Bortezomib Retreatment in Relapsed Multiple Myeloma (MM): Results from a Binational, Multicenter Retrospective Survey

Abstract

In myeloma therapy retreatment after successful therapy is frequently considered. Here we present pooled data from a German and Swiss multicenter, retrospective survey (26866138MMY4014). The survey started in Germany and was later extended to Switzerland. German data have already been published before. Here we report on the entire cohort of patients for the first time. For inclusion into this analysis, patients with MM had to have had preceding bortezomib treatment, resulting in at least partial remission and a second therapy with Bortezomib on relapse. The intention of this trial was to provide further evidence of the value of a retreatment with bortezomib, description of predisposing factors and comparison of response quality and remission duration in this predefined patient group of bortezomib responders. Data from 36 centers and 94 patients were available for safety analysis. 34 patients had to be excluded from the efficacy analysis due to major deviations from the inclusion criteria, i.e. concomitant antineoplastic treatment, retreatment with bortezomib not being completed, no response during initial bortezomib treatment or missing information about MM-specific interim therapy. Thus 60 patients were left for the per protocol population (PP). Patients had a mean age of 65.5 years (40–89), 56.4% being male. Patients had received a mean of 3.7 prior therapies for multiple myeloma before initial bortezomib therapy, most frequently melphalan-prednisone (44.7%), dexamethasone (38.3%) and/or vincristine-adriamycin-dexamethasone (31.9%). Stem cell transplantation was undertaken in 26.6% of the patients. Mean cycle numbers for initial bortezomib therapy and retreatment were 5.8 and 4.5, respectively. The majority of patients (85.1% and 78.7%, respectively) received a bortezomib dose of 1.3 mg/m2. Concomitant dexamethasone therapy was administered to 43.6% and 62.8% of the patients, respectively. Between the initial bortezomib therapy and bortezomib retreatment 13.8% of the patients received other MM-specific interim therapy. The efficacy analysis was based on the PP population and revealed very encouraging responses. Overall response (OR) was defined as complete response (CR), nearly complete response (nCR) and partial response (PR). With a pre-defined OR of 100% for the initial bortezomib therapy, 63% (49.9–75.4%) responded again to retreatment. Best response is summarized in the table below. Subgroup analyses of the rates of clinical benefit (CR, nCR, PR or SD) were performed by treatment free interval (TFI) after initial bortezomib therapy (<= 6 months versus > 6 months) and by concomitant dexamethasone treatment. In patients with TFI > 6 months a higher rate of clinical benefit (89.7%) could be achieved as compared to TFI <= 6 months (61.9%). Concomitant dexamethasone treatment was associated with a lower rate of clinical benefit (76.5%) than without (84.6%). For 44 patients (46.8%) a total of 125 adverse drug reactions (ADRs) were documented. 21 serious ADRs were documented in 11 (11.7%) patients. 30 patients had died at the time of analysis. 2 patients died due to adverse events (pneumonia and pulmonary oedema) assessed as at least possibly related to bortezomib. For one fatal outcome (pneumonia) causality assessment has not been provided. This binational retrospective survey suggests that the safety profile is in line with the current summary of product characteristics of Velcade and that high remission rates and durable TFIs can be achieved by bortezomib retreatment. A TFI > 6 months could be a good clinical marker for a higher rate of clinical benefit. Results of an ongoing prospective trial on bortezomib retreatment are awaited to confirm these results. Initial bortezomib therapy (N=60) Bortezomib retreatment (N=60) * based on n=47 patients responding to bortezomib retreatment. Complete response (CR) 12 (20%) 8 (13.3%) Nearly complete response (nCR) 7 (11.7%) 3 (5%) Partial response (PR) 41 (68.3%) 27 (45%) Stable disease (SD) - (not allowed by selection criteria) 10 (16.7%) Progressive disease (PD) - (not allowed by selection criteria) 12 (20%) Median time to response 3.1 months 3.3 months* Median duration of response 6.9 months 6.1 months* Median treatment free interval 8.6 months 5.7 months

Retreatment with bortezomib alone or in combination for patients with multiple myeloma following an initial response to bortezomib

“…In conclusion, data from this prospective trial show that retreatment with bortezomib is feasible, effective, and well tolerated in patients with MM who have shown a response to initial bortezomib treatment lasting for at least 4 months. Together with data from other retreatment studies [11][12][13][14][15][16][17], these findings suggest that bortezomib retreatment offers another treatment option for patients, who typically receive several different treatment regimens throughout their clinical course.…”

“…The NCCN clinical practice guidelines state that patients with MM who are not refractory to their initial therapy (i.e., they relapse >6 months after completion of induction therapy) may be retreated with the same regimen [8]. Furthermore, a number of studies have suggested that retreatment with bortezomib after prior therapy with bortezomib or a bortezomib-based regimen is effective, resulting in substantial clinical response rates and no new or cumulative toxicity compared with initial bortezomib therapy [11][12][13][14][15][16]. Patients in these studies had frequently received intervening therapy between initial and subsequent bortezomib treatment, and although some of the studies included only patients who had responded to prior bortezomib therapy [11,13], others also included patients who had not responded to initial treatment [12,16].…”

“…Furthermore, a number of studies have suggested that retreatment with bortezomib after prior therapy with bortezomib or a bortezomib-based regimen is effective, resulting in substantial clinical response rates and no new or cumulative toxicity compared with initial bortezomib therapy [11][12][13][14][15][16]. Patients in these studies had frequently received intervening therapy between initial and subsequent bortezomib treatment, and although some of the studies included only patients who had responded to prior bortezomib therapy [11,13], others also included patients who had not responded to initial treatment [12,16]. Based on the available evidence, retreatment with bortezomib after a prior bortezomib regimen would appear to be feasible and offer the potential for further clinical benefit in patients with relapsed MM.…”

Treatment strategies in relapsed and refractory multiple myeloma: a focus on drug sequencing and ‘retreatment’ approaches in the era of novel agents

“…61 Although response rates to retreatment were higher in patients who had responded to initial bortezomib treatment, 13% of patients with less than a PR with the initial therapy had an objective response following retreatment. 61 In addition, in a study by Hrusovsky et al 62 subgroup analyses of the rates of clinical benefit (CR, near CR, PR or stable disease) were performed according to treatment-free interval (TFI) after initial bortezomib therapy (p6 months vs 46 months) and according to concomitant dexamethasone treatment. In patients with a TFI 46 months a higher rate of clinical benefit (89.7%) could be achieved as compared with patients with a TFI p6 months (61.9%).…”

“…64 From a safety and toxicity perspective, retreatment with bortezomib is further supported by the results derived from regimens using weekly bortezomib dosing schedules [65][66][67] or subcutaneous administration. 68 A number of additional prospective and retrospective studies have been conducted to examine retreatment with bortezomib, 62,[69][70][71] (Table 2) and all of these studies suggest that re-using bortezomib in later lines is feasible and can result in responses in a considerable proportion of patients.…”