Maintenance vs. no maintenance
- Patient Characteristics
The clinical data and biological characteristics of 181 patients with maintenance and 45 patients without maintenance were summarized in Table 1. Significant differences can be observed in ASCT. The proportion of patients who adopted ASCT was higher in the maintenance group (17.1 vs. 2.3%). Other baseline characteristics were basically balanced.
- Survival
The median follow-up duration for all patients was 36.9(3.6—86.0)months,
the median PFS was 41.1 (95%CI: 34.5-47.7) months for the patients who received maintenance treatments, and 10.5 (95%CI: 8.0-13.1) months for the no maintenance group (p < 0.001) (Figure 1A). The median OS of the arm adopted maintenance was not reached, the median OS of the patients who without maintenance was 38.6 (95%CI: 27.0-50.2) months, the survival was distinctly prolonged for patients who adopted maintenance (p < 0.001) (Figure 1B).
- Response
During maintenance, the upgrade of response from PR to at least VGPR was more common in the maintenance group ( 34.3 vs. 13.3%, p= 0.006). The best response after maintenance, the PR rate was 17.7%, and at least VGPR rate was 82.3% in patients who received maintenance versus 42.9% and 57.8% in the no maintenance group (p < 0.001).
Proteasome inhibitor vs. Immunomodulators
- Patient Characteristics
Baseline characteristics of 181 patients who received maintenance treatments, including 127 with PI and 54 with IMiDs, were presented in Table 2. No significant statistical difference was observed between the two groups of variables. The patients who received PI maintenance were slightly younger, with a median age of 62 years old compared to 63 years old in the IMiDs group. The proportion of patients using PD as the induction regimens was slightly higher in the PI group (16.5 vs. 7.4%). The CR rate after induction and consolidation therapy was higher in the PI group (44.9 vs. 29.6%). In the PI group, there are 7 (5.5%) patients with PAD maintenance, 93 (73.2%) patients with PCD maintenance, 21 (16.5%) patients with PD maintenance, and 6 (4.8%) patients with VRD maintenance. In the IMiDs group, there are 5 (9.3%) patients with R maintenance, 28 (51.9%) patients with RD maintenance, 19 (35.2%) with T maintenance, and 2 (3.7%) with TD maintenance.
- Survival
The median follow-up of the total maintenance patients was 39.2 (3.6-86.0) months. During the follow-up, 62 patients (48.8%) and 38 patients (70.4%) had disease recurrence or progression in PI group and IMiDs group respectively, with a median PFS of 43.7 (95% CI: 30.3 - 57.1) months versus 38.5 (95% CI: 19.1 – 58.0) months (p = 0.034) (Figure 2A). As for the overall survival, 21 patients (16.5%) and 17 patients (31.5%) died during the follow-up, with a median OS not reached in the PI group versus 78.5 (50.1– 106.9) months in the IMiDs group (p = 0.041) (Figure 2B).
- Subgroup Analysis
3.1 Age and Creatinine
For patients younger than 65 years, maintenance with PI significantly prolonged the OS (p= 0.032), with a 5-year OS of 81.5 versus 66.1%, respectively. No statistical difference was observed in PFS between the two groups, with a 3-year PFS of 56.6 versus 55%. As for patients aged 65 years and older, there was no significant difference in neither PFS nor OS between the two groups. For renal function, OS benefit was observed in the PI group in patients with baseline serum creatinine < 2 mg/dl, with a 5-year OS of 76.8 vs. 64.9% (p=0.036). In those patients with normal renal function, PI maintenance therapy also improved the PFS compared with the IMiDs group, with a 3-year PFS of 58.4 vs. 52.0% (p= 0.07), although the statistical difference was not significant. In the patients whose baseline serum creatinine ≥ 2 mg/dl, there was no difference in PFS and OS between the two maintenance treatment options (Table 3).
3.2 Response after induction and consolidation therapy
Patients achieving the only PR after induction and consolidation therapy experienced a significantly longer PFS and OS with PI maintenance compared with IMiDs, with 3-year-PFS of 44.8 and 25.0% (p= 0.007), 5-year-OS of 77.9 and 45.1% (p= 0.002). However, in the patients achieving at least VGPR, no difference was observed between the two groups in PFS or OS (Table 3).
3.3 Clinical Stages
Patients were stratified according to clinical stages. Patients in ISS 1, DS 1, and RISS 1 were classified as non-high risk; the other patients in ISS 2-3, DS 2-3, and RISS 2-3 were classified as high risk. Overall, high-risk patients receiving PI maintenance therapy can improve survival. The 3-year PFS of high-risk patients with PI or IMiDs maintenance was 57.0 vs. 40.3%, 56.5 vs. 49.5%, 52.4 vs. 48.6%, respectively (p= 0.002, 0.02, 0.06). The 5-year OS of high-risk patients with PI or IMiDs maintenance was 71.4 vs. 55.2%, 73.9 vs. 62.9%, 75.6 vs. 62.6%, respectively (p=0.059, 0.047, 0.044). In non-high-risk patients, no difference was observed in PFS or OS between two maintenance therapy options (Table 3).
- Adverse Reactions
During maintenance treatment, the incidence of second primary malignancies was higher in the IMiDs group (0 vs. 3.7%, p= 0.029). There were no significant statistical differences in other adverse reactions between the two maintenance treatment options. The most common hematological adverse events are thrombocytopenia (5.5 vs. 7.5%) and Neutropenia (4.7 vs. 3.7%). For non-hematological adverse events, the most frequent were peripheral neuropathy (23.0 vs. 33.3%) and infection (22.0 vs. 25.9%). The results were presented in Table 4.
Treatment Duration of Proteasome Inhibitor Maintenance
Proteasome Inhibitor bortezomib-based regimens are the main maintenance therapy options in recent years, with 3-month a cycle. This paradigm of long-term treatment needs to consider many other factors such as patients’ quality of life, convenience, and burden of long-term treatment. Thus, we perform a secondary analysis to find the optimal treatment duration. The median treatment duration of the patients who received bortezomib-based maintenance after induction and consolidation therapy was 12.9 (0.8-45.1) months. The PFS was improved with the increasing treatment duration (p< 0.001). The OS was significantly prolonged in the patients who received ≥12 months of bortezomib-based maintenance than those with maintenance <12 months, with the 5-year OS of 91.9 vs. 51.1% (p< 0.001) (Figure 3A). However, no difference was observed in OS between the patients who received the 12-24 or ≥ 24months of bortezomib-based maintenance (p= 0.292), with a 5-year OS of 96.4 vs 86.6% (Figure 3B).
The relationship between the maintenance treatment course and the outcome is basically consistent with the above result. The median maintenance cycles were 4 (1-14) of the patients completed after induction and consolidation therapy. The PFS was improved with the increase of the number of the treatment course (p< 0.001), the OS was significantly different in patients with < 4 vs. ≥4 maintenance treatment courses (p< 0.001), with a 5-year OS of 42.3 vs. 92.7%. The OS between patients with 4-9 vs. ≥ 9 maintenance treatment courses was not statistically significant (p=0.214), with a 5-year OS of 95.5 vs. 83.7%.