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Maintenance therapy in MM: Continuing therapy vs discontinuation according to MRD status
By Sabina Ray
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The introduction of novel drugs and treatment advances has provided more options for patients post-autologous hematopoietic stem cell transplant (auto-HSCT). However, there remains debate around post-auto-HSCT therapies in patients with relapsed/refractory multiple myeloma (MM) due to contrasting study results.
Here, we summarize key learning outcomes from the GEM2014MAIN (NCT02406144) trial and a post-trial letter discussing whether intensifying maintenance therapy could decrease relapse in patients with MM and enhance survival outcomes, specifically addressing the addition of ixazomib to lenalidomide-dexamethasone maintenance therapy post-auto-HSCT.
GEM2014MAIN summary
This open-label maintenance study compared the results of post-auto-HSCT maintenance therapy with lenalidomide and dexamethasone (RD) vs lenalidomide and dexamethasone plus ixazomib (IRD) in patients with MM.1 Eligible patients were:
- aged ≥65 years;
- in minimal response; and
- included in the GEM12MENOS65 trial.
A total of 332 patients were randomly assigned to the RD (n = 161) and IRD (n = 171) arms at specific dosing schedules (Figure 1). The primary endpoint was progression-free survival (PFS).
Figure 1. GEM2014MAIN study design*
RD, lenalidomide and dexamethasone; IRD, lenalidomide and dexamethasone plus ixazomib.
*Adapted from Rosiñol, et al.1
† Administered at 2 mg/d, Days 1‒21.
‡ Administered subcutaneously dose at given days of each cycle.
§ Administered at 40 mg at given days by 4-week intervals for six cycles.
‖ Administered at melphalan 200 mg/m2 or intravenous busulfan at 9.6 mg/kg plus melphalan at 140 mg/m2 followed by consolidation therapy with two additional cycles of bortezomib, lenalidomide and dexamethasone.
Key results
Baseline characteristics were well matched between the two groups (Table 1).
Table 1. Baseline characteristics overall and from RD and IRD subgroups*
|
Baseline characteristic, % (unless otherwise specified) |
Overall |
RD |
IRD |
|---|---|---|---|
|
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 |
|
CR, complete response; IRD, lenalidomide and dexamethasone plus ixazomib; ISS, International staging system; MRD, measurable residual disease; RD, lenalidomide and dexamethasone; sCR, stringent CR. |
|||
- 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*
|
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 |
|
*Adapted from Zweegman and van de Donk.2 |
|
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*
|
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. |
|
IFM, Intergroupe Francophone du Myélome; MM, multiple myeloma; MRD, measurable residual disease; PFS, progression-free survival. |
|
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
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