Benefits of Salvage Autologous Stem Cell Transplantation in Multiple Myeloma May Outweigh Short-Term Effects on QoL and Pain

Sam H. Ahmedzai, MBChB

Sam H. Ahmedzai, MBChB

Patient-reported outcomes from the phase III myeloma X trial suggested that although patients with relapsed multiple myeloma who received salvage autologous stem cell transplantation (sASCT) had an initial reduction in quality of life (QoL) and experienced a greater impact of adverse events (AEs), they had better long-term outcomes compared with patients who received nontransplantation consolidation (NTC).¹

“The small and diminishing differences in global health status and side effects of treatment need to be considered alongside the results of Myeloma X, which showed a significant benefit of sASCT on overall survival (OS). The benefits of sASCT should be considered alongside the relatively short-term negative effects on QoL and pain when making patient treatment decisions and further support the use of sASCT,” wrote the investigators, led by Sam H. Ahmedzai, MBChB, in a report published in theJournal of Clinical Oncology.

Due to a demonstrated improvement in OS and progression-free survival (PFS) in several randomized trials, ASCT is regarded as standard of care for patients with newly diagnosed multiple myeloma. Although options to manage relapsed disease exist, no standard treatment has been clearly defined. The Myeloma X investigators set out to evaluate if using ASCT as a salvage therapy at relapse had the potential to provide long-term disease control with reasonable tolerability.

The trial, which was stopped early because it crossed a stopping boundary for efficacy at an interim analysis, assessed the use of sASCT in patients with relapsed multiple myeloma after previous ASCT. Results from the trial showed the use of high-dose melphalan plus ASCT at relapse significantly prolonged time to progression (TTP) compared with cyclophosphamide therapy (median, 19 vs 11 months; HR, 0.36; 95% CI, 0.25-0.53;P<.0001). At 3 years, the OS rate was 80.3% in the sASCT arm compared with 62.9% in the cyclophosphamide group. The investigators reported that the results were durable after re-induction therapy with bortezomib (Velcade), doxorubicin, and dexamethasone.²

The primary endpoint of the study was TTP, with secondary endpoints of response rate, PFS, OS, toxicity and safety, pain, and QoL.

Between 2008 and 2012, 288 of the 297 patients enrolled on the Myeloma X trial consented to be a part of the sub-study, which evaluated pain and QoL via patient-reported questionnaires at specified time points throughout the study.

The investigators evaluated QoL during reinduction and randomized treatment using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the EORTC myeloma-specific module (EORTC QLQ-MY20). Pain was evaluated using the Brief Pain Inventory (short form; BPI-SF), which assesses the severity and impact of pain on a patient&rsquo;s daily life. The Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) was also used as a self-assessed pain scale to determine it patients&rsquo; pain was neuropathic.

Questionnaires were given before registration and after completion of reinduction. Randomly assigned patients had questionnaires administered in the clinic before randomization, unless it was within 2 weeks of the previous questionnaires. Additional questionnaires were sent to patients by mail 100 days after random assignment, 6 and 12 months after random assignment, and then annually until it reached 2 years after the last randomly assigned patient had been assigned.

The Myeloma X trial ultimately randomized a total of 174 patients to receive sASCT (n = 89) or NTC (n = 85). Eighty-eight patients who received sASCT and 83 patients who received NTC consented to participate in the sub-study. Baseline demographics and disease characteristics were well balanced between the 2 groups, with a median age of 61 across the trial. The investigators noted there was a higher proportion of patients with International Staging System stage III disease in the transplantation group.

In terms of compliance, 76.1% of all questionnaires were returned among the patients, and the return rate was similar between the 2 groups. The greatest noncompliance rate for the EORTC QLQ-C30 and QLQ-MY20 questionnaires was seen at the randomization baseline, with only 59.6% of patients complying. At the same time point, the return rate for the S-LANSS and BPI-SF questionnaires were 54.4% and 53.8%, respectively.

Findings from the reinduction questionnaire showed there were medium-sized clinically relevant differences in global health status, fatigue, and diarrhea and small clinically relevant differences in role functioning, social functioning, nausea/vomiting, appetite loss, constipation, insomnia, and dyspnea compared with the trial entry. The pain interference score increased slightly, although the BPI-SF pain severity score was similar to trial entry.

Quality of life at 100 days after random assignment was significantly different between the 2 groups (P= .0496), but was not significantly different at any other time point after randomization. A small-medium size difference was seen between the 2 groups with regard to global health status score, with the NTC group reporting a score 9.2 points higher overall.

&ldquo;This deterioration in global health status for patients receiving sASCT compared with NTC dissipated to a trivial difference at 6 months and a smaller trivial difference at 1 year. The difference at 2 years favored sASCT but was still trivial,&rdquo; the study authors wrote. The subscale for AEs was higher in the sASCT group compared with the NTC group at 100 days and 6 months after randomization (7.6 points higher and 5.9 points higher at 100 days and 6 months, respectively), but subsequently dissipated.

There was no significant difference seen between the trial groups in terms of pain interference at 100 days post-randomization; however, significant differences were seen at 6 months and up to 2 years. At all the time points considered, pain interference was approximately 1 point lower in the NTC group, which was considered a clinically relevant difference.

A post-hoc exploratory analysis of TTP by randomly assigned allocation suggested that patients with a global health status greater than the median at the time of randomization and who had received sASCT had a significant TTP advantage over patients receiving NTC (HR, 0.3; 95% CI, 0.15-0.61;P= .006). However, this was not found to be significant on multivariate analysis with stratification factors. Patients who had a lower than median score in terms of side effects of treatment and received sASCT had an improved TTP compared with those who received NTC (HR, 0.24; 95% CI, 0.10-0.55;P= .003), which was maintained in multivariate analysis. Additionally, pain scores were not considered to be significantly predictive of either TTP or OS.

References:

1. Ahmedzai SH, Snowden JA, Ashcroft AJ, et al; National Cancer Research Institute Haemato-Oncology Clinical Studies Group. Patient-reported outcome results from the open-label, randomized phase III Myeloma X trial evaluating salvage autologous stem-cell transplantation in relapsed multiple myeloma [published online April 10, 2019].J Clin Oncol. doi: 10.1200/JCO.18.01006.
2. Cook G, Williams C, Brown JM, et al; National Cancer Research Institute Haemato-Oncology Clinical Studies Group. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial.Lancet Oncol. 2014;15(8):874-885. doi: 10.1016/S1470-2045(14)70245-1.