ASCO 2019 | E3A06: Lenalidomide versus observation for high-risk smoldering multiple myeloma

During this year’s American Society of Clinical Oncology (ASCO) meeting, held in Chicago, US, our Co-Chair, Sagar Lonial, Winship Cancer Institute of Emory University, Atlanta, US, presented the results of the E3A06 trial of lenalidomide for high-risk smoldering multiple myeloma (SMM).¹

The main challenges currently facing physicians who treat patients with SMM are; identifying the patients who are truly at a higher risk of progression to multiple myeloma (MM), intervening appropriately to prevent organ damage, not over-treating patients with SMM who ultimately are unlikely to progress to symptomatic MM. There are multiple risk stratification models for SMM and many opinions on when to intervene, meaning there is currently a lack of consensus on the SMM treatment paradigm.

Study design and patient characteristics

The E3A06 trial was designed to compare early intervention with lenalidomide treatment to observation alone in patients with intermediate and high-risk SMM. The study design is shown below:

• Phase II portion (N = 44):
  • Lenalidomide (25mg) on days 1–21 of a 28-day cycle
    • Aspirin (325mg) on days 1–28
    • Until disease progression (PD) or toxicity
• Phase III portion (N = 182); randomization to either:
  • Lenalidomide (25mg) on days 1–21 of a 28-day cycle (n = 90)
    • Aspirin (325mg) on days 1–28
    • Until PD or unacceptable toxicity
• Observation until PD (n = 92)

The primary objectives were:

• Phase II: evaluate safety and success of stem cell mobilization
• Phase III: compare progression-free survival (PFS) of lenalidomide versus observation
  • PFS defined as both biochemical and CRAB (elevated calcium, renal failure, anemia and bone lesions) progression

Secondary objectives of the phase III study were to compare:

• Overall survival (OS)
• Response rates including; very good partial response (VGPR) or better, partial response (PR) or better and stable disease (SD) or better
• Patient quality-of-life (QoL)
• Toxicity
• Correlatives

Table 1: Patient characteristics of note by trial phase and arm

	Lenalidomide	Lenalidomide	Observation	Total
Phase	II	III	III	III
Median age (years)	62 (36–83)	63 (31–82)	64 (33–96)	64 (31–86)
Race (white)	86.0%	84.7%	77.3%	80.9%
ECOG PS>0	9.1%	27.0%	26.1%	26.4%
Time since high-risk SMM diagnosis (≤1 year)	100.0%	93.3%	89.0%	91.1%
Cytogenetic risk (high)*	22.2%	9.3%	8.1%	8.8%
Mayo 2018 risk-stratification (high - 2–3 risk factors)2	59.1%	42.2%	47.8%	45.0%
* Using fluorescence in situ hybridization. ECOG, Eastern cooperative oncology group; SMM, smoldering, multiple myeloma

Efficacy

The response rates of the phase II and III parts of the study are shown in Table 2. The PFS rates at 1-year, 3-years and 5-years for the phase II portion are in Table 3 with the phase III data for PFS at 1-year, 2-years and 3-years in Table 4.

Table 2: Response rates; phase II results of lenalidomide treatment and phase III results of lenalidomide versus observation

PR, partial response; SD, stable disease; VGPR, very good partial response
	Lenalidomide	Lenalidomide	Observation
Phase	II	III	III
n	44	90	92
≥VGPR (%)	9.1	4.4	0.0
≥PR (%)	47.7	48.9	0.0
≥SD (%)	95.5	93.3	87.0

The treatment hazard ratio (HR) for lenalidomide versus observation in the phase III arm is 0.28, at a 95% confidence interval (0.12–0.63) with a P value of 0.0005.

Table 3: Phase II PFS at a median follow-up of 82 months

	Lenalidomide
1-year	0.98
3-year	0.87
5-year	0.78

Table 4: Phase III PFS in the intention-to-treat (ITT) population at a median follow-up of 35 months

	Lenalidomide	Observation
1-year	0.98	0.89
2-year	0.93	0.76
3-year	0.91	0.66

• Treatment duration:
  • Phase II:
    • Remain on treatment: 20%, median 89 cycles
    • Discontinued: 79%, median 15 cycles
      • Most common reason for discontinuation: AE
  • Phase III:
    • Remain on treatment: 50%, median 36 cycles
• Subgroup analysis: all subgroups benefitted equally, aside from African-American patients
• QoL: no significant difference between arms, indicating no detriment in early therapy
• PFS benefit observed across intermediate and high-risk subgroups

Safety

The most common adverse events (AEs) experienced by patients in the phase III arm of the trial were infections (n= 9), hypertension (n= 8) and a decreased neutrophil count (n= 8). In the phase II arm, two grade 5 events occurred. The treatment-related toxicities are shown in Table 5.

Table 5: Overall treatment-related toxicity, grade 3-5, from lenalidomide in both phases of the trial

	Lenalidomide, phase II (n = 44)			Lenalidomide, phase III (n = 88)
	3	4	5	3	4	5
Non-hematologic	12 (27.3%)	3 (6.8%)	2 (4.5%)	25 (28.4%)	-	-
Hematologic and non-hematologic	15 (34.1%)	5 (11.4%)	2 (4.5%)	31 (35.2%)	5 (5.7%)	-

Table 6 below shows the rate of secondary primary malignancies (SPMs) which was higher in the lenalidomide arm with a cumulative incidence of 11.0%, compared to 4.8% in the observation arm.

Table 6: SPMs in the phase II and phase III portions of the trial

	Lenalidomide (n= 44)	Lenalidomide (n= 88)	Observation (n= 92)
Phase	II	III	III
Solid Tumors	1 (2.3%)	3 (3.4%)	2 (2.2%)
Hematologic malignancies	2 (4.5%)	1 (1.1%)	0 (0.0%)
Total invasive SPMs	3 (6.8%)	4 (4.5%)	2 (2.2%)
Cumulative incidence	4 year: 4.9%	3 year: 5.2%	3 year: 3.5%
Total SPMs	6 (13.6%)	10 (11.4%)	3 (3.4%)
Cumulative incidence	4 year: 9.7%	3 year: 11.0%	3 year: 4.8%
SPMs, secondary primary malignancies

Conclusion

This study supports the use of early intervention, using lenalidomide, for high-risk SMM using the Mayo 2018 risk criteria, or the updated International Myeloma Working Group (IMWG) criteria presented by Professor Maria Victoria Mateos during ASCO 2019.^2,3