Reduced intensity VMP with lenalidomide plus dexamethasone consolidation and lenalidomide maintenance for NDMM

The combination of bortezomib with melphalan and prednisolone (VMP) is a standard induction regimen for patients with newly diagnosed multiple myeloma (NDMM). Tadao Ishida and colleagues investigated whether a reduced intensity dosing of VMP could provide an improved safety profile while maintaining the efficacy, which is particularly of interest for older patients. An article published in Annals of Hematology, reported results of the phase II study of VMP induction therapy followed by lenalidomide plus dexamethasone (Rd) consolidation and lenalidomide maintenance in transplant-ineligible patients with NDMM.¹

The article is in line with the current editorial theme on the Multiple Myeloma (MM) Hub, which focuses on developments to improve frontline treatment for NDMM.

Methods

• Multicenter, open-label, single-arm, phase II clinical trial UMIN000009042
• Eligible patients were symptomatic, aged ≥ 20 years, with untreated NDMM and were not eligible for high-dose therapy with autologous hematopoietic stem cell transplantation (auto-HSCT)
• Dosing schedule:
  • VMP induction – five cycles of weekly bortezomib at 1.3 mg/m² in combination with melphalan 6 mg/m² and prednisolone 40 mg/m², once daily on Days 1–4 of a 35-day cycle
  • Rd consolidation – six cycles of lenalidomide 25 mg daily on Days 1–21 and dexamethasone 40 mg weekly of a 28-day cycle (dexamethasone was reduced to 20 mg weekly in patients aged ≥ 75 years)
  • Lenalidomide maintenance – lenalidomide 10 mg daily on Days 1–21 of a 28-day cycle until progression
• Patients who achieved complete response (CR) following VMP moved directly to maintenance with lenalidomide
• Responses were assessed on Day 1 of each cycle and toxicity at each clinic visit
• Endpoints:
  • Primary – progression-free survival (PFS)
  • Secondary – overall survival (OS), overall response rates and safety

Results

Patient and disease characteristics:

• In total, 83 patients were recruited between October 2012 and August 2014. Patient characteristics are presented in Table 1
• The analysis cut-off date was September 16, 2017

Table 1. Patient and disease characteristics

Ig, immunoglobulin; ISS, international staging system *data available for 80 patients
Characteristics	Patients (N = 83)
Median age (range), years	74 (61–84)
Age ≥ 75, %	37.3
Female gender, %	55.4
Myeloma type IgG IgA Light chain only	65.1 22.9 12.0
ISS stage, % I II III	30.1 49.4 20.5
High-risk cytogenetics, %* t(4;14) and/or del(17p) t(4;14) and/or del(17p), and/or gain(1q)	23.8 46.3

Efficacy

• In total, 79 patients completed ≥ 1 cycle of VMP and 57 patients received both Rd consolidation and lenalidomide maintenance therapy
  • Eight patients achieved a CR with VMP and moved straight to lenalidomide maintenance
• Patients who received Rd showed improved clinical responses compared to induction only. The addition of lenalidomide maintenance therapy resulted in further enhanced responses. Best responses during therapy are presented in Table 2
• Best response of ≥ very good partial response (VGPR) according to cytogenetics were:
  • 2% in patients with del(17p) or t(4;14) (n = 19)
  • 5% in the patients with del(17p) or t(4;14) (n = 19)
  • 4%, in patients without del(17p), t(4;14) and gain(1q) (n = 46)
• Older patients (≥ 75 years) had higher rates of ≥ CR (38.7% vs0%) and similar rates of ≥ VGPR (51.6% vs 48.1%) compared with patients < 75 years
  • Indicates a favorable response in elderly patients

Table 2. Best response during therapy

CR, complete response; PD, progressive disease; PR, partial response; Rd, lenalidomide plus dexamethasone; sCR, stringent CR; SD, stable disease; VGPR, very good partial response; VMP, bortezomib with melphalan and prednisolone
Best response	VMP induction  (n = 83)	Rd consolidation  (n = 57)	Lenalidomide maintenance  (n = 57)
sCR	2.4	12.3	29.8
CR	7.2	8.8	15.8
VGPR	18.0	24.6	21.1
PR	39.8	47.4	28.1
SD	27.7	5.3	5.2
PD	0	1.8	0
Unevaluable	4.8	0	0

• The median PFS was 28.0 (95% CI, 19.6–36.7) months
  • 23.2 months in patients with t(4;14) and/or del (17p) vs 28.6 months in patients without this cytogenetic profile
  • 20.5 months in patients with t(4;14) or/and del(17p), or/and gain(1q) vs 33.1 in patients without those abnormalities (p = 0.1071)

• Patients with ≥ VGPR experienced the greatest improvement in PFS with lenalidomide maintenance compared to patients with lower best responses (41.8 vs7 months, respectively; p = 0.007)
• The median OS was 55.3 (95% CI, 51.6–not established) months
• There was no significant difference in the median OS based on the level of response of ≥ VGPR compared to lesser levels of response (not reached vs3; p = 0.1645)
• Age (< 75 vs ≥ 75 years) did not appear to have an impact on the median PFS (20.7 vs 7 months; p = 0.194)

Safety

• The incidence of Grade ≥ 3 treatment-related adverse events (TEAEs) was relatively low:
  • The most frequently reported Grade ≥ 3 AEs with VMP were anemia, neutropenia, and thrombocytopenia (Table 3)
• The discontinuation rate due to toxicity was 4.8%

Table 3. Grade 3 and 4 TEAEs

Rd, lenalidomide plus dexamethasone; VMP, bortezomib with melphalan and prednisolone
TEAE	VMP induction (N = 83)		Rd consolidation (n = 57)		Lenalidomide maintenance (n = 54)
	Grade 3	Grade 4	Grade 3	Grade 4	Grade 3	Grade 4
Anemia	28.9	0	3.5	0	7.4	0
Neutropenia	12	3.6	1.8	0	18.5	5.6
Thrombocytopenia	4.8	1.2	0	0	1.9	0
Infection	0	0	0	0	1.9	0
Diarrhea	0	0	0	0	1.9	0
Constipation	1.2	0	0	0	0	0
Nausea	1.2	0	0	0	0	0
Peripheral neuropathy	2.4	0	0	0	0	0
Skin rash	1.2	1.2	5.3	0	1.9	0

Conclusion

The results from the study revealed that reduced-intensity VMP followed by Rd consolidation and lenalidomide maintenance is an effective treatment for patients with NDMM who are not eligible for transplant. Patients who achieved ≥ VGPR prior to lenalidomide maintenance appeared to benefit most from this additional therapy. The authors suggest that this regimen would be particularly suitable for older patients due to a more manageable toxicity profile than current standard of care regimens.