Bortezomib-bendamustine-melphalan or high-dose melphalan in autologous hematopoietic stem cell transplantation for previously transplanted relapsed multiple myeloma – a single center retrospective cohort study Free

Introduction Despite the introduction of numerous novel agents, high-dose melphalan (HDM) followed by autologous hematopoietic stem cell transplantation (ASCT) remains a cornerstone of treatment for eligible multiple myeloma (MM) patients. Both the proteasome inhibitor bortezomib (Roussel (2017) Blood, Gimsing (2015) BMT), and the alkylating agent bendamustine (Mark (2013) BBMT, Martino (2016) BMT, Gomez-Atreaga (2019) BMT) has been investigated in combination with melphalan and ASCT without significant increase in toxicity. To mitigate the expected decrease in time to next treatment (TNT) and progression following ASCT in second line (ASCT2) compared to first line (ASCT1), the conditioning regimen for patients eligible for ASCT2 at Uppsala University Hospital (UUH) was changed to the combination bortezomib-bendamustine-melphalan (BBM).

Method This retrospective cohort study evaluates the use of BBM, given to 43 consecutive patients with relapsed MM after HDM and ASCT1, during the period of 1 Nov 2011 until 31 Oct 2018 at UUH. The cohort was compared to 21 consecutive patients receiving standard HDM at ASCT2 between Jun 2006 and Jul 2011, and 22 patients between Nov 2018 and Feb 2023. Patients were identified through the local European Society for Blood and Marrow Transplantation registry. Data was collected from electronic medical records.

Inclusion criteria was a diagnosis of MM, and ASCT2 performed in second treatment line at UUH. Exclusion criteria were tandem ASCT or lack of follow-up data.

The BBM protocol consisted of bortezomib 1.3 mg/m² subcutaneously on day -5 and -2, bendamustine 100 mg/m² intravenously (IV) on day -3 and -2 and melphalan 200 mg/m² IV (or 140 mg/m² if the glomerular filtration rate was estimated below 30 ml/minute) on day -2.

Results The cohorts were balanced. The average Charlson Comorbidity Index was 1.70 for BBM and 2.23 for HDM patients, p=0.47, and the time between ASCT1 and ASCT2 were 42.0 months and 42.3 months respectively.

The Kaplan-Meier estimated median TNT for BBM-treated patients was 28.9 months (CI 24.2-34.9) after ASCT1 and 21.4 months (CI 15.6-29.7) after ASCT2, and 32.1 months (CI 25.0-42.2) and 19.4 months (CI 16.4-40.0) for HDM-patients. The reduction of TNT for ASCT2 was 26% for BBM and 39% for HDM cohort, p=0.198. The corresponding reduction of progression-free survival (PFS) for ASCT2 was significantly in favor of BBM with 15% (21.6 to 18.4 months) compared to HDM with 39% (25.0 to 15.4), p=0.0122.

The Kaplan-Meier estimated median overall survival after ASCT2 was 72.2 months (CI 40.8-125.3) for BBM and 51.5 months (CI 29.5-81.4) for HDM, p=0.14. The TNT after ASCT2 was on average 0.75 (±0.45) of the TNT after ASCT1 for each individual patient in the BBM cohort, and 0.66 (±0.41) for the HDM cohort, p=0.41. Eight patients in the HDM cohort received daratumumab as induction treatment for ASCT2, of which 75% achieved at least very good partial remission (VGPR), which can be compared with 34% in the rest of the HDM cohort, p=0.034, and 35% in the BBM cohort at ASCT2. The use of either consolidation or maintenance therapy after ASCT2 was 19% in the BBM cohort and 42% in the HDM-cohort, p=0.019.

The average time to neutrophil recovery was 13.4 days (±1.70) for the BBM, and 13.0 days (±2.86) for the HDM cohort, p=0.43. The average time of hospitalization after stem cell infusion were 16.7 days (±4.38) for BBM- and 15.3 days (±2.57) for HDM-patients, p=0.074.

There was no statistically significant difference in the total frequency of severe adverse events (AE). Oral mucositis and hypokalemia were more common in the BBM cohort, and nausea more common in the HDM cohort. The most common severe AE were febrile neutropenia (FN) in both cohorts. There was a statistically non-significant trend towards febrile neutropenia being more common in the BBM cohort, 26 BBM- vs 17 HDM-patients, p=0.052. There were no cases of invasive fungal infection or fatal COVID-19.

Conclusion Adding bortezomib and bendamustine to HDM as conditioning therapy with ASCT for multiple myeloma was well tolerated and the profile of adverse events falls within the expected for HDM alone. The relative reduction in PFS between ASCT2 and ASCT1 was significantly lower in the BBM cohort. In addition, a trend toward better efficacy with BBM was seen in all endpoints, most notably in overall survival, supporting the need for larger prospective studies.

ClinicalTrials.gov ID:NCT06245629