How effective is Pembro-Rd consolidation therapy after ASCT for high-risk multiple myeloma?

Multiple myeloma (MM) is a heterogeneous disease, and 34,920 newly diagnosed cases of MM are expected in the United States in 2021
.

With the application of proteasome inhibitors (PI), immunomodulators (IMiD) and monoclonal antibodies, the overall survival (OS) of standard-risk MM patients has exceeded 10 years
.

However, there are still 25%-45% of high-risk MM patients with a poor prognosis, with a median OS of 18-24 months
.

MM patients with or without lenalidomide (Len) maintenance treatment after autologous hematopoietic stem cell transplantation (ASCT) will face relapse
.

Previous studies have shown that the clonal expansion of T cells after ASCT is related to the improvement of patients' clinical outcomes
.

Therefore, the researchers hypothesized that the use of checkpoint inhibitors for post-ASCT consolidation therapy in MM patients can re-stimulate the inflammatory phenotype of T cells to target residual MM
.

In addition, Len can enhance the effects of T cells and NK cells to achieve anti-MM effects and reduce PD-L1 expression on MM cells
.

Based on this, the researchers conducted an open-label, phase II single-arm clinical trial to evaluate the PD-1 inhibitor pembrolizumab combined with lenalidomide and dexamethasone (Pembro-Rd) after ASCT in MM patients Consolidate the efficacy and safety of treatment
.

Research method Patients were enrolled between day +60 and day +180 after ASCT and received Pembro-Rd treatment for 4 cycles
.

After completing the fourth cycle, each subject was followed up for 30 days
.

Collect serious adverse events within 90 days after the end of treatment
.

Subjects who discontinued treatment for reasons other than disease progression continued treatment and followed up
.

The patients included in this study are all high-risk MM (HRMM) adult patients, and high-risk is defined as any of the following: International staging system (ISS) is stage III; del(13q) determined by cytogenetics; FISH with 1q amplification , 1p deletion, p53 deletion, t(4;14), t(14;16), t(14;20), low diploid; high-risk gene expression profile score
.

For patients who have achieved ≥very good partial remission (VGPR), minimal residual disease (MRD) assessment will be performed 30 days after the fourth cycle
.

Research results The study plans to enroll 58 patients
.

However, due to the higher incidence of immune-related toxicity and death in the Pembro group, the FDA stopped all studies evaluating the combination of PD-1 or PD-L1 inhibitors and IMiD on July 3, 2017
.

At the time of the FDA suspension, 12 patients had been enrolled and follow-up was allowed
.

1 Among the 12 patients enrolled with baseline characteristics, 5 cases (41.
7%) had ISS as stage III, 6 cases (50%) showed p53 deletion by FISH, 3 cases (25%) showed 1q21 amplification, and FISH showed coexistence There are 2 cases (17%) of ultra-high-risk patients with 1q21 amplification and 13q deletion
.

All patients received triple or quadruple induction therapy, of which 5 patients (42%) received bortezomib-Len-Dex (VRd) induction therapy; 4 patients (33%) received carfilzomib-Len-Dex (KRd) Induction therapy; 2 patients (24.
9%) received bortezomib-cyclophosphamide-Dex (VCd) induction therapy; 1 patient received bortezomib-cyclophosphamide-Len-Dex (VCRd) induction therapy
.

2 The median follow-up time for efficacy was 50.
7 months (range: 6-55.
5 months), and the median progression-free survival (PFS) of all patients from the date of ASCT was 27.
7 months (95% CI: 22.
6-not reached )
.

The 1-year and 2-year PFS rates were 90.
9% and 63.
6%, respectively
.

The patient's overall response rate (ORR) at the time of best response is 100%
.

The patient's complete remission (sCR) rate in the strict sense was 33% at the end of the induction therapy, 83.
3% at the end of the consolidation, and at the pre-set 7th follow-up point (median time after completion of treatment was 19 months) 83.
3% (Figure 1)
.

During the 2-year follow-up, 11/12 patients (91.
7%) had CR ≥CR, and 10/12 patients (83.
3%) achieved sCR
.

Of the 11 patients who completed the treatment, 8 patients were assessed for MRD status, of which 7 patients (87.
5%) were MRD negative by multi-parameter flow cytometry (cutoff value 10-5)
.

Figure 1: The best remission of patients in each follow-up period.
3 Safety.
All patients had one or more adverse events (AE) attributable to Pembro, Len, or Dex
.

Of the 97 reported AEs, 6.
2% were grade 3 and 93.
8% were grade 1 or 2
.

The most common non-hematological AEs were cough, diarrhea, and constipation, all of which were grade 1 or 2.
The most common hematological AE was neutropenia
.

Immune-mediated AEs of grade 1-3 include diarrhea (4 cases), fever (1 case), maculopapular rash (1 case) and dyspnea (2 cases), all of which are grade 1 or 2, and there is 1 serious AE.
Haemophilus influenzae pneumonia requires hospitalization, but it has nothing to do with Pembro
.

4 Effector T cell changes Compared with the beginning of the first treatment cycle (C1D1), the percentage of median effector memory CD4+ T cells in the CD3 compartment steadily decreased before C4D1 (P = 0.
037)
.

The effector memory CD8 compartment in the CD3 cell population showed a small decrease in the second cycle (C2D1) (P = 0.
032), and returned to a level that did not increase significantly in the third cycle (P = 0.
199)
.

In the second cycle (C2D1) and the third cycle (C3D1), the median memory Tregs decreased (P = 1.
0, P = 0.
199, respectively)
.

Research conclusions The results of this study show that the combination of PD-1 inhibitors and Len as post-ASCT consolidation therapy is well tolerated and effective in 12 patients with HRMM.
The median PFS is 2.
3 years, which exceeds the maintenance without Len in historical studies.
PFS in treated HRMM patients
.

Immune-mediated AEs were all grade 1 or 2, and the 1 severe AE observed was not related to Pembro
.

References: Noa Biran, Elli Gourna Paleoudis, Rena Feinman, Pembrolizumab, lenalidomide and dexamethasone post autologous transplant in patients with high-risk multiple myeloma.
Am J Hematol.
2021 Nov 1;96(11):E430-E433.
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