Maintenance therapy in MM: Continuing therapy vs discontinuation according to MRD status

Key results

Baseline characteristics were well matched between the two groups (Table 1).

Table 1. Baseline characteristics overall and from RD and IRD subgroups*

CR, complete response; IRD, lenalidomide and dexamethasone plus ixazomib; ISS, International staging system; MRD, measurable residual disease; RD, lenalidomide and dexamethasone; sCR, stringent CR. *Adapted from Rosiñol, et al.1
Baseline characteristic, % (unless otherwise specified)	Overall (N = 332)	RD (n = 161)	IRD (n = 171)
Median age, years	58	58	59
Male	54	58	51
ISS
I	40.9	42.8	39.1
II	34.9	30.459	39.1
III	22.5	24.259	21.0
High-risk cytogenetics	22.5	24.6	20.6
Plasmacytomas	20.1	18.6	21.6
Depth of response
sCR/CR	69.5	65.0	73.0
MRD-negative	55.4	50.9	59.6

• PFS was similar between patients in the RD and IRD arms after 6 years of monitoring
  • 61.3% vs 55.6%, respectively (95% confidence interval [CI], 0.809–1.603)
• Patients who were measurable residual disease (MRD) negative after discontinuing maintenance therapy after two years had low progressive disease rates compared with patients who were MRD positive and had continued maintenance therapy for an extra 3 years
  • 17.2% vs 50.4%, respectively, at 4 years after discontinuation

Maintain maintenance in MM?

Following the results from GEM2014MAIN trial, Sonja Zweegman and van de Donk wrote a letter to the editor addressing whether intensifying maintenance therapy can enhance survival outcomes in patients with MM and whether maintenance therapy is limited to 2 years in patients who reach MRD negativity.²

Intensifying maintenance therapy as an alternative therapy in MM

Intensifying maintenance therapy was predicted to enhance survival outcomes by decreasing relapses.^1,2 However, results remain controversial.²

• PFS was similar to the current standard of care maintenance therapy, lenalidomide-dexamethasone, and intensified treatment with lenalidomide-dexamethasone plus ixazomib in the GEM2014MAIN trial.
  • Lenalidomide-dexamethasone was used in combination; an investigation of lenalidomide monotherapy vs lenalidomide-ixazomib could have produced different results.
• PFS was improved after the addition of carfilzomib to lenalidomide compared with lenalidomide monotherapy regardless of MRD status, as seen in the FORTE trial (NCT02203643).

Ongoing clinical trials continue to investigate the benefits of intensified maintenance therapy vs current maintenance therapies (Table 2).

Table 2. Current clinical trials investigating maintenance therapies in patients with newly diagnosed MM*

*Adapted from Zweegman and van de Donk.2
Study	Therapies investigated
GRIFFIN (NCT02874742; Phase II)	Daratumumab, lenalidomide, bortezomib, and dexamethasone vs lenalidomide, bortezomib, and dexamethasone
MajesTEC-4 (NCT05243797; Phase III)	Lenalidomide and teclistamab vs lenalidomide
MajesTEC-5 (NCT05695508; Phase II)	Teclistamab plus daratumumab and lenalidomide with differing induction therapies

Continuation vs discontinuation of maintenance according to MRD status

Many patients remain on long-term maintenance therapy and with no evidence of disease progression²; however, treatment is associated with adverse events and a decreased quality of life. Current trials investigating long-term maintenance therapy vs discontinuation also provide contrasting results (Table 3).

Table 3. Long-term maintenance therapy vs discontinuation in patients with MM*

IFM, Intergroupe Francophone du Myélome; MM, multiple myeloma; MRD, measurable residual disease; PFS, progression-free survival. *Adapted from Zweegman and van de Donk.2
Long-term maintenance therapy benefits	Discontinuation of long-term maintenance therapy benefits
Patients given lenalidomide maintenance therapy until disease progression (DETERMINATION; NCT01208662) vs for 1 year (IFM 2009; NCT01191060) had longer PFS (20.2 months longer).	Initial evidence from the MASTER trial (NCT03224507) showed that discontinuing maintenance therapy in patients with sustained MRD negativity may be safe and worth consideration.
Myeloma XI (ISRCTN49407852) showed lenalidomide maintenance therapy improved PFS compared with observation for 3 years.	The same post-hoc analysis showed this improved PFS diminished after 4–5 years.

Conclusions

Current restrictions associated with MRD-based maintenance limit further research to discontinue maintenance therapy in patients with MM who are MRD negative.² This is due to the potential yielding of false-negative MRD results from poor quality bone marrow samples or the multifocal nature of the disease. Therefore, there is a need for²:

• Minimally invasive techniques, such as blood-based targeted mass spectrometry assays
• Improved and dynamic guidance on which patients can safely discontinue treatment
• Use of data acquired from new diagnostic techniques to identify patients who may benefit from alternative, intensified maintenance therapies