Comparison of Two Alkylating Agents Among Refractory Multiple Myeloma: Published and Our Retrospective Bendamustine Combination Experience with Melflufen As Single Agent

Introduction: Bendamustine is a synthetic alkylating agent made of both mustard and benzimidazole groups. It is used mainly in myeloma patients who have run out of classical treatment options and yet, have eligible performance status. Although data is still accumulating, there is not enough information to recommend a certain standard bendamustine dose or regimen in multiple myeloma. Melflufen is also an alkylator that is activated once metabolized by peptidases [1]. The logic this molecule selects and exterminates myeloma tumor cells by is that, myeloma cells overexpress aminopeptidases. Here, we have compared our and published bendamustine combination with melfufen data.

Methods: We retrospectively analyzed our relapsed or refractory multiple myeloma patients who received bendamustine between 2002 and 2020 at Ankara University Medical School. All statistical analyses were performed via SPSS statistics version 20.0 software. After Pubmed search, all published bendamustine combination and melflufen clinical data among relapse refractory myeloma patients were included in the analysis.

Results: Female/ male ratio was 14/ 18 (43.7 % / 56.3 %). Median age was 62 (36- 77) years. 22 (68.7 %) patients had Ig G myeloma, 6 (18.7 %) had Ig A myeloma and 4 (12.6 %) had light chain myeloma. ISS scores were as follows: I/ II/ III: 8 (25 %)/ 17 (53.1 %)/ 7 (21.9 %). FISH defined cytogenetics were available for 18 patients; 8 of them had normal chromosome analysis, 3 had only del13q, 1 had tri7. High risk cytogenetics was observed among 6 (33.3 %). R-ISS scores were as follows: I/ II/ III: 4 (22.2 %)/ 12 (66.7 %)/ 2 (11.1 %). Median prior lines of therapy was 3 (1- 6).

30 (93.8 %) patients had a history of bortezomib, 21 (65.6 %) had lenalidomide, 9 (28.1 %) had thalidomide. 21 (65.6 %) patients had undergone high-dose chemotherapy supported by autologous stem cell transplantation before bendamustine. 15 (46.9 %) patients were in treatment- refractory status at bendamustin initiation while 17 (53.1 %) used it for disease progression. Bendamustin was given either with Dexa (n= 13, 40.6 %) Bortezomib+ Dexa (n=6, 18.8 %), Lenalidomide+ Dexa (n=6, 18.8 %), Pomalidomide+ Dexa (n=5, 15.6 %) or Thalidomide+ Dexa (n= 2, 6.3 %). Bendamustine dose was 100- 120 mg/ m2/ day, 2 days monthly.

32 patients were followed up for median 26 months. Response to bendamustine treatment were as follows: Complete remission 4 (12.5 %), very good partial response 12 (37.5 %), partial response 8 (25 %), unresponsive 8 (25 %). Median progression free survival (PFS) was 5.6 (1- 40.6) months and overall survival (OS) was 17.3 (2- 79) months with bendamustine based treatment protocols. 15 (46.9 %) patients suffered grade ≥3 myelosuppression. Febrile neutropenia was experienced by 7 (21.9 %) patients, and 6 (18.7 %) had CMV reactivation during bendamustine treatment. There was no drug related mortality.

Conclusion: Although bendamustine is effective among highly refractory myeloma patients, toxicity profile and immune plus myelosuppression prevents long term use. Bendamustine in our experience in combination has provided efficacy comparable to earlier publications. Current single agent Melflufen data in advanced stages may be even more promising if combined with proteasome inhibitors or IMIDs.

References

1. Richardson, P.G., et al., Melflufen plus dexamethasone in relapsed and refractory multiple myeloma (O-12-M1): a multicentre, international, open-label, phase 1-2 study. The Lancet Haematology, 2020.

2. Knop, S., et al., The efficacy and toxicity of bendamustine in recurrent multiple myeloma after high-dose chemotherapy. haematologica, 2005. 90(9): p. 1287-1288.

3. Grey‐Davies, E., et al., Bendamustine, thalidomide and dexamethasone is an effective salvage regimen for advanced stage multiple myeloma. British journal of haematology, 2012. 156(4): p. 552-555.

4. Damaj, G., et al., Efficacy of bendamustine in relapsed/refractory myeloma patients: results from the French compassionate use program. Leukemia & lymphoma, 2012. 53(4): p. 632-634.

5. Ludwig, H., et al., Bendamustine-bortezomib-dexamethasone is an active and well-tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood, The Journal of the American Society of Hematology, 2014. 123(7): p. 985-991.

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