Endocrine therapy has been the standard of care for patients with metastatic hormone receptor (HR)‐positive, HER2‐negative breast cancer since the 1970s, improving survival while avoiding the toxicities associated with cytotoxic chemotherapy. However, all HR‐positive tumors ultimately develop resistance to endocrine therapy. Cyclin‐dependent kinase 4 and 6 (CDK4/6) inhibitors have more recently become an important component of the management of this breast cancer subtype, significantly delaying time to the disease progression and improving survival when combined with endocrine therapy. However, as with endocrine therapy alone, treatment resistance remains a universal phenomenon. As more women receive CDK4/6 inhibitors as part of their treatment, the management of de novo and acquired resistance to combined CDK4/CDK6 inhibitor plus endocrine therapy regimens has emerged as an important clinical challenge. Several resistance mechanisms have been described, including alterations in the CDK4/6/cyclin D complex or its major effector retinoblastoma protein (pRb), bypass signaling through other cyclin/CDK complexes and activation of upstream signaling pathways, in particular the PI3K/mTOR pathway, but robust biomarkers to predict resistance remain elusive, and the role for continuing CDK4/6 inhibitors after progression remains under investigation. Novel strategies being evaluated in clinical trials include the continuation of CDK4/6 inhibitors through progression, as well as triplet therapy combinations with PI3K inhibitors or immune checkpoint inhibitors.

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Aim: High-dose melphalan followed by autologous haematopoietic cell transplantation remains the standard-of-care therapy for multiple myeloma (MM). Gastrointestinal toxicity concomitant with electrolyte derangement is a primary cause of morbidity from transplant. Here, we assessed the dynamics of electrolyte imbalances and its role in hematologic counts and engraftment. Ω Patients and Methods One hundred and eighteen MM patients that received transplant were studied.Results: Engraftment speed (ES) was calculated as the period between the first rise in the absolute neutrophil count (ANC) and full engraftment defined as the first of three consecutive days with ANC > 500 × 10 6 /L. The defined median ES was 2 days (range 0-5 days) and 40 patients had ES ≤2 days. Engraftment occurred at a median of 10 days. The median time-to-nadir for phosphorus and potassium was 10 and

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Despite advent of a rich anti-myeloma armamentarium, autologous hematopoietic cell transplant (HCT) has been increasingly utilized to achieve prolonged survival for patients (pts) with multiple myeloma (MM). Short-term metabolic abnormalities have been associated with this treatment modality. Electrolyte abnormalities may lead to increased patient morbidity by prolonging hospital stay as well as central line use. The incidence, temporal course, severity, and impact of metabolic derangement during the peri-engraftment period on clinical outcomes have not thoroughly been studied in MM pts. Here, we sought to investigate the dynamics of electrolyte changes throughout the course of transplant and assess its association with decline and rise in peripheral blood cell count. Methods: All consecutive MM pts that underwent inpatient autologous SCT from January 2012 through July 2016 in our institutions were included. Engraftment Speed (ES) was calculated as the period between the first rise in the absolute neutrophil count (ANC) to engraftment (fist of 3 consecutive days in which ANC>500 mm3). Time to "no need for electrolyte replacement" was calculated from the day of stem cell infusion to the last day of replacement. Survival distribution was estimated using Kaplan-Meier methods. The effect of electrolyte abnormalities on OS and PFS was estimated using a Cox model after controlling for the effects of age, gender, number of prior therapies, and time from diagnosis to transplant. Results: Patient characteristics are listed in Table 1. Pre- and post-SCT nadir values, total amount of replaced electrolyte and replacement frequency are listed in Table 2. The most frequently replaced electrolyte was K followed by Mg, Ca, and P. As expected, there was a direct correlation between magnitude of drop in K, Ca, and Mg and total amount of replacement (Pearson coefficient: 0.673, p = 0.001). Pts dropped a median of 17 ml/min in GFR throughout the transplant process and the nadir occurred on median of transplant day 6. Median ANC nadir occurred on day 6 (range: 2-8) while ANC<500/ml was recorded on median day 5. One hundred and six pts (90%) had all-grade diarrhea while 37 pts (31%) had grade II or higher. Grade II and higher diarrhea was associated with significant drop in K but not with drop in P, Ca or Mg. (Figs. 1, 2). All-grade nausea occurred among 113 pts (95%), while grade II and higher nausea complicated the transplant course in 42 pts (35%). All-grade oral mucositis happened in 68 pts (57%), while 27 pts (23%) suffered from grade II and higher. There was no statistically significant difference between the drop in P, Ca, Mg or K based on severity of nausea or oral mucositis. A multivariate model to assess the impact of potential risk factors on electrolyte abnormalities, included age, gender, CD34+ cell dose, pre-HCT performance status and presence of severe GI toxicity (Table 3). Median ES was 3 days (range: 0-5) and 40 pts (36%) had ES ≤ 2 days. Engraftment occurred at a median of 11 days (standard deviation (SD): 1.50 days, after HCT). The median time-to-nadir for both P and K was 10 days (SD: 3.10 days and 4.28 days for P and K, respectively). The drop in P was statistically higher in the group with ES ≤ 2 days in comparison to the group with ES > 2 days (Median: 1.4 vs. 0.9 mg/dL, p-value: 0.000) as well as the drop in K (median: 1.1 vs. 0.7 mmol/L, p=0.039). There was no difference in the Ca or Mg drop between the two ES groups. (Fig. 1). There was also no statistical significance in frequency of post-engraftment Hb<7.5 gr/dL between two cohorts, whereas more pts in the cohort with ES>2 had post-engraftment Plt<10 x 106/L than pts with ES ≤ 2 (45% vs 15%, p=0.001) suggesting a more robust graft in the latter group. There was no significant difference in post-transplant PFS or OS between the two ES patient cohorts. Conclusions: Our results indicate that there is a significant correlation between the magnitude of drop in potassium and phosphorous following stem cell transplant and a steep rise in neutrophil counts around engraftment period. These events are consistent with a "genesis syndrome" which is characterized by a rapid, massive transfer of electrolytes into proliferating cells as has been previously described in certain high-grade lymphomas and leukemias. Disclosures Malek: Celgene: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Medpacto: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Adaptive: Consultancy.