ENDURANCE phase III results: KRd is not superior to VRd for newly diagnosed MM

At the 2020 annual meeting of the American Society of Clinical Oncology (ASCO), Shaji Kumar presented the interim results from the phase III ENDURANCE trial (NCT01863550). This study compared induction with bortezomib, lenalidomide, and dexamethasone (VRd) with carfilzomib, lenalidomide, and dexamethasone (KRd), in newly diagnosed multiple myeloma (MM) patients.¹

The current standard of care for patients with newly diagnosed MM is VRd. This triplet was established following the significantly improved overall survival (OS) obtained with VRd when compared with lenalidomide and dexamethasone (Rd) in the phase III trial SWOG S0777 (NCT00644228).² Since those results, the efficacy of VRd has been demonstrated in multiple settings, including as backbone and post-induction to autologous stem cell transplantation (auto-SCT).³

Carfilzomib has shown great promise in the relapsed MM setting when used in combination with dexamethasone or Rd, leading to increased progression-free survival (PFS) and deeper responses when compared with arms without carfilzomib.³ The KRd arm in the FORTE trial revealed the promising efficacy of this triplet in the front-line setting too, with a complete response rate of 43%, a very good partial response (VGPR) of ≥ 87% and measurable (minimal) residual disease (MRD) negativity of 54%.³

Until the phase III ENDURANCE trial there had been no direct comparison of KRd to VRd in any MM setting. The results of this pivotal study, as presented by Shaji Kumar at ASCO 2020, are summarized below.^{1, 4}

Study design¹

• The trial included newly diagnosed MM patients with no intention for immediate stem cell transplantation (SCT) and without the following high-risk features: del17p, t(14;16), t(14;20), plasma cell leukemia or lactate dehydrogenase levels more than 2× upper limit of normal
• Patients were randomized 1:1 to induction with either
  • VRd (12 three-week cycles), as follows:
    • Bortezomib 1.3 mg/m² on Days 1, 4, 8, 11 for Cycles 1–8, and on Days 1 and 8 for Cycles 9–12
    • Lenalidomide 25 mg on Days 1–14
    • Dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12 for Cycles 1–4, 10 mg on the same days for Cycles 5–8, and 10 mg on Days 1, 2, 8, 9 for Cycles 9–12
  • KRd (9 four-week cycles), as follows:
    • Carfilzomib 20 mg/m² on Days 1, 2, and then 36 mg/m² on Days 8, 9, 15, 16 of Cycle 1, and 36 mg/m² for Days 1, 2, 8, 9, 15, 16 of Cycles 2–9
    • Lenalidomide 25 mg on Days 1–21
    • Dexamethasone: 40 mg on Days 1, 8, 15, 22 of cycles 1–4, and 20 mg on the same days for Cycles 5–9
• Patients completing induction were then randomized a second time to receive 15 mg lenalidomide maintenance (24 four-week cycles) or indefinitely until disease progression or unacceptable toxicity at the same dosing schedule
• Primary endpoints were PFS for the induction randomization and OS for the second randomization, while secondary endpoints included overall response rate, MRD negativity rate, time-to-progression, and toxicity
• The patient baseline characteristics were well balanced between the two arms and are shown in Table 1. Of note, approximately 30% of the enrolled patients were ≥ 70 years old, 10% were African Americans, and 10% had a t(4;14) translocation

Table 1. Baseline characteristics of patients in the ENDURANCE phase III trial²

ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; KRd, carfilzomib, lenalidomide, dexamethasone; VRd: bortezomib, lenalidomide, dexamethasone
	VRd (n = 542)	KRd (n = 545)
Median age (range), years ≥ 70 years, % ≥ 65 years, %	64 (32–88) 30.8 48.7	65 (32–86) 32.5 52.8
Race, % White Black Other	84.5 13.0 2.5	86.3 11.4 2.3
ISS Stage, % I II III	30.6 43.1 26.3	32.5 42.9 24.6
ECOG PS, % 0 1 2-3	39.1 49.8 11.1	44.2 45.7 10.1
Cytogenetics, % Normal t(11;14) t(4;14)	71.8 20.6 10.4	72.3 18.7 8.4

 Results¹

• The focus of this interim analysis was on the first co-primary endpoint: PFS for the randomization to induction treatment
• Overall, 27.4% patients proceeded to autologous SCT (auto-SCT) following induction (26.8% in the KRd arm and 28.0% in the VRd arm) with a median time to auto-SCT of 6.5 months for VRd and 8.9 months for KRd
• The PFS rates from this interim analysis in each arm after a median follow-up of 15 months and for different subpopulation analyses are shown in Table 2

Table 2. Survival outcomes results from the ENDURANCE phase III trial²

Auto-SCT, autologous stem cell transplantation; HR, hazard ratio; KRd, carfilzomib, lenalidomide, dexamethasone; NE, not estimated; OS, overall survival; PFS, progression-free survival; VRd: bortezomib, lenalidomide, dexamethasone
	VRd	KRd	HR (95% CI); p value
Median PFS, (95% CI)	34.4 months (30.1–NE)	34.6 months (28.8–37.8)	1.04 (0.83–1.31); p = 0.742
Median PFS for patients ≥ 70 years, (95% CI)	37.0 months (29.0–NE)	28.0 months (24–36)	—
Median PFS with censoring at auto-SCT or other therapy (95% CI)	31.7 months (28.5–44.6)	32.8 months (27.2–37.5)	—
3-year OS from randomization to induction, probability (95% CI)	0.84 (0.80–0.88)	0.86 (0.82–0.89)	—

• In summary, both arms performed similarly with regards to median PFS even in various subgroup analyses (i.e. patients ≥ 70 years old; Table 2), with no statistically significant differences
• However, when looking at the response rates, a significantly higher rates of VGPR or better response was seen in the KRd arm. All the response rates for both arms are shown below in Table 3

Table 3. Response rates from the phase III ENDURANCE trial²

Statistically significant p values are indicated by bold font CR, complete response; KRd, carfilzomib, lenalidomide, dexamethasone; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response; VRd: bortezomib, lenalidomide, dexamethasone
	VRd (n = 527)	KRd (n = 526)	p value
≥ CR, %	14.8	18.3	0.261
CR, %	10.8	12.4	—
VGPR, %	49.9	55.5	0.002
PR, %	19.5	12.9	0.132
SD, %	7.6	6.5	—
PD, %	0.2	0.0	—
Unevaluable/insufficient, %	8.0	6.8	—

 

• When looking at the safety profiles of the two triplets, Grade ≥ 3 cardiac, pulmonary and renal adverse events were higher in the KRd arm (16.1% versus 4.8%; p < 0.001).
• However, Grade ≥ 3 peripheral neuropathy incidences was higher in the VRd arm (53.4% versus 24.4%; p < 0.001)
• Secondary primary tumors were comparable between the arms
• In terms of quality of life, the neurotoxicity-related fact scores were lower in the VRd group due to the increased incidence of neuropathy, but the functional scores were similar for both regimens

Conclusions — Further discussion³

The results of the ENDURANCE phase III trial showed that KRd does not improve the PFS of patients with newly diagnosed MM when compared with the standard of care VRd. OS and secondary endpoints including MRD negativity rates will be published in a later follow-up.

These results were further discussed by Jesus Berdeja, Director of Myeloma Research at the Sarah Cannon Institute.³ Berdeja summarised the results of ENDURANCE and highlighted some additional interesting points regarding the toxicity profiles and costs of KRd versus VRd. The incidence of peripheral neuropathy was higher with VRd, while the incidence of cardiac, pulmonary, and renal treatment-related events was higher with KRd treatment. Thus, he concluded that patient-specific comorbidities and toxicity profiles should lead the choice between the two triplets on an individual basis.

Moreover, he highlighted that since high-risk patients were excluded from ENDURANCE, there are still unanswered questions regarding the efficacy of KRd in high-risk patients (t(14;20), t(14;16), del17p, high serum lactate dehydrogenase), as there is no true standard of care for these patients.

He concluded that ‘‘Both VRd and KRd remain excellent triplets for the front-line therapy of newly diagnosed multiple myeloma. VRd enthusiasts can now stand proud and cite the ENDURANCE trial to support their decision.’’

You can also listen to Shaji Kumar himself discussing these results in our podcast below.