Impact of melphalan day -1 vs day -2 on outcomes after autologous stem cell transplant for multiple myeloma.

Background: Melphalan is the most common conditioning regimen used prior to autologous stem cell transplant (ASCT); however, there are varying data on optimal melphalan timing prior to transplant for best safety and efficacy. Historically, ASCT conditioning consisted of melphalan 200 mg/m2 on day 2 (D-2) (48 h prior to ASCT), but many institutions have since adopted a melphalan protocol with administration on day 1 (D-1) (24 h prior to SCT) or split dosing over the 2 days. The optimal timing of melphalan has yet to be determined. Methods: In this single-center retrospective study, we analyzed transplant outcomes for patients between March 2011 and September 2020 admitted for high-dose, single-agent melphalan 200 mg/m2 on D-1 vs. D-2. The primary outcomes were time to neutrophil and platelet engraftment. Secondary outcomes include incidence of hospital readmission within 30 days, 2-year progression-free survival, and 2-year overall survival. Results: A total of 366 patients were studied (D-2 n = 269 and D-1 n = 97). The incidence of high-risk cytogenetics was similar between the two groups (37% vs. 40%). Median days to absolute neutrophil count engraftment was similar at 11 days in the D-2 and D-1 cohort (n = 269, range 0-14, IQR 11-11 vs. n = 97, range 0-14, IQR 11-12). Median days to platelet engraftment >20,000/mcL was 18 days for D-2 melphalan (range: 0-28, IQR 17-20) versus 19 days for D-1 melphalan (range: 0-32, IQR 17-21). Overall survival at 2 years post-transplant was similar in both cohorts (94%; p = 0.76), and PFS was 70% in D-2 compared with 78% in D-1 (p = 0.15). In a multivariable model including age and performance status, hospital readmission within 30 days of transplant was higher in the D-1 cohort (odds ratio 1.9; p = 0.01). Conclusion: This study demonstrates similar neutrophil and platelet engraftment in D-1 and D-2 melphalan cohorts with similar 2-year PFS and OS. Either D-2 or D-1 melphalan dosing schedule is safe and effective.

Pembrolizumab for metastatic castration-resistant prostate cancer: trials and tribulations.

INTRODUCTION: Immunotherapies have revolutionized the management of various malignancies but have only recently been evaluated systematically in prostate cancer. Pembrolizumab, a programmed-death 1 (PD-1) blocking antibody, has been utilized in a small subset of prostate cancer patients with mismatch repair deficiency/microsatellite instability, but has now been assessed in broader populations of metastatic prostate cancer patients. AREAS COVERED: The results of four pembrolizumab-based phase III clinical trials for metastatic castration-resistant prostate cancer (mCRPC) and metastatic hormone-sensitive prostate cancer (mHSPC) patients, including KEYNOTE-641, KEYNOTE-921, KEYNOTE-991, and KEYLYNK-010 are summarized. Programmed death-ligand 1 (PD-L1) expression, the efficacy of pembrolizumab in prostate cancer patients with certain molecular defects, and emerging pembrolizumab-based therapeutic combinations are also reviewed. EXPERT OPINION: Pembrolizumab has not benefitted unselected metastatic prostate cancer patients when combined with chemotherapy, next-generation hormonal agents (NHA), or poly(ADP-ribose) polymerase inhibitors (PARPi). PD-L1 positivity does not predict the response to pembrolizumab in this disease. A small number of responding patients can likely be explained by rare genetic and molecular defects, and more innovative combination strategies are needed to improve outcomes in prostate cancer patients who are not sensitive to pembrolizumab. Emphasis should be placed on developing additional or alternative immuno-oncology approaches beyond classical immune checkpoint inhibition.