Tim H. Bruemmendorf

Autotransplant with and without induction chemotherapy in older multiple myeloma patients: long-term outcome of a randomized trial

Autologous transplantation is controversial for older patients with multiple myeloma. The role of age-adjusted high-dose melphalan and the impact of induction chemotherapy cycles is still unclear. A total of 434 patients aged 60–70 years were randomly assigned to 4 cycles of standard anthracycline-based induction chemotherapy or no induction. For all patients, double autologous transplantation after melphalan 140 mg/m2 (MEL140) was planned. The primary end point was progression-free survival. Of 420 eligible patients, 85% received a first transplant and 69% completed double transplantation. Treatment duration was short with a median of 7.7 months with induction chemotherapy cycles and 4.6 months without induction. On an intention-to-treat basis, median progression-free survival with induction chemotherapy cycles (207 patients) was 21.4 months versus 20.0 months with no induction cycles (213 patients) (hazard ratio 1.04, 95% confidence interval 0.84–1.28; P=0.36). Per protocol, progression-free survival was 23.7 months versus 23.0 months (P=0.28). Patients aged 65 years or over (55%) did not have an inferior outcome. Patients with low-risk cytogenetics [absence of del17p13, t(4;14) and 1q21 gains] showed a favorable overall survival and included the patients with sustained first remission. MEL140 was associated with a low rate of severe mucositis (10%) and treatment-related deaths (1%). Based on hazard ratio, the short treatment arm consisting of mobilization chemotherapy and tandem MEL140 achieved 96% of the progression-free survival, demonstrating its value as an independent component of therapy in older patients with multiple myeloma who are considered fit for autologous transplantation. (clinicaltrials.gov identifier: 02288741)

Drugging the unfolded protein response in acute leukemias

The unfolded protein response (UPR), an endoplasmic reticulum (ER) stress-induced signaling cascade, is mediated by three major stress sensors IRE-1α, PERK, and ATF6α. Studies described the UPR as a critical network in selection, adaptation, and survival of cancer cells. While previous reviews focused mainly on solid cancer cells, in this review, we summarize the recent findings focusing on acute leukemias. We take into account the impact of the underlying genetic alterations of acute leukemia cells, the leukemia stem cell pool, and provide an outline on the current genetic, clinical, and therapeutic findings. Furthermore, we shed light on the important oncogene-specific regulation of individual UPR signaling branches and the therapeutic relevance of this information to answer the question if the UPR could be an attractive novel target in acute leukemias.