ASCO 2019 | Risk subgroup analysis from the FORTE trial

On Sunday 02 June, 2019, Francesca Gay, University of Torino, Torino, IT, presented an updated risk analysis from the FORTE trial (NCT02203643) during the American Society of Clinical Oncology (ASCO) annual meeting. This analysis compared carfilzomib (K), lenalidomide (R) and dexamethasone (d) (KRd) induction, followed by high-dose melphalan (HDM) plus autologous stem cell transplant (ASCT) and KRd maintenance, to KRd alone in patients with newly diagnosed multiple myeloma (NDMM).

Study design and background

The design of the FORTE trial, in transplant eligible patients with NDMM ≤65 years is shown in Table 1 with patients randomized 1:1:1 to one of the three arms. The dosing of the drugs was as below;

• K: 36 mg/m² on days 1–2, 8–9 and 15–16
• Cyclophosphamide(C): 300 mg/m² on days 1, 8 and 15
• R: 25 mg on days 1–21
• d: 20 mg on days 1–2, 8–9, 15–16 and 22–23

A second randomization (1:1) was then conducted to either lenalidomide or carfilzomib and lenalidomide maintenance. The pre-maintenance response rates for the intention-to-treat (ITT) population are shown in Table 2.

Table 1: Trial design

ASCT, autologous stem cell transplant; C, cyclophosphamide; d, dexamethasone; HDM, high-dose melphalan; K, carfilzomib; R, lenalidomide
Arm	Induction	ASCT +/-	Consolidation
KCd_ASCT	KCd, 4 cycles	HDM + ASCT	KCd, 4 cycles
KRd_ASCT	KRd, 4 cycles	HDM + ASCT	KRd, 4 cycles
KRd12	KRd, 4 cycles	KRd, 4 cycles	KRd, 4 cycles

Table 2: Pre-maintenance analysis in the ITT population

* Evaluated by second generation flow cytometry. ASCT, autologous stem cell transplant; C, cyclophosphamide; CR, complete response; d, dexamethasone; K, carfilzomib; MRD, minimum residual disease; NR, not reached;  R, lenalidomide; s, stringent; VGPR, very good partial response
	KCd_ASCT	KRd_ASCT	KRd12
Number of patients	159	158	157
VGPR	29%	29%	26%
CR	15%	16%	18%
sCR	32%	44%	43%
≥VGPR	76%	89%	87%
MRD negativity (10-5)*	42%	58%	54%
Number of patients evaluable for persistent MRD negativity	NR	72	64
Persistent MRD negativity at 1-year (10-5)*	NR	90%	78%

Updated risk analysis

• For the purposes of this risk analysis, KRd_ASCT was compared to KRd12 
• Evaluations were conducted in patients with standard- and high-risk disease
• Aims:
  • Evaluate the pre-maintenance response rates of sCR, ≥CR and ≥VGPR, and MRD negativity as well as 1-year persistent MRD negativity
  • Evaluate rate of early relapse (≤18 months from first randomization)
• Median follow-up: 25 months

The subgroup analysis results are shown below in Tables 3–6.

Table 3: Patient characteristics of note

ASCT, autologous stem cell transplant; d, dexamethasone; ISS, International Staging System; K, carfilzomib; MRD, minimum residual disease; NR, not reached; R, lenalidomide
	KRd_ASCT (n = 158)	KRd12 (n = 157)
Median age (years)	57 (52–62)	57 (51–62)
Patients ≥60 years	39%	38%
ISS stage III	15%	20%
High-risk cytogenetics	33%	28%
R-ISS stage III	11%	10%

Table 4: Pre-maintenance response rate, by R-ISS stage of disease

	KRd_ASCT	KRd12	KRd_ASCT	KRd12
Number of patients	48	39	92	94
R-ISS stage	I	I	II/III	II/III
VGPR	32%	15%	30%	29%
CR	14%	15%	17%	19%
scR	46%	49%	39%	38%
≥VGPR	92%	79%	86%	86%
MRD negativity (10-5)*	69%	62%	51%	49%
Number of patients evaluable for MRD negativity at 1-year	21	20	41	33
Persistent 1-year MRD negativity (10-5)*	90%	85%	90%	72%
* Evaluated by second generation flow cytometry. ASCT, autologous stem cell transplant; C, cyclophosphamide; CR, complete response; d, dexamethasone; K, carfilzomib; MRD, minimum residual disease; NR, not reached;  R, lenalidomide; R-ISS, revised-International Staging System; s, stringent; VGPR, very good partial response

Table 5: Early relapse rate (≤18 months) after first randomization

ASCT, autologous stem cell transplant;  d, dexamethasone; K, carfilzomib; MRD, minimum residual disease; NR, not reached;  R, lenalidomide; R-ISS, revised-International Staging System
	R-ISS stage	Number of patients (n)	Early relapses (n)	P value	MRD positive
KRd_ASCT	Overall	158	12	0.015	-
KRd12	Overall	157	26	-	-
KRd_ASCT	I	48	0	NR	-
KRd12	I	39	2	-	-
KRd_ASCT	II/III	92	11	0.05	73% (n = 8)
KRd12	II/III	94	22	-	77% (n = 17)

Table 6: Factors associated with early relapse using a multivariate logistic regression model

	OR	95% CI	P value	Effect on risk of early relapse
ASCT, autologous stem cell transplant; d, dexamethasone; K, carfilzomib; MRD, minimum residual disease; NR, not reached;  OR, overall response; R, lenalidomide; R-ISS, revised-International Staging System
R-ISS II/III vs R-ISS I	3.78	1.71–8.35	0.001	Increased
KRd_ASCT vs KRd12	0.41	0.19–0.88	0.022	Reduced
MRD negative (10-5)	0.21	0.12–0.40	<0.001	Reduced

Conclusion

Both KRd_ASCT and KRd12 induced high quality responses in this study, with good MRD negativity rates, which were higher in the KRd_ASCT arm. The risk of early relapse was reduced in high-risk patients who underwent ASCT, showing a benefit of ASCT in this population. Longer term follow-up is required to evaluate both progression-free survival and overall survival.