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. 2017 Jul;102(7):e261-e265.
doi: 10.3324/haematol.2016.162321. Epub 2017 Apr 6.

Double autophagy stimulation using chemotherapy and mTOR inhibition combined with hydroxychloroquine for autophagy modulation in patients with relapsed or refractory multiple myeloma

Emma C Scott  1 , Richard T Maziarz  2 , Stephen E Spurgeon  2 , Eva Medvedova  2 , James Gajewski  2 , Shara Reasor-Heard  2 , Byung Park  3 , Anne Kratz  2 , George V Thomas  4 , Marc Loriaux  4 , Michael Cascio  4 , Jennifer Podolak  4 , Miranda Gordon  2 , Jennifer Botelho  2 , Edward Stadtmauer  5 , Ravi Amaravadi  5 , Dan T Vogl  5
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Double autophagy stimulation using chemotherapy and mTOR inhibition combined with hydroxychloroquine for autophagy modulation in patients with relapsed or refractory multiple myeloma

Emma C Scott et al. Haematologica. 2017 Jul.
No abstract available

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Figures

Figure 1.
Figure 1.
Treatment schema. (A) Treatment schema depicting the first 2 cycles of therapy. Black arrows indicate time points when bone marrow sampling occurred on the phase I trial. Patients received cyclophosphamide 300 mg/m2 daily as a continuous intravenous infusion and dexamethasone 40 mg daily by mouth (po) for four days, rapamycin po from cycle 1 day –2 (12 mg loading dose followed by 4 mg daily for 5 more days) AND hydroxychloroquine (HCQ) po from cycle 1 day 5 onwards (phase I trial), OR hydroxychloroquine (pilot trial). Hydroxychloroquine started at cycle 1 day 5 after rapamycin, alkylator and steroid exposure in order to analyze autophagy at baseline, after chemotherapy and before adding the hydroxychloroquine effect. Maximal autophagy inhibition was anticipated to occur after several weeks of daily hydroxychloroquine due to its long half life (32–50 days). Steady state rapamycin trough levels of 4 to 12 ng/mL were targeted with a loading dose of 12 mg and a daily dose of 4 mg. Due to limited single agent activity of mTOR inhibitors in multiple myeloma and a concern for ongoing immunosuppression, rapamycin duration was limited to six days in total each cycle. Pegfilgrastim 6 mg was administered subcutaneously 24–48 hours after completing cyclophosphamide each cycle. All cycles beyond were identical to cycle 2, repeated every 28 days. (B–D) Therapy-associated autophagy modulation in myeloma cells from patients receiving cyclophosphamide, dexamethasone, rapamycin, and hydroxychloroquine. Representative electron micrographs (EMs) from CD 138-selected bone marrow plasma cells from subjects at baseline; after six days of rapamycin plus four days of cyclophosphamide and dexamethasone on cycle 1 day 5; and on cycle 2 day 5 hydroxychloroquine (HCQ) has been taken for 28 days. EM, direct magnification 4800×, green scale bar: 1 μm. Red arrows indicate autophagic vesicles (AV). (B) Cohort 4 (1200 mg HCQ) subject EM. (C) Cohort 3 (800 mg HCQ) subject EM. (D) Therapy-associated autophagy modulation in myeloma cells from all patients treated. Mean AVs in bone marrow plasma cells. The mean AV difference between baseline and cycle 1 day 5 is 0.260 [standard error (SE) 0.148, P=0.0939], between baseline and cycle 2 day 5 is −0.098 (SE 0.171, P=0.5738) and between cycle 1 day 5 and cycle 2 day 5 is −0.358 (SE 0.171, P=0.0488). (E) Mean and range of hydroxychloroquine trough levels across the 4 dose cohorts. The graph shows the median (center line), 25th-75th percentiles [interquartile range (IRQ), box], and 5th-95th percentiles (IRQ whiskers).
Figure 2.
Figure 2.
Therapy-associated mTOR pathway evaluation in myeloma cells from patients receiving cyclophosphamide, dexamethasone, rapamycin and hydroxychloroquine. (A) Immunofluorescence (IF) analysis of phospho-S6 ribosomal protein before and after treatment with rapamycin in 7 subjects. (B) An average of 3 images from 7 independent baseline and treated subjects’ bone marrow biopsies. Quantification of immunofluorescence was performed by InFORM image analysis software. Images were captured at 40× magnification. Data are means±standard error of mean (SEM). P value was calculated using two-sided Student’s t-test, P=0.0004. (C) Mean phospho-S6 ribosomal protein field coverage in paired samples and (D) concomitant mutations from the next-generation sequencing panel in 7 subjects.
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