Real world experience of bortezomib re-treatment for patients with multiple myeloma at first relapse (2016)

The routine use of proteasome inhibitors and immunomodulatory agents has improved the outcomes for patients with multiple myeloma (MM). In the United Kingdom (UK), bortezomib (Velcade, Janssen-Cilag Ltd, High Wycombe, UK) based triplet regimens are commonly used as first-line therapy for both transplant eligible and ineligible patients. The efficacy of re-treatment with bortezomib monotherapy or bortezomib plus dexamethasone in subsequent lines of therapy has been previously reported (Petrucci et al, 2013), (Sood et al, 2009). However there are limited data on re-treatment at first relapse, particularly with bortezomib-based triplet regimens, which are more commonly used in current practice. This was a retrospective analysis of MM patients at first relapse treated with bortezomib, who had also received bortezomib as first line therapy. Twenty-three sequential patients from a single UK centre who had achieved at least a partial response (≥PR) and a treatment-free interval of a minimum of 60 days from first line bortezomib treatment [i.e. not refractory (Anderson et al, 2008)] were identified. All patients had completed first relapse therapy at least 2 months prior to the data cut-off for analysis. Response to treatment and disease progression were defined by the International Myeloma Working Group criteria. Patient demographics are shown in Table S1.The median age at initial treatment was 63·3 years (range 38·7–97·7). Eleven patients (48%) were International Staging System (ISS) stage 1, six (26%) were stage 2 and six (26%) were stage 3. Fourteen patients (78%) had cytogenetic data available, of which five (22%) had adverse risk features as defined by the presence of t(4;14), t(14;16) or del(17p). Median follow up was 3·8 years from start of initial treatment. A triplet bortezomib combination was used as first line therapy in 78% of patients (n = 18/23) with a median of five cycles given (range 4–8) (Table 1). Ten patients (43%) received consolidation with high dose melphalan and autologous stem cell transplantation (ASCT). All patients responded to first line therapy (PR 13%, very good partial response (VGPR), 61%, complete response (CR) 26%), with five patients improving their response post-ASCT. No patient received maintenance therapy. The median time to best response (TTBR) was 3·5 months (range 0·7–9·0) and the median duration of response (DOR) was 14·9 months (range 4·7–44·5). Treatment regimens at first relapse are listed in Table S1. A similar proportion received triplet combinations at relapse (83%) as compared to at first line (78%). The overall response rate (ORR) to bortezomib re-treatment was 87% (PR 39%, VGPR 35%, CR 13%) with 48% achieving at least a VGPR (Table 1). The median TTBR was 4·1 months (range 0·7–15·0) and median DOR was 11·5 months (range 1·0–18·5). The three patients who achieved CR with bortezomib retreatment had all achieved a CR with first line treatment and were ISS stage 1. The six patients with adverse risk genetics all achieved ≥VGPR with first line bortezomib and three VGPR, two PR and one ≤PR after re-treatment. Patients received a median of five cycles (range 1–8) and 11 patients (48%) proceeded to a salvage ASCT. Outcomes for the two treatment lines are shown in Fig 1. After front line bortezomib, the median time to progression was 18·9 months (range 7·3–49·6) whilst it was 14·4 months (range 1·4–16·6) at first relapse (although only 14 patients had disease progression at the time of analysis). The median treatment-free interval was 20·7 months (range 2·0–62·8) after first-line bortezomib and 10·4 months (range 1·0–14·0) after bortezomib re-treatment. Ten patients received ASCT at first line compared to 11 at first relapse. Treatment-related toxicity was also evaluated. At first line, 11 patients (48%) experienced peripheral neuropathy (PN) (all grade 1). Dose reductions were all due to PN (n = 6, 26%), except for one due to frailty. There were three (13%) grade 3–4 adverse events (AEs), which were all infections. Six patients (26%) were hospitalized; three for infection, one for headache, one for bone pain and one for a new fracture (grade 2). Previous recommendations have suggested that the dose of bortezomib at re-treatment should start at that which was tolerated previously. In this dataset, all but one patient restarted bortezomib at full dose at relapse. Only two patients (11%) required a subsequent dose reduction (for PN), one of whom had had a dose reduction at first line. Eleven patients (61%) experienced PN with re-treatment (eight grade 1, three grade 2). There were two grade 3 AEs (diarrhoea and febrile neutropenia). Three patients (11%) were hospitalized during first relapse treatment (febrile neutropenia, progressive disease, hypercalcaemia). All patients who relapsed a second time were able to proceed to a third line regimen, which was most commonly lenalidomide and dexamethasone (data not shown). Bortezomib has previously been shown to be highly effective in the treatment of newly diagnosed myeloma (San Miguel et al, 2008; Harousseau et al, 2010) and at relapse (Richardson et al, 2005; Jagannath et al, 2004). Several studies have demonstrated that patients with relapsed disease who have received bortezomib salvage are able to respond again to bortezomib re-treatment either as monotherapy or in combination with dexamethasone (Mateos et al, 2010; Petrucci et al, 2013; Sood et al, 2009). Our data extend these observations to re-treatment at first relapse, and with triplet regimens, in a real life setting. Our findings compare favourably with Oriol et al (2015) who reported an ORR of 80% and median progression-free survial of 15 months with second-line bortezomib re-treatment. Our data indicate that bortezomib re-treatment at first relapse can produce durable responses in a high proportion of patients, with acceptable toxicity. With an increasing number of multi-drug options for relapsed disease, physicians and patients are likely to select therapy according to performance status and co-morbidities. Thus, the addition of relatively low cost agents, such as cyclophosphamide or thalidomide, to bortezomib re-treatment in patients previously tolerant of this agent may be an attractive option at first relapse. Bortezomib combinations have also been demonstrated to be an effective re-induction regimen prior to a salvage ASCT (Cook et al, 2014). This single centre study in real life patients demonstrates that bortezomib combinations used at first line and sequentially at first relapse represent a valid treatment strategy for selected patients. YR and KY designed the study and wrote the manuscript. RP, AR, SDS, NR, KY contributed clinical data. YR, SC and KY collated the data. YR performed the data analysis. All authors were involved in data interpretation, manuscript critique, and had final approval. None Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.