Pano/GemBuMel May Be Safe/Effective for Treatment of High-Risk, R/R Myeloma

Yago Nieto, MD, PhD

The combination of panobinostat (Farydak),, gemcitabine, busulfan, and melphalan (Pano/GemBuMel) for patients with high-risk or relapsed/refractory (R/R) myeloma is safe and effective, according to findings from a phase 2 trial (NCT02506959) presented at the 2023 Transplantation and Cellular Therapy Meeting (TCT).

In the trial, investigators evaluated the Pano/GemBuMel regimen among 80 patients, including 48 in the autologous stem cell transplant (ASCT)-1 cohort and 32 in ASCT-2. Patients aged 18-65 years with a diagnosis of R/R myeloma with high-risk cytogenetic abnormalities or plasma cell leukemia were included. Patients were also required to have adequate organ function to be enrolled.

The primary end point of the study was progression-free survival (PFS), and secondary end points included complete response (CR), overall response rate (ORR), overall survival (OS), and post-ASCT minimal residual disease (MRD) by multiparametric flow cytometry (sensitivity: 10^-5).

Findings presented at TCT revealed that at a median follow-up of 51 (8-78) months, the median PFS for patients receiving a frontline ASCT-1 was 45 months,ompared with 21 months for those receiving a first salvage ASCT-1, and 32 months for the ASCT-2 group, respectively. The median OS was not reached in any subgroup. The ORR and CR in patients with measurable disease at ASCT were 67% for the ASCT-1 cohort and 40% for ASCT-2.After ASCT-1 and -2, MRD-negativity improved (8.5%-23%, P < .0001; 34%-55%, P = .02).

For safety, 2 treatment-related deaths were observed in the ASCT-2 cohort. Grade 2 or 3 toxicities seen in the study consisted of mucositis in 52 and 17 patients, diarrhea in 18 and 9), rash in 14 and 1, and transaminitis in 14 and 21 patients in the ASCT-1 vs ASCT-2 cohorts.

“Our conclusion is that panobinostat/GemBuMel is a regimen that is highly active. It leads to MRD-negativity in a significant number of patients, even patients with R/R disease, and it seems better in this non-randomized but concurrent match pair comparison with concurrent controls,” said Yago Nieto, MD, PhD, in an interview with Targeted Oncology^TM.

In the interview, Nieto, The University of Texas MD Anderson Cancer Center, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, discussed the full data from the phase 2 trial of Pano/GemBuMel for patients with high-risk, R/R myeloma.

Targeted Oncology: Can you provide a high-level overview of your presentation on at TCT 2023?

Nieto: I presented a study we did in in high-risk, relapsed/refractory myeloma, studying a new regimen of panobinostat with gemcitabine, busulfan, and melphalan, also known as Pano/GemBuMel, that we did based on our prior lab work that has shown a striking synergy between those agents. We completed the study with 80 patients, and we did a matched pair comparison of study patients with concurrent controls, who were patients eligible for the study, but instead received a standard-of-care transplant with melphalan or busulfan, and melphalan at our center.

What were the methods and design behind the study?

This study was a prospective phase 2 trial with 2 different cohorts. The first cohort included patients who were receiving a first transplant, either for high-risk disease based on high-risk cytogenetic abnormalities, or for relapse disease. The second cohort were patients receiving a second transplant. That is patients who had failed a previous transplant. The regimen consisted of oral panobinostat given concurrently with gemcitabine, busulfan, and melphalan, which is a regimen we had previously studied in in refractory myeloma and we had published. Following the completion of the regimen, the patient received stem cell infusion, and then usual maintenance as any other post-transplant maintenance as any other myeloma patient.

What were the findings from the study?

We enrolled 48 patients in the first cohort, that is a patient receiving a first transplant, and 32 patients in the second cohort, which were patients receiving a second transplant. The study was conducted between the end of 2015 and 2021, so over the course of 6 years.

The response rate in patients in the first cohort was 67% with 40% complete remissions, and that was in patients with measurable disease at transplant. In patients receiving a second transplant, the overall response and complete response rates were 93% and 64%, respectively. Importantly, we saw an improvement of bone marrow MRD-negativity. determined by multiparametric flow cytometry, which has a high sensitivity of 10^-5 from before to after transplant in both settings. In patients receiving a first transplant, it went from 8% to 23%, and in patients receiving a second transplant, it went from 34% to 55%. In both cases this was statistically significant, and this has been shown in other studies before. Achieving an MRD-negativity had important favorable prognostic implications.

What can you tell us about the safety results?

The regimen in terms of toxicities was safe. There was the expected adverse event profile that we had seen with GemBuMel of mucositis and asymptomatic elevation of transaminase. The treatment-related mortality was 2% in the study, and then we did the matched pair analysis with concurrent controls. We had around 370 concurrent controls, and those were matched in either setting, either getting a first transplant or a second transplant. They were matched for age, deletion 17 P, number of prior lines of therapy, and response at the time of transplant.

What we saw was that the panobinostat GemBuMel significantly improved progression-free survival, when done as a first transplant compared with matched controls, but the outcomes were very similar when done as the second transplant. For overall survival, there were some numerical differences in favor of pano/GemBuMel, but they didn't reach statistical significance for overall survival. Our conclusion is that panobinostat GemBuMel is a regimen that is highly active. It leads to MRD-negativity in a significant number of patients, even patients with relapsed and refractory disease, and it seems better in this non-randomized but concurrent match pair comparison with concurrent controls. It seems better when done as a first transplant up to now with standard regimens.

What do these findings mean for community oncologists who are treating patients with myeloma?

The field of myeloma is moving rapidly now, which is great news. We have seen a lot of new drugs and [chimeric antigen receptor] T-cell therapies, and bispecific antibodies. Now, there are a lot of options for patients. Transplant remains an option, particularly first transplants. For second transplants which were done in good prognosis, in patients who had relapsed more than a year after the first transplant, and who had good productive features, I think are going to fall more out of favor, given that we have good options like CAR T and bispecific antibodies. But for patients who had never seen a transplant, this remains a good option.

In addition to all the other new therapies, we are still improving high-dose chemotherapy regimens. I think it's good news and this study builds off of [prior research]. I think it's good news for patients who are otherwise fit, younger than 65 with adequate organ function, and who are good candidates for high-dose chemotherapy. It's been useful that we have more effective high dose regimens than just single-agent melphalan.