Outcomes with Panobinostat in Heavily Pretreated Multiple Myeloma Patients

Background: Multiple myeloma remains a largely incurable disease despite major advances in therapy. Panobinostat (pano) is an oral pan histone-deacetylase (HDAC) inhibitor which improves outcomes when added to bortezomib and dexamethasone for multiple myeloma in early relapse and even re-sensitizes myeloma to proteasome inhibitors. In 2021, the FDA withdrew pano from the US market but it is still utilized to this day in Europe. Notwithstanding, this drug remains a viable option for patients who have progressed beyond many of our standard therapies. Here, we report the use of pano-based combinations at an academic medical center in a heavily pretreated population.

Methods: We retrospectively analyzed 105 patients who were treated with pano for multiple myeloma at The Mount Sinai Hospital between October 2012 and October 2021. We reviewed baseline demographics, treatment characteristics including the doses of pano used and the agents it was combined with, as well as safety, tolerability, and efficacy. The objective response rate (ORR) and clinical benefit rate (CBR) will be reported along with 95% exact confidence intervals (CI). The outcomes of duration of response (DOR), progression free survival (PFS), and overall survival (OS) will be estimated using the method of Kaplan-Meier. The confidence interval for the median DOR, PFS, and OS times will be constructed based on the method of Brookmeyer and Crowley.

Results: In total, 105 patients were treated with pano of whom 56.8% were female with a median age of 65 (range 37-87). Patients were heavily pretreated with a median of 6 prior lines of therapy, with 70.5% of them having had prior transplants, and over half (53.3%) being triple class refractory. Fifty-four percent had high-risk cytogenetics. The 20 mg dose of pano was most commonly used (64.8%), followed by the 10 mg (22.9%) and 15 mg (11.4%) doses, and pano was generally used as part of a triplet (61.0%) or quadruplet (30.5%) combination. Pano was combined with steroids along with a 3^rd and sometimes 4^th drug, most commonly with lenalidomide, pomalidomide, carfilzomib, and daratumumab in descending order of utilization. The most common grade 3+ toxicities were hematologic, primarily neutropenia (34.3%), thrombocytopenia (27.6%), and anemia (19.1%), while the most common non-hematologic grade 3+ toxicity was fatigue in 15.2% of patients. Of the 101 response evaluable patients, ORR was 23.8% (95% CI 16.0%-33.1%) with a median DOR of 7.3 months (95% CI 3.7-15.7 months; range 0.4-20.9 months), while the CBR was 35.2% (95% CI 26.2%-45.2%). The patients had a median PFS of 3.3 months (95% CI 2.1-4.2 months) and OS of 19.1 months (95% CI 15.9-30.5 months).

Conclusion: Pano-based combination therapies were well-tolerated and yielded modest response and clinical benefit rates in heavily pretreated patients. Over half of the patients in this cohort were triple class refractory. Immunomodulators (IMiDs) were most frequently combined with pano to attain these results, although, to date there are no randomized trials demonstrating benefit with these combinations. As a convenient oral option with a unique mechanism of action, pano may play an important role in recapturing responses in patients who have relapsed beyond standard therapies. The utility of pano in combination with IMiDs, in particular, warrants further investigation.

Richter:Oncopeptides: Consultancy, Honoraria; Secura Bio: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy.