number	%
Age, median (range)		58 (42–65)
Sex	Male	25	60
	Female	17	40
PS	0	16	38
	1	18	43
	2	1	2
	3	7	17
WBC (/μL), median (range)		5450 (2120–13160)
HB (g/dL), median (range)		10.6 (4.5–15.4)
PLT (×10^4/μL), median (range)		20.0 (7.8–47.3)
Cre (mg/dL), median (range)		0.83 (0.31–2.47)
Ca (mg/dL), median (range)		9.3 (7.1–13.1)
Alb (g/dL), median (range)		3.5 (1.6–5.2)
β2MG (mg/L), median (range)		2.92 (1.61–7.60)
M protein	IgG	26	62
	IgA	9	21
	BJP	7	17
FLC	Kappa	21	50
	Lambda	21	50
D&S	I	5	12
	II	7	17
	III	30	71
ISS	I	17	40
	II	20	48
	III	5	12
FISH
del(13q)	Positive	4	10
	Negative	37	88
	No data	1	2
t(4;14)	Positive	6	14
	Negative	28	67
	No data	8	19
del(17p)	Positive	7	17
	Negative	28	67
	No data	7	17
t(14;16)	Positive	1	2
	Negative	32	76
	No data	9	21

PS: Performance Status, WBC: white blood cell, HB: hemoglobin, PLT: platelet, Cre: serum creatinine, Ca: serum calcium, Alb: serum albumin, β2MG: serum beta 2 microglobulin, BJP: Bence Jones protein, FLC: Free light chain, D&S: Durie and Salmon, ISS: International Staging System, FISH: fluorescence in situ hybridization.

Table 2. Grade 3/4 adverse events.

	Induction (n = 42)		PBSCH (n = 26)		ASCT (n = 26)		Consolidation (n = 24)		Maintenance (n = 18)
	Grade 3	Grade 4	Grade 3	Grade 4	Grade 3	Grade 4	Grade 3	Grade 4	Grade 3	Grade 4
Leukocytopenia				2
Neutropenia	6	2		4		4	1
Anemia	7		1		6		1
Thrombocytopenia	2		2	2	3	4	7		1
Febrile neutropenia			10		17
Anorexia					2
Nausea			1		6
Vomiting					1
Diarrhea					4
Fatigue					1
Lung infection	1
Pneumonitis		2
Rash maculopapular	1		1
Pharyngitis	1
Lymph gland infection			1
Hematuria							1
Stroke										1
AST elevation	1
ALT elevation	2
Hyponatremia	1

PBSCH: peripheral blood stem cell harvest, ASCT: autologous stem cell transplantation, AST: aspartate aminotransferase, ALT: alanine aminotransferase.

Figure 2. Changes in the responses after the treatments. Responses after induction, ASCT and consolidation, and maximum responses after transplantation. sCR: stringent complete response, CR: complete response, VGPR: very good partial response, PR: partial response, SD: stable disease, PD: progressive disease, ASCT: autologous stem cell transplantation.

Figure 3. Survival and time to next treatment. (A) Overall survival, (B) Progression-free survival, and (C) Time to next treatment of all patients.

Figure 4. Comparison of survivals by chromosomal abnormalities and response after transplantation. (A) Overall survival and (B) Progression-free survival of the patients with or without high-risk chromosomal abnormalities. (C) Overall survival and (D) Progression-free survival of the patients whose stages in international staging systems were I/II or III. (E) Overall survival and (F) Progression-free survival of the patients who achieved complete response after transplantation or not.

Table 3. Previously reported VCD induction trials.

Study	Phase	Patients (n)	Dose and schedule			Interval (days)	Cycles	Response after induction (%)
			Bor mg/m^2	CPA mg/m^2	Dexa mg			≥CR	≥nCR	≥VGPR	≥PR
Reeder et al. [5,6]		33	1.3 i.v.	300 p.o.	40 p.o.	28	4		39	61	88
			(d1, 4, 8, 11)	(d1, 8, 15, 22)	(d1–4, 9–12, 17–20)
		30	1.5 i.v.	300 p.o.	40 p.o.	28	4		43	60	93
			(d1, 8, 15, 22)	(d1, 8, 15, 22)	(d1–4, 9–12, 17–20) *
Kumar et al. [7]	2	33	1.3 i.v.	500 p.o.	40 p.o.	21	4	3	3	13	63
			(d1, 4, 8, 11)	(d1, 8)	(d1, 8, 15)
		17	1.3 i.v.	500 p.o.	40 p.o.	21	4	12	24	41	82
			(d1, 4, 8, 11)	(d1, 8, 15)	(d1, 8, 15)
Einsele et al. [8]	2	414	1.3 i.v.	900 i.v.	40 p.o.	21	3	7.4			85.4
			(d1, 4, 8, 11)	(d1)	(d1, 2, 4, 5, 8, 9, 11, 12)
Mai et al. [9]	3	251	1.3 i.v.	900 i.v.	40 p.o.	21	3	8.4	22.3	37	78.1
			(d1, 4, 8, 11)	(d1)	(d1, 2, 4, 5, 8, 9, 11, 12)
Moureau et al. [10]	3	169	1.3 s.c.	500 p.o.	40 p.o.	21	4	8.9		56.2	83
			(d1, 4, 8, 11)	(d1, 8, 15)	(d1–4, 9–12)
Sunami et al. [23]	2	64	1.3 i.v.	500 p.o.	40 p.o.	35 **	3	20		39	80
			(d1, 8, 15, 22) **	(d1, 8, 15) **	(d1, 8, 15, 22) **

Bor: bortezomib, CPA: cyclophosphamide, Dexa: dexamethasone, CR: complete response, nCR: near complete response, VGPR: very good partial response, PR: partial response, i.v.: intravenous, p.o.: per os, s.c.: subcutaneous, d: days, * In the 3rd/4th cycle, dexamethasone was reduced to day 1, 8, 15 and 22. ** In the first 3 weeks, bortezomib 1.3 mg/m² on days 1, 4, 8, and 11, cyclophosphamide 500 mg/m² on days 1 and 8, dexamethasone 40 mg on days 1, 4, 8, and 11 were given.

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Data availability statement

The data that support the findings of the present study are available from the corresponding author on reasonable request.