Escalation Treatment Algorithm with Bortezomib, Dexamethasone and Bendamustine for Patients with Relapsed or Refractory Multiple Myeloma: A Singel Centre Experience.
Authors: Fenk Roland , Michael Mark , Zohren Fabian , Graef Thorsten , Czibere Arkosch , Balleisen Sebastian , Neumann Frank , Rohr Ulrich-Peter , Steidl Ulrich , Haas Rainer , Kobbe Guido 
Published: October 2019

Abstract
Bortezomib has improved the outcome of patients with multiple myeloma. Nevertheless, bortezomib monotherapy achieves responses in less than 50% of patients with advanced disease. Combination therapy can improve response rates but is associated with more adverse events such as neuropathy or myelosuppression. Therefore, we evaluated a step-wise escalation treatment algorithm for patients with relapsed or refractory myeloma.
The initial treatment (step1) consisted of bortezomib monotherapy (1.3mg/m2 on day 1,4,8,11). Patients who did not show a at least 25% reduction of paraprotein at the beginning of cycle 2 received an escalated treatment (step2) with bortezomib and dexamethasone (40mg on day 1,4,8,11). The next treatment escalation (step3) was performed by addition of bendamustine (50–100mg/m2 on day 1 + 8) to bortezomib and dexamethasone. Step3 was used for patients who did respond with less than a minor response to one cycle of step2 treatment.
We report on 48 patients who have been treated at our institution according to this regimen. Patients median age was 59 years with a median β2-microglobuline level of 3.8 g/dl and median albumine level of 3.7 g/dl. All patients were heavily pre-treated with in median three prior treatment regimen including high-dose therapy and thalidomide in more than 90% of patients. Escalation therapy was applied as planned to 36 (75%) patients, whereas 12 (25%) patients received step2 at the beginning of treatment due to physicians decision because of fulminant disease progression with hypercalcemia or severe tumor burden. Toxicity was as expected for bortezomib monotherapy and was manageable with escalated treatment steps. Response rates for patients in step1 were 11% nCR, 36% PR and 11% MR. In step2 (n=26) response rates were 31% PR, 15% MR and in step3 (n = 7) 43% PR and 29% MR. This results in an overall response rate of 80% for all patients. Patients with fulminant progressive disease who needed upfront treatment with step2 had an inferior overall response rate of 42% in comparison to 90% for patients who were treated according to the planned treatment schedule. With a median follow-up of 26 months the median time to progression and overall survival was 9 months and not reached for patients in the planned program and 2 and 4 months for the patients with upfront escalated therapy. Univariate analysis including several conventional prognostic parameters revealed physicians decision for upfront escalated treatment and age >60 years as the only bad prognostic factors. Interestingly, for patients within the planned treatment schedule, response to previous therapies, the extent of paraprotein reduction and the required escalation step had no impact on response duration.
Another interesting observation of our single center study was that re-exposure of step3 treatment at the time of relapse (n=8) resulted in a new remission in 50% and in stable disease in 38% of patients.
In conclusion, escalating therapy with bortezomib, dexamethasone and bendamustine induces durable remissions in the majority of patients, even in the presence of poor prognostic parameters. However, this treatment algorithm is not applicable for patients presenting with fulminant disease progression, as these patients need more aggressive regimens.