Pembrolizumab in combination with Pomalidomide and Dexamethasone for relapsed / refractory multiple myeloma
Immunotherapy in multiple myeloma is emerging as an effective modality in therapy of multiple myeloma with the approval of several monoclonal antibodies and encouraging results for vaccines and T cell therapy.
Programmed death 1 ( PD-1 ) receptor and its ligand ( PD-L1 ) is one mechanism of immune evasion by multiple myeloma to suppress T cell function.
Researchers have hypothesized that Pembrolizumab ( Keytruda ), a PD-1-blocking antibody, would enhance immune modulatory properties of Pomalidomide ( US: Pomalyst; EU: Imnovid ) in patients with relapsed / refractory multiple myeloma ( RRMM ).
In this single center, phase II study, 48 patients with RRMM received 28-day cycles of Pembrolizumab ( at a dose of 200 mg IV ) every 2 weeks ( in a run in phase, first 6 patients received 200 mg IV every 4 weeks ) plus Pomalidomide ( 4 mg daily x 21 days ) and Dexamethasone 40 mg weekly.
Study objectives were measurements of safety & efficacy and correlation of the CD3/PD-1 on T cells and PD-L1 on plasma cells with response.
The median age was 64 years ( range: 35-82 ); 38% were black and 65% were men, Patients had a median of 3 lines of prior therapy ( range: 2-6 );
All patients had received both IMids ( immunomodulatory drugs ) and proteosome inhibitors; 70% had prior auto-stem cell transplant.
80% were double refractory to both IMids ( Lenalidomide ) and proteosome inhibitors [ Bortezomib ( n=18 ) or Carfilzomib ( n=20 ) ] and an additional 20% were refractory to Lenalidomide.
The median time from multiple myeloma diagnosis to study entry was 4 years ( range: 1-25 ).
Most common cytogenetic abnormalities were 1q+ ( 60% ), hyperdiploidy ( 15% ) and high-risk FISH [ del 17p, t(4:14) and/or t(14:16) ] in 38%.
Six patients had soft tissue extramedullary plasmacytomas.
There were no infusion-related reactions. Hematologic toxicities ( greater than or equal to grade 3 ) were anemia ( 21% ), neutropenia ( 40% ), lymphopenia ( 15% ) and thrombocytopenia ( 8% ).
Non-hematologic events grade greater than or equal to 3 were fatigue ( 15% ), hyperglycemia ( 25% ), upper respiratory tract infections ( 21% ), rash ( 10% ); and most frequent grade greater than or equal to 2 were dyspnea ( 54% ), dizziness ( 44% ), increased creatinine ( 38% ), edema ( 35% ), rash ( 30% ), constipation ( 30% ) and arrhythmias ( 19% ).
Events of clinical significance, autoimmune mediated, included interstitial pneumonitis ( 13% ), hypothyroidism ( 10% ), transaminitis ( 6% ), adrenal insufficiency ( 4% ) and vitiligo ( 2% ).
Nine patients had Pomalidomide dose reductions due to rash, neutropenia, palpitations and fatigue; one patient reduced Pembrolizumab for pneumonitis.
At a median follow up of 10 months ( range: 2-18 ): 25 patients continue on the study and 23 patients discontinued therapy due to disease progression ( n= 15 ), side effects ( n=7 ) and protocol violation ( n=1 ).
Five patients died while on study due to progressive disease ( n=3 ), sepsis ( n=1 ), and one from a cardiac event.
Three additional patients died off therapy.
On intent to treat analysis; the overall response rate ( ORR ) with greater or equal to partial response were observed in of 27 of 48 pts ( 56% ) including: sCR [ stringent complete response ] ( n=4, 8% ), nCR [ near complete response ] ( n=3, 6% ), VGPR [ very good partial response ] ( n=6, 13% ), PR [ partial response ] ( n=14, 29% ).
Additionally, 7 patients ( 15% ) had minimal response, 9 ( 19% ) had stable disease, 2 progressed and 3 were not evaluable for response.
Of 38 double refractory patients ORR was 55% including, sCR ( n=2, 5% ), nCR ( n=2, 5% ), VGPR ( n=4, 10% ) and PR ( n=13, 27% ).
Of 18 high-risk patients ORR was 33% including VGPR ( n=2, 11% ) and PR ( n=4, 22% ).
Median duration of response for responding patients was 8.8 months and for patients greater than or equal to VGPR, duration of response was 10.7 months.
In conclusion, Pembrolizumab, Pomalidomide and Dexamethasone regimen has shown promising durable therapeutic activity and an acceptable safety profile in patients with relapsed / refractory multiple myeloma. ( Xagena )
Badros AZ et al, ASH ( American Society of Hematology ) Meeting, 2016
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