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Dysgeusia is a common but understudied complication in patients undergoing autologous hematopoietic cell transplantation (auto-HCT). We assessed the feasibility of using chemical gustometry (CG) to measure dysgeusia and explored its associations with symptom burden, nutrition, chemotherapy pharmacokinetics (PK), and the oral microbiome.We conducted a single-center, prospective feasibility study (NCT03276481) of patients with multiple myeloma undergoing auto-HCT. CG was performed longitudinally testing five flavors (sweet, sour, salty, bitter, umami) to calculate a total taste score (maximum score, 30). We measured caloric intake and patient-reported symptoms, assessing their correlation with oral microbiota composition and salivary and blood melphalan PK exposure.Among all 45 patients, 39 (87%) completed at least four (60%) and 22 (49%) completed all six CG assessments. Median total CG scores remained stable over time but were lowest at day +7 (27, range 24-30) with recovery by day +100. Symptom burden was highest by day +10 (area under the curve, 2.9; range, 1.0-4.6) corresponding with the lowest median overall caloric intake (1624 kcal; range, 1345-2267). Higher serum/salivary melphalan levels correlated with higher patient-reported dysgeusia and lower caloric intake. Oral microbiota α-diversity was stable early and increased slightly by day +100.Assessment of dysgeusia by CG is feasible after auto-HCT. Most dysgeusia, symptom burden, and lowest caloric intake occurred during the blood count nadir. Higher melphalan concentrations correlated with more dysgeusia and poorer caloric intake. Future studies will aim to modulate melphalan exposure by PK-targeted dosing and characterize patient taste preferences to personalize diets for improved nutritional intake.Taste changes after cancer treatments are very common. We used chemical gustometry (taste testing) to study taste changes and to better understand why patients with multiple myeloma experience this symptom after autologous hematopoietic cell transplantation. We found that taste testing was feasible, taste changes peaked when blood counts were lowest, and most patients recovered their taste by 100 days after transplantation. Taste changes correlated with lower food intake and with higher levels of chemotherapy in the body. Future work will focus on using personalized chemotherapy doses to reduce taste changes and to match patients' individual taste preferences with their diets.

Background Body surface area-based dosing of melphalan prior to AHCT for MM and AL patients causes inter-patient variability in exposure measured by area under the curve (AUC). Higher AUC is associated with increased toxicity, but prolonged survival (Shaw et al., BBMT 2012). Using Evomela (PGF-MEL, Acrotech Biopharma LLC), a more stable and possibly less toxic intravenous formulation of melphalan, we examined the feasibility of PK-directed dosing to individualize and optimize therapy. Methods Prospectively, patients received 100mg/m2 of PGF-MEL on day -2 prior to AHCT. Serum samples were collected at 5, 15, 30, 40, 75, and 150 min after the dose and AUC PK modeling (Phoenix WinNonlin v6.4) was used to determine the dose required to achieve a target AUC of 13.5mg/L*h (+/-1). On day -1, patients received the balance of the calculated dose with samples collected at the same timepoints to calculate the total AUC. After 5 patients were enrolled, the protocol was amended to increase the maximum allowable dose to the equivalent of 260mg/m2 from 220mg/m2. On day +1, 6, 11, 30, 60, and 90, patients reported symptom burden was collected using the MD Anderson Symptom Inventory – MM (MDASI-MM). Results Results of 15 patients are presented with 11 having MM and 4 AL, 60% male, median age 62yr (range 48-71), median body surface area 1.9 (range 1.5-2.2), and median creatinine on day of Mel 0.8mg/dL (range 0.7-1.6). Target doses were calculated and given in 100% of patients. Thirteen of 15 patients (87%) achieved the target AUC. The median AUCs on day -2 and day -1 were 6.3 mg/L*h (range 4.2-11.4) and 5.6 (range 3.1 – 8.4) respectively, with a median total AUC of 13.2 (range 9.6-15.2, Figure 1). Three patients received the capped dose of 220mg/m2 prior to the amendment and achieved their predicted AUC; 1 patient received the minimum 140mg/m2 and also achieved the predicted AUC which was higher than the target AUC, as expected. 9/15 patients had AUCs between 12.5-14.5 with 4/6 patients out of range for the above reasons. Neutropenic fevers occurred in 40% and grade 2 diarrhea for at least 1 day in 80% (median 2 days, range 0-7). Median time to neutrophil engraftment was 9 days (range 9-12). The median number of red cell and platelet transfusions required were 0 (range 0-3) and 1 (range 0-8), respectively. Engraftment syndrome was seen in 30% of patients. The hematologic response rate post AHCT was 100%, including complete remission in 20% and ≥ very good partial response 73%. With median follow-up of 6.4 months (range 2.8-13.1 months), one patient with MM whose AUC was below the target (10.1 units) has relapsed. No patient has died. Conclusion We show for the first time that personalization of therapy to a target AUC using PK-directed PGF-MEL was logistically feasible and prevented underdosing. Full trial results for 35 patients, as well as patient-reported outcomes and toxicities will be presented at the meeting.

Introduction Dysgeusia commonly influences nutritional intake and quality of life after HCT, yet its pathobiology is poorly understood and methods to study it are not established. We report interim results of a prospective feasibility study of chemical gustometry (CG) to measure dysgeusia in pts with multiple myeloma (MM) undergoing high-dose melphalan and autologous HCT (mel-AHCT). We evaluated associations between dysgeusia and symptoms, nutrition, mel pharmacokinetics (PK), and oral microbiota composition. We hypothesized that mel penetration into saliva contributes to dysgeusia. Methods CG was performed by the Henkin method pre-AHCT and on days (d) -1, +7, +14, +30 testing 5 flavors (sweet, sour, salty, bitter, umami) to calculate a total taste score (max value 30). CG was considered feasible if > 60% of pts could complete > 60% of all evaluations. Caloric intake (kcal) was calculated with 24-hr recall using the USDA 5-Step Multiple-Pass Method, and pt-reported symptoms were assessed using the MD Anderson Symptom Inventory (MDASI) at the above times and on d +3 and +10. Salivary microbiome diversity was assessed longitudinally by 16S sequencing and the inverse Simpson index. 6-point serum mel concentrations were used to calculate an area under the curve (AUC) and peak salivary mel was obtained 75 min post-infusion. Spearman rank-sum correlation was used to assess associations. Results 22 mel-AHCT MM pts have follow-up through d +30. 18 pts (82%) completed > 60% of all assessments. Median age was 62 (range 41-75). 11 pts (50%) were male. Mel 200 mg/m2 and 140 mg/m2 was given in 19 (86%) and 3 (14%) pts, respectively. Median serum mel AUC was 12.6 mg*h/L (range 5.8-17.5); median salivary mel was 119 ng/ml (range 25-662). Higher serum mel AUC correlated with higher salivary mel levels, p=0.004, and associated with poorer caloric intake from pre-ASCT to d +30, p=0.04. Higher serum mel AUC associated with higher MDASI scores (worse symptom burden) from pre-AHCT to d +30, p=0.005, but not with taste scores. Higher salivary mel associated with poorer caloric intake from pre-AHCT to d +30, p=0.02. MDASI scores peaked d +10, coincident with nadirs in taste scores and caloric intake on d +7 and +10, respectively. Taste scores partially recovered by d +30, but often did not return to baseline (Fig 1A-C). Oral microbiota diversity was stable early after AHCT but increased by d+100. D+7 diversity did not correlate with serum mel AUC, p=0.4, or salivary mel, p=0.84 (Fig 2A-C). Conclusion CG is a feasible method to evaluate dysgeusia after AHCT. Dysgeusia peaked by d +7 and often persisted through d +30. Oral microbiota diversity was stable early after AHCT. Higher serum and salivary mel levels did not correlate with microbiota diversity but were associated with poorer caloric intake and higher MDASI scores suggesting that using targeted mel PK dosing may improve caloric intake and limit symptom burden after AHCT.