Short Survival, Despite Promising Response Rates, after Bortezomib Treatment of Multiple Myeloma Patients with a 13q-Deletion.
Authors: Drach Johannes , Kuenburg E. , Sagaster Verena , Zojer Niklas , Kaufmann Hannes , Ackermann Jutta , Ludwig Heinz 
Published: April 2020

Abstract
Presence of a chromosome 13q-deletion confers a poor prognosis to patients with multiple myeloma (MM) irrespective of the treatment modality (standard-dose chemotherapy, high-dose melphalan with autologous transplantation, allogeneic transplantation, thalidomide), which underlines the need for effective therapy in this high-risk MM patient population. Bortezomib (B) is the first compound of a new class of agents - the proteasome inhibitors - showing activitiy in relapsed and chemotherapy-refractory MM. Preliminary evidence suggests that B may also be active in MM with unfavorable standard prognostic factors. Therefore, the aim of our investigation was to study the activity of B in relapsed MM in the context of chromosomal aberrations (in particular deletion of chromosome 13q14 [del(13q14)] and 14q-translocations [t(14q32)]) as detected by interphase fluorescence in situ hybridization (FISH). Up to now, 52 patients with relapsed/refractory MM (47 after ≥2 lines of prior therapy) were treated with B (1.3 mg/m2 on days 1, 4, 8, 11; q21 days). Patients not achieving at least a minor response to single-agent B were treated with B plus dexamethasone (DEX; 8–20mg); subsequently, melphalan (10 mg/m2) or doxorubicin (9 mg/m2) was added to B/DEX treatment. To date 44 patients are evaluable for response, time to treatment failure (TTF), overall survival (OS), and association with prognostic factors. 23 evaluable patients (52%) experienced an objective response, with 8 patients (18%) achieving a CR/near-CR (&gt;90% paraprotein reduction), 12 patients (27%) achieving a PR (50 – 90% paraprotein reduction), and 3 patients (75) showing a MR (25 – 50% paraprotein reduction). Median time to response was 3 weeks (range, 3 – 9 weeks). According to FISH, 22 patients (50%) had a del(13q14). B was effective for remission induction in both del(13q14) MM patients (18% CR/nearCR, 18% PR, 5% MR) and 13q-normal patients (18% CR/nearCR, 36% PR); however, median TTF (2.6 versus 6.7 months) and median OS (6.1 months versus not yet reached; P = .047) were shorter for del(13q14) patients compared to 13q-normal patients. Of note, failure to respond to B and short OS was observed in 2 patients with del(13q14) and concomitant amplification of CKS1B (1q21). Additional studies regarding 1q21 are in progress. Remission rates, TTF, and OS were similar in patients with and without a t(14q32). One patient with a t(4;14)(p16;q32) responded not only to single agent B with a remission lasting for 7 months, but later also responded to B/DEX and the B/DEX/chemotherapy combination with remissions lasting for several months each. On the other hand, only one of 5 patients with a t(11;14)(q13;q32) achieved a response (MR) to B. Beta-2-microglobulin did not influence treatment outcome after B. Significantly shortened OS following B treatment was noted in MM patients with serum albumin &lt;3.5 g/dl (4.7 months versus median not yet reached) and bone marrow plasma cells &gt;50% (6.4 months versus not yet reached). In conclusion, B is an effective salvage treatment for MM patients with relapsed/refractory MM, even in those with prognostically adverse cytogenetic features such as del(13q14). Due to the still short TTF and OS, MM patients with adverse prognostic indicators (unfavorable cytogenetics, low serum albumin, high bone marrow plasma cell infiltration) may derive a particular benefit from combining B with other anti-MM agents.