Latest updates on the Myeloma XI trial from ASH 2022

Lenalidomide, an immunomodulator, is commonly prescribed for patients with multiple myeloma (MM) and is associated with improved survival outcomes.¹ Lenalidomide maintenance therapy is the standard of care for patients with MM who received autologous hematopoietic stem cell transplantation (auto-HSCT); however, more information is needed on the optimal duration of treatment.²

Time-limited lenalidomide maintenance therapy may be as effective as treatment until progression.² Despite the improved survival outcomes, data have emerged showing an association between treatment with lenalidomide and the development of second primary malignancies (SPM) in patients with MM.^1,3

The phase III UK National Cancer Research Institute (NCRI) Myeloma XI randomized controlled trial, which has been extensively covered by the Multiple Myeloma Hub, investigated lenalidomide as an induction and maintenance therapy in patients with MM. Several presentations at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition discussed data from the UK NCRI Myeloma XI trial. Below, we summarize presentations by Pawlyn² investigating the optimal duration of lenalidomide maintenance therapy following auto-HSCT in patients with MM and by Jones³ on the association between lenalidomide treatment and the development of SPM. We also summarize key findings from a systematic review and meta-analysis of SPM in patients with hematologic malignancies treated with lenalidomide by Saleem et al.¹ published in The Lancet Hematology.

Optimal duration of lenalidomide maintenance²

Study design and patient characteristics

• The analysis included 1,248 patients with newly diagnosed MM who were eligible for transplant.
• Patients were randomized to observation (n = 518) or to receive lenalidomide maintenance therapy (n = 730) following auto-HSCT in the UK NCRI Myeloma XI trial.
• The median follow-up was 44.7 months.
• Baseline characteristics were similar between the two groups.
  • Patients categorized as standard risk (SR), high risk (HiR; defined as the presence of one high-risk genetic feature), or ultra-high risk (UHiR; defined as >1 HiR lesion).
• Progression-free survival (PFS) was analyzed at the 2-, 3-, 4-, and 5-year time points.

Key findings

Median PFS and median time from randomization to progression on second-line therapy (PFS2) were longer in the lenalidomide group. The PFS benefit was observed in both SR and HiR/UHiR patients and in both measurable residual disease (MRD) positive and negative patients (Table 1).

Table 1. Median PFS and PFS2*

Cl, confidence interval; HiR, high risk; HR, hazard ratio; MRD, measurable residual disease; NE, not evaluable; PFS, progression-free survival; PFS2, time from randomization to progression on second-line therapy; SR, standard risk; UHiR, ultra-high risk. *Adapted from Pawlyn.2
Outcome, months	Lenalidomide (n = 730)	Observation (n = 518)	HR (95% CI)	p value
Median PFS	64	32	0.52 (0.45–0.61)	<0.001
SR patients	67	36	0.40 (0.28–0.58)	<0.0001
HiR/UHiR patients	38	21	0.50 (0.35–0.70)	<0.0011
MRD-negative patients	59	44	0.72 (0.55–0.95)	0.022
MRD-positive patients	47	18	0.37 (0.27–0.50)	<0.0001
Median PFS2	NE	61	0.66 (0.54–0.81)	<0.0001

Lenalidomide improved PFS and PFS2 when compared with the observation group at the 2-, 3- and 4-year intervals, but not at the 5-year interval (Table 2).

Table 2. PFS and PFS2 at 2-, 3-, 4- and 5-year intervals*

Cl, confidence interval; HR, hazard ratio; NE, not evaluable; PFS, progression-free survival; PFS2, time from randomization to progression on second-line therapy. *Adapted from Pawlyn.2
Outcome, months	Lenalidomide (n = 730)	Observation (n = 518)	HR (95% CI)	p value
PFS
2-year interval	61	29	0.51 (0.40–0.66)	<0.0001
3-year interval	51	31	0.47 (0.33–0.67)	<0.0001
4-year interval	39	NE	0.56 (0.33–0.695)	<0.031
5-year interval	NE	NE	0.83 (0.36–1.95)	0.672
PFS2
2-year interval	NE	55	0.70 (0.54–0.91)	<0.007
3-year interval	NE	46	0.65 (0.47–0.92)	0.014
4-year interval	NE	39	0.54 (0.33–0.88)	0.014
5-year interval	NE	NE	0.64 (0.29–1.40)	0.265

In patients categorized as SR, lenalidomide was associated with improved PFS when compared with the observational group at the 2-year and 3-year intervals, whilst in patients categorized as HiR/UHiR the benefit was only observed at the 2-year interval. In MRD-negative patients, PFS was higher in the lenalidomide group than in the observation group at the 2-year interval, with the benefit maintained through the 3- and 4-year intervals in MRD-positive patients (Table 3).

Table 3. PFS over time by risk group and MRD status*

Cl, confidence interval; HiR, high risk; HR, hazard ratio; MRD, measurable residual disease; NE, not evaluable; PFS, progression-free survival; SR, standard risk; UHiR, ultra-high risk. *Adapted from Pawlyn.2
PFS, months	Lenalidomide (n = 730)	Observation (n = 518)	HR (95% CI)	p value
SR
2-year interval	53	29	0.44 (0.26–0.74)	<0.002
3-year interval	NE	28	0.46 (0.25–0.88)	0.019
4-year interval	NE	31	0.71 (0.29–1.75)	0.462
5-year interval	NE	19	0.46 (0.13–1.62)	0.227
HiR/UHiR
2-year interval	48	20	0.44 (0.24–0.80)	0.008
3-year interval	NE	21	0.59 (0.21–1.65)	0.314
4-year interval	NE	NE	0.54 (0.14–2.09)	0.372
MRD negative
2-year interval	53	33	0.63 (0.43–0.94)	0.025
3-year interval	NE	31	0.65 (0.36–1.15)	0.140
4-year interval	NE	NE	0.68 (0.27–1.69)	0.403
5-year interval	NE	NE	0.43 (0.11–1.72)	0.232
MRD positive
2-year interval	61	20	0.34 (0.19–0.59)	<0.0001
3-year interval	49	16	0.26 (0.11–0.58)	0.001
4-year interval	37	6	0.14 (0.04–0.48)	0.002

No evidence of cumulative hematologic toxicity was identified.

This study suggests that, following auto-HSCT, continuing lenalidomide maintenance therapy beyond 4–5 years may continue to provide a PFS benefit. In patients who are MRD negative, continuing lenalidomide maintenance therapy for ≥3 years can continue to improve PFS.

Secondary primary malignancies in the Myeloma XI trial³

Study design and patient characteristics

This analysis included 4,358 patients with newly diagnosed MM in the UK NCRI Myeloma XI trial, which compared cyclophosphamide, thalidomide, lenalidomide, carfilzomib, and bortezomib induction combinations, and lenalidomide with or without vorinostat maintenance therapy or active observation. Patients eligible for transplant received high-dose melphalan and auto-HSCT. The median follow-up was 68 months.⁴

Key findings

Within the transplant-eligible group:

• 701 patients did not receive lenalidomide at induction or maintenance, 1,263 received lenalidomide at induction or maintenance (single exposure), and 568 received lenalidomide at induction and maintenance (double exposure).⁴
• The 7-year cumulative incidences of SPM were higher in patients who received lenalidomide maintenance therapy versus patients who received active observation (Table 4).

Table 4. Rates of secondary malignancy in the group eligible for transplant*

SPM, second primary malignancy. *Adapted from Jones.3
Incidence of SPM, %	Lenalidomide (n = 875)	Active observation (n = 566)	p value
7-year cumulative incidences of SPM	12.2	5.8	0.006
Type of SPM, %	Lenalidomide (n = 884)	Active observation (n = 557)	p value
Hematologic malignancies	2.6	0.4	—
Solid tumors	3.1	2.7	—
Non-melanoma skin cancers	2.5	0.2	—

• Myelodysplastic syndromes, prostate cancer, and non-melanoma skin cancers (NMSC) occurred at incidences >1%.
• Hematologic malignancies and NMSC were almost confined to patients who received lenalidomide maintenance therapy, while the rate of solid tumors was similar between groups.
• The rates of SPM were higher in the lenalidomide maintenance group (8.2%) than in the observed group (3.2%).
• The greatest incidences of SPM occurred in patients who received double exposure to lenalidomide (7.6%), while patients who received single exposure to lenalidomide (5.0%) had a higher rate than patients who had no exposure (4.2%).

Within the group not eligible for transplant:

• 677 were not treated with lenalidomide, 899 were single exposed, and 260 were double exposed.⁴

• The 5-year cumulative incidences of SPM were numerically but not significantly higher in patients who received lenalidomide maintenance therapy compared with active observation (Table 5).

Table 5. Rates of secondary malignancy in the groups not eligible for transplant*

SPM, second primary malignancy. *Adapted from Jones.3
Incidence of SPM, %	Lenalidomide (n = 493)	Active observation (n = 340)	p value
5-year cumulative incidences of SPM	17.1	10	0.10
Type of SPM, %	Lenalidomide (n = 501)	Active observation (n = 333)	p value
Hematologic malignancies	1	1	—
Solid tumors	8	5	—
Non-melanoma skin cancers	8	4	—

• Colon cancer and NMSC occurred at rates >1%.
• Hematologic malignancies were rare in both groups, while NMSC were predominant, particularly in the lenalidomide maintenance group.
• The rates of SPM were higher in the lenalidomide maintenance group (17%) when compared with the observation group (10%).
• Patients who received double exposure to lenalidomide (16.9%) had a higher rate of SPM than patients who received single exposure (11.7%) and patients who had no exposure (11.2%).

Lenalidomide maintenance improved overall survival in both patients eligible for transplant and patients not eligible for transplant patients. Death due to MM was higher in patients who received active observation than in patients who received lenalidomide maintenance, while non-MM deaths were comparable between the groups. Deaths due to SPM were low in the group eligible for transplant, while the highest rate of death due to SPM was observed in patients not eligible for transplant who received lenalidomide maintenance (6.1%).⁴

Overall, there was a higher cumulative incidence of SPM in patients receiving lenalidomide maintenance and in particular, patients who received lenalidomide at induction and maintenance, possibly due to a cumulative dose effect.

Systematic review and meta-analysis¹

Key findings

• Saleem et al.¹ performed a systematic review of randomized controlled trials that reported SPM in patients who received lenalidomide therapy.
• The risk ratio of SPM following exposure to lenalidomide across all malignancies was 1.16; however, there was heterogeneity across indications (p = 0.020).
• The risk ratio of SPM when patients with MM were treated with lenalidomide was 1.42.
• In MM trials, lenalidomide increased both solid and hematological SPM.

This analysis suggested that SPM induced by lenalidomide occurs exclusively in patients with MM.

Conclusion

Lenalidomide is an effective treatment for patients with MM and is associated with improved survival outcomes versus observation. Lenalidomide maintenance beyond 3 years is associated with improved PFS; however, the benefit may diminish between 4 years and 5 years.² Further studies with long-term follow up are warranted to determine optimal lenalidomide maintenance duration.

While the benefits of lenalidomide have been demonstrated, there is an association between receiving lenalidomide treatment and the development of SPM in patients with MM.^1,3 Patients should be monitored for signs and symptoms of SPM to improve diagnosis and intervention. Risk factors such as age should also be considered.³