Phase I/II Trial of the Efficacy and Safety of Combination Therapy with Lenalidomide/Bortezomib/Dexamethasone (RVD) and Panobinostat in Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma

Background:  Induction therapy prior to autologous stem cell transplantation (ASCT) continues to improve with the use of multi-drug combination regimens.  Panobinostat (pano), a deacetylase inhibitor, was recently approved in combination with bortezomib/dexamethasone for relapsed myeloma based on the phase III PANORMA I trial for RRMM.  The addition of pano in PANORAMA demonstrated a near doubling in CR rate from 15 to 27%.  We previously reported phase I trial data of RVD + pano in newly diagnosed myeloma (NDMM) and demonstrated the pano can be safely combined with RVD.  Based on the encouraging preliminary data we pursued a phase II dose expansion to further explore the potential improvement in depth of response with RVD + pano in NDMM.

Methods:  The primary objective was to determine the safety/tolerability of pano and RVD in NDMM.  Secondary objectives were to determine efficacy as measured by the CR/nCR rate after 4 cycles, ORR, tolerability/toxicity, and progression free survival.  Patients had to have NDMM with indication for therapy and be eligible for ASCT with adequate organ function.  Panobinostat 10 mg was administered on days 1, 3, 5, 8, 10, 12; bortezomib 1.3 mg/m² was administered subcutaneously on days 1, 4, 8, 11; lenalidomide 25 mg on days 1-14; dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 on a 21 day cycle.  Adverse events (AEs) were graded by NCI-CTCAE v4 and responses were assessed by the modified International Uniform Response Criteria.

Results:  42 patients (pts) were enrolled; 12 in the dose escalation and 30 in the dose expansion.  The median age was 60 (range 44-79); male (n=30); ISS stage I (n=28); ISS stage II (n=10); ISS stage III (n=4); 14/42 pts had high risk myeloma (1 pt with t(4:14) and del17p; 1 pt with del 17p and 1q21; and 12 pts with only 1q21 amplification).

Among 42 pts, 2 completed only 1-2 cycles and 1 pt was inevaluable for response.  Among the 39 pts who completed 4 cycles and were evaluable for efficacy the ORR (≥PR) after 4 cycles was 93% (36/39) including nCR/CR in 17/39 (44%), VGPR in 10/39 (26%), PR in 9/39 (23%), and SD in 3/39 (8%) pts.  In 12 of 14 pts with high risk disease, who were evaluable for response, the ORR was 100% (12/12); the nCR/CR in 6/12 pts; VGPR in 4/12 pts; and 2/12 pts achieved a PR. 

25/42 (59%) pts completed induction therapy and underwent consolidation with ASCT; 5 pts completed induction therapy, came off study and did not proceed to ASCT.  8 pts choose a delayed transplant approach, completed induction therapy and stem cell collection.  6 of those 8 pts remain on trial with maintenance therapy (len/dex/pano) per protocol.  2 pts, neither with high risk disease, progressed after cycles 10 and 11 with extramedullary disease and plasma cell leukemia/central nervous system involvement, respectively.  4 additional patients have completed 2, 3, and 5 cycles of therapy and are pending ASCT.

Grade 3-4 hematologic adverse events included anemia (5); neutropenia (10); thrombocytopenia (16). Grade 3-4 nonhematologic toxicities included ALT elevation (1); AST elevation (1); constipation (2); diarrhea (4); dyspnea (2); fatigue/muscle weakness (5); syncope (2); MI (1); nausea (3); peripheral neuropathy (2); rash (1); DVT/VTE (3).

Infectious complications included grade 2 (G2) urinary tract infection (2); G2 upper respiratory tract infection (5); pneumonia (5); osteomyelitis/musculoskeletal (3); infection (3).

Treatment emergent serious adverse events related to therapy observed were: G3 pneumonia (9); G2 fever (5), G3-4 venous thromboembolic events (2); G3 diarrhea (2); atrial fibrillation (2). Other events included 1 pt each with G3 cellulitis, G3 myocardial infarction (MI), G3 febrile neutropenia, G2 diarrhea, G2 seizure, G3 hypotension and G3 sinusitis.  1 pt had a second primary malignancy – a newly diagnosed breast cancer during cycle 9 of therapy.

Conclusions:  Panobinostat 10 mg can be safely combined with full dose RVD in NDMM.  The side effect profile with use of subcutaneous bortezomib demonstrated minimal gastrointestinal toxicity/diarrhea and was a well-tolerated combination.  The combination of RVD+ pano lead to rapid disease control with high response rate after 4 cycles of therapy and ORR of 93% and significant depth of response with a 4 cycle nCR/CR rate of 44%.  Enrollment in dose expansion is near completion and full data will be presented at ASH and supports the study of panobinostat in a randomized trial for NDMM.