All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit the International Myeloma Foundation or HealthTree for Multiple Myeloma.
Join our
How to sequence BCMA-directed therapies in early relapsed/ refractory multiple myeloma
At the ESH 7th Translational Research Conference:
Multiple Myeloma
with Martin Kaiser, Mohamad Mohty, and Rakesh Popat
Saturday, October 5, 2024 | 09:10-10:10 CEST
Register nowThis independent educational activity is funded by GSK. All content is developed independently by the faculty. The funders are allowed no influence on the content of this activity.
The Multiple Myeloma Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the Multiple Myeloma Hub cannot guarantee the accuracy of translated content. The Multiple Myeloma Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.
Minimal/measurable residual disease (MRD) following primary treatment is prognostic of the long-term outcomes in patients with newly diagnosed multiple myeloma (NDMM). However, MRD measurements have not been used to modify therapy. The MASTER trial (NCT03224507) combined daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) to treat patients with NDMM, and used MRD by next-generation sequencing (NGS) to inform the need for and duration of post-transplant therapy.1
Below you will find a summary of the final primary endpoint analysis of the MASTER trial, presented at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition by Luciano J. Costa.2 Although this study is the first of its kind, there have been significant expectations for it and its practice-changing potential.
Figure 1. Treatment schedule for the MASTER trial*
ASCT, autologous stem cell transplantation; d, dexamethasone; Dara, daratumumab; IV, intravenous; K, carfilzomib; MRD, minimal/measurable residual disease; NGS, next-generation sequencing; PO, oral; R, lenalidomide.
*Adapted from Costa2 and data obtained from Costa et al.1
†Patients were evaluated every 8 weeks for the first 24 weeks and every 16 weeks thereafter, and MRD assessment was performed 24 and 72 weeks after completing therapy.
The study enrolled 123 patients from five sites between March 2018 and September 2020. Patient characteristics are presented in Table 1. The median follow-up was 23.8 months, and MRD status was reported in 118 patients (95%). Primary endpoint results are presented in Figure 2.
Table 1. Patient characteristics*
Characteristics, % (unless otherwise stated) |
Standard risk |
High-risk |
Ultra high-risk |
Total |
---|---|---|---|---|
Female |
38 |
48 |
46 |
43 |
Age |
|
|
|
|
Range, years |
36–79 |
35–77 |
41–72 |
35–79 |
Age ≥70 years |
23 |
22 |
8 |
20 |
Race/ethnicity |
|
|
|
|
White |
79 |
72 |
79 |
76 |
Racial/ethnic minorities |
21 |
28 |
21 |
23 |
ECOG 0–1 |
79 |
87 |
71 |
80 |
LDH ≥ULN |
15 |
26 |
25 |
21 |
Cytogenetic abnormality |
|
|
|
|
Hyperploidy |
51 |
44 |
17 |
41 |
del(13q) |
36 |
44 |
75 |
46 |
Gain/amplification of 1q |
0 |
52 |
83 |
36 |
del(1p) |
6 |
9 |
21 |
10 |
t(11;14) |
14 |
15 |
0 |
17 |
t(4;14) |
0 |
17 |
54 |
17 |
t(14;16) |
0 |
4 |
17 |
5 |
del(17p) |
0 |
26 |
58 |
21 |
R-ISS III |
2 |
26 |
46 |
20 |
ECOG, Eastern Cooperative Oncology Group; HRCA, high-risk cytogenetic abnormality; LDH, lactate dehydrogenase; R-ISS, revised International Staging System; ULN, upper limit of normal. |
Figure 2. Primary endpoint: MRD negativity (<10−5) at different timepoints
ASCT, autologous stem cell transplantation; HRCA, high-risk cytogenetic abnormality; MRD, minimal/measurable residual disease.
Treatment-related severe adverse events were reported in 22 patients (18%), the most common being pneumonia (n = 8) and pulmonary embolism (n = 3).1 Three patients died during treatment. All adverse events are shown in Table 2.
Table 2. Adverse events reported in >25% of patients*
Adverse events, % |
Any grade |
Grade ≥3 |
---|---|---|
Any |
100 |
74 |
Hematologic |
|
|
Neutropenia |
41 |
35 |
Lymphopenia |
28 |
22 |
Non-hematologic |
|
|
Fatigue |
55 |
9 |
Bone pain |
55 |
6 |
Rash maculo-papular |
41 |
4 |
Nausea |
40 |
0 |
Constipation |
39 |
0 |
Upper respiratory infection |
37 |
1 |
Diarrhea |
35 |
4 |
Insomnia |
28 |
2 |
Infusion-related reaction |
28 |
2 |
Dyspnea |
28 |
2 |
Cough |
26 |
0 |
Hypertension |
26 |
10 |
*Adapted from Costa.2 |
In summary, induction therapy with Dara-KRD, followed by ASCT, MRD-guided consolidation, and treatment cessation was feasible in ~96% of patients, with 72% reaching an MRD-free, treatment-free state (‘MRD-SURE’). Patients with standard and high-risk NDMM had comparable depths of response and a low risk of MRD reappearance or progression when treated with Dara-KRd and ASCT, and therapy was stopped according to MRD status. The quadruplet treatment combined with MRD assessment may provide an alternative treatment strategy, which offers the prospect of a sustained deep response without indefinite maintenance therapy. However, there is still an unmet need for a consolidation treatment option that can clear MRD and improve outcomes in patients with ultra-high risk MM.
Costa also presented the design of the MASTER 2 trial. The design of MASTER 2 will include the quadruplet therapy as induction, but extending it to six cycles, and using MRD as a decisive factor for further treatment. MRD-negative patients will be randomized between an additional three cycles of quadruplet therapy versus ASCT, followed by 1-year maintenance therapy with an anti-CD38 monoclonal antibody plus lenalidomide. Conversely, patients who remain MRD-positive after induction will be given ASCT consolidation and offered early deployment of a T-cell redirecting therapy versus anti-CD38 combined with lenalidomide as consolidation and maintenance. For all patients, the need of further maintenance therapy beyond 1 year will be decided upon using MRD status, as in the initial MASTER trial.
Your opinion matters
Subscribe to get the best content related to multiple myeloma delivered to your inbox