Netupitant/palonosetron is effective for preventing chemotherapy-induced nausea and vomiting in high-dose melphalan conditioning before autologous stem cell transplantation: A real-world analysis

Abstract

High-dose melphalan (HDM) is the standard conditioning regimen before autologous stem cell transplantation (ASCT) in plasma cell malignancies. Despite prophylactic antiemetics, chemotherapy-induced nausea and vomiting (CINV) remains a prevalent challenge. We retrospectively compared the efficacy of netupitant and palonosetron (NEPA) plus dexamethasone with that of serotonin receptor antagonist (5-HT₃RA)-based regimens (the control group) for patients receiving HDM. The primary endpoint was complete resolution (CR) of CINV in the acute (0–24 hours) and delayed (24–168 hours) phases. Secondary endpoints included overall response rate (ORR), subgroup benefit, and nutritional outcomes. In total, 108 patients were included (NEPA, n = 38; control, n = 70). The NEPA group exhibited higher CR rates in both acute (65.8% vs 32.9%; p < 0.010) and delayed phases (50.0% vs 12.9%; p < 0.010). NEPA achieved a higher ORR (73.7% vs 24.3%; p < 0.010). Subgroup analysis indicated consistent benefits across most clinical strata. Multivariable analysis identified NEPA and male gender as independent factors predicting CR. The median duration of parenteral nutrition (PN) was shorter in the NEPA group than in the control group (median, 2 days [range 1–2] vs 3 days [range, 3–5.75]; p = 0.046). Compared to standard 5-HT₃RA regimens, NEPA significantly improved antiemetic efficacy in patients undergoing HDM conditioning.

1. INTRODUCTION

Multiple myeloma (MM) accounts for approximately 10% of newly diagnosed hematologic malignancies and remains an incurable disorder of plasma cells.¹ Hematopoietic stem cell transplantation (HSCT) plays a key role in the treatment of hematologic malignancies.^2–4 For eligible patients, high-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) continues to serve as the standard treatment, even with the introduction of novel agents, such as proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs).^5–8 Attal et al⁵ showed that incorporating ASCT into bortezomib, lenalidomide, and dexamethasone (VRd) induction regimen can significantly improve median progression-free survival (PFS) compared to VRd alone (50 vs 36 months; p < .001), with higher rates of complete resolution (CR) and minimal residual disease negativity.

Severe CINV during the HDM conditioning regimen significantly affects the outcome of ASCT.^9,10 According to the National Comprehensive Cancer Network’s (NCCN) antiemesis guidelines (2.2024), HDM at doses of 140 mg/m² or higher is categorized as highly emetogenic chemotherapy (HEC). In a study with 33 patients with myeloma who were treated with the HDM regimen, 85% experienced vomiting, and 83% endured more than 2 episodes of emesis.¹¹ The use of an aprepitant-based 3-drug regimen (aprepitant + serotonin receptor antagonist [5HT3RA] + dexamethasone) demonstrated a CR rate of only 58% for the prevention of CINV during HDM conditioning.¹²

Netupitant/palonosetron (NEPA), a fixed-dose combination of the neurokinin-1 (NK-1) receptor antagonist netupitant and the 5-HT3 antagonist palonosetron, has been approved by the National Medical Products Administration (NMPA) in China as a prophylactic antiemetic for CINV. Recently, the fixed-dose combination of NEPA has demonstrated remarkable efficacy as an antiemetic for patients with solid tumors.^13,14 A single-arm study conducted by Loteta et al¹⁵ showed that NEPA, without DEX, can effectively prevent 93% of emesis in single-day HDM conditioning regimens (n = 70). However, few studies have compared the efficacy of NEPA and other antiemetic protocols for HMD conditioning regimens.

To address this gap, we conducted a real-world study to investigate the antiemetic efficacy of a NEPA-based regimen in patients with plasma cell malignancies who received HDM pretransplant treatments. Furthermore, we compared the efficacy of NEPA and other triplet regimens without NEPA.

2. MATERIALS AND METHODS

2.1. Patients

Patients undergoing HDM conditioning following ASCT at Peking University People’s Hospital between May 1, 2023, and November 30, 2024, were consecutively enrolled in this study. The inclusion criteria were as follows: aged 18 years or older; being diagnosed with plasma cell malignancies and receiving a 2-day regimen of HDM (−3d, −2d, 140 or 200 mg/m²) following ASCT; and receiving a NEPA-based regimen as CINV prophylaxis.

The exclusion criteria were as follows: experiencing nausea or vomiting within 12 hours before the initiation of the conditioning regimens; missing key antiemetic efficacy data; and being unable to return for infusion due to complications. Rescue antiemetics, such as fosaprepitant, were allowed to manage breakthrough nausea or vomiting despite prophylaxis, following the Declaration of Helsinki. The follow-up started on the first day of conditioning chemotherapy (day −3) and ended on the day of discharge after ASCT. The discharge date was the final follow-up time for collecting efficacy and supportive treatment data. Informed consent was obtained from all patients, and the study was conducted following the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Peking University People’s Hospital.

2.2. Prophylactic antiemetic therapy

All patients received one of the following antiemetic regimens: NEPA-based regimen: A single oral dose of NEPA (fixed-dose combination of netupitant 300 mg/palonosetron 0.5 mg) was administered every 48 hours, combined with intravenous dexamethasone (5 mg daily), from 30 minutes before melphalan conditioning until 72 hours (day +3) after ASCT. Olanzapine was not routinely used in this group but could be prescribed as rescue medication at the physician’s discretion. 5-HT₃RA-based regimen (control group): Tropisetron (intravenous, 5 mg, once daily) or oral ondansetron (4 mg three times daily, or equivalent intravenous dose), combined with intravenous dexamethasone (5 mg daily) and oral olanzapine (2.5 mg once daily), was administered from 30 minutes before melphalan until day +3. Olanzapine was routinely administered in this group.

2.3. Outcomes definition

In this study, the primary outcome measure was the CR rate, defined as the absence of vomiting and not using rescue medication in all phases. Secondary outcome measures included: acute phase control rate, defined as the CR rate within the first 24 hours following treatment with melphalan; delayed phase control rate defined as the CR rate from 24 to 168 hours (7 days) after treatment with melphalan; partial response (PR) defined as no vomiting, but needing rescue antiemetics (ie, vomiting was prevented with additional medications); objective response rate (ORR) defined as the absence of vomiting, regardless of the need for rescue antiemetics. High-frequency vomiting was characterized as vomiting occurring more than 3 times. Endpoints of CR and PR were assessed separately during the acute and delayed phases. Vomiting volume was recorded as an exploratory endpoint. In this regard, emesis was collected in pre-marked containers and its volume was measured (in mL) by nursing staff. Albumin (ALB) levels and the duration of parenteral nutrition indicate the effect of CINV and the timing of hematopoietic cell engraftment. All efficacy data were collected prospectively from nursing records and physicians’ order books.

2.4. Statistical analysis

Statistical analyses were conducted using SPSS 27.0 (IBM, Armonk, New York). Baseline characteristics of patients are presented as means ± standard deviations (SDs) or frequencies (percentages). The Mann–Whitney U test was employed to compare the primary efficacy outcome among different subgroups of patients based on weight, albumin level, and the number of administered antiemetic rescue doses. The Fisher exact test was employed when any expected count was <5, as the χ² test may not be valid under such circumstances. Logistic regression was utilized to conduct both multivariable analyses and subgroup analyses. Forest plots were generated using the “Forest Plot Drawing” module of the Mengte Cloud Statistical Platform, accessible at https://mengte.pro/forest_plot. A p value of <0.050 was considered statistically significant. Variables with non-estimable odds ratios (NE) were included, indicating complete separation in the data.

3. RESULTS

3.1. General characteristics of patients

This study included 108 patients who underwent HDM and subsequent ASCT. Baseline demographic and clinical characteristics are summarized in Table 1. Overall, except for the number of CD34+ cells reinfused and prior cycles of chemotherapy, baseline characteristics were comparable between the 2 groups.

Table 1.

Baseline demographic and clinical characteristics of patients.

Characteristics	NEPA (n = 38)	Control (n = 70)	p Value
Age (y)	57 (50–61)	57.5 (50–61)	0.789
BMI (kg/m2)	25.31 ± 3.04	25.81 ± 3.07	0.477
ALB (g/L)	43.80 (41.28–46.00)	41.30 (38.88–43.40)	0.035
CD34+ cell (E + 9/kg)	3.48 (2.88–4.02)	6.49 (4.35–10.50)	<.001
Gender, n (%)			0.964
Male	21 (55.3)	39 (55.7)
Female	17 (44.7)	31 (44.3)
Diagnose, n (%)			0.310
MM	36 (94.7)	68 (97.1)
AL	2(5.2)	0
POEMS syndrome	0	1 (1.4)
PCL	0	1 (1.4)
DS stage of MM, n (%)			0.337
I	1 (2.8)	2 (2.9)
II	3 (8.3)	1 (1.5)
III	32 (88.9)	65 (95.6)
Best response of disease before ASCT, n (%)			0.013
Complete remission	16 (42.1)	38 (54.3)
Very good partial response	18 (47.4)	14 (20.0)
Partial response	3 (7.9)	16 (22.9)
Stable disease	1 (2.6)	2 (2.9)
Dose of melphalan, n (%)			0.250
200 mg/m2	26 (68.4)	55 (78.6)
140 mg/m2	12 (31.6)	15 (21.4)
HCT-CI score, n (%)			0.789
0	29 (76.3)	55 (78.6)
1	6 (76.3)	10 (14.3)
2	3 (7.9)	4 (7.1)
Prior cycles of chemotherapy, n (%)			<0.010
2–4	15 (39.5)	45 (64.3)
5–7	20 (39.5)	24 (34.3)
≥8	3 (39.5)	1 (1.4)
Pre-existing gastrointestinal comorbidities, n (%)			0.570
Gastric ulcer	1 (2.6)	0
Gastroesophageal reflux disease	1 (2.6)	1 (1.4)
Gastrointestinal cancers	1 (2.6)	0

AL = amyloidosis, ALB = albumin, ASCT = autologous stem cell transplantation, BMI = body mass index, DS = Durie-Salmon, HCT-CI = hematopoietic cell transplantation-comorbidity index, MM = multiple myeloma, NEPA = netupitant/palonosetron, PCL = plasma cell leukemia, POEMS = polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes.

3.2. Efficacy of antiemetics

Table 2 presents the results of efficacy analysis across 2 groups. The CR rate for vomiting during the acute and delayed phases was significantly higher in the NEPA group than in the control group. Subgroup analysis showed that specific groups of patients, particularly those aged 60 years or older, female patients, those who achieved complete disease remission, individuals receiving a melphalan reduction regimen, and patients without comorbidities before transplantation, benefited more from the NEPA-based antiemetic regimen (Fig. 1A). In the delayed phase, most subgroups exhibited significantly positive responses to NEPA, except for patients with incomplete disease remission (p = 0.083), those with comorbidities before transplantation (p = 0.728),and small subgroups where results could not be estimated (Fig. 1A). Furthermore, the multivariable analysis identified NEPA use and male sex as independent factors associated with higher CR rates (Fig. 1B).

Table 2.

Comparison of antiemetic efficacy between NEPA and control groups in patients receiving HDM conditioning.

End point	NEPA (n = 38)	Control (n = 70)	OR (95% CI)	p Value
CR of vomiting, N (%)
Acute phase*	25 (65.8)	23 (32.9)	3.93 (1.70–9.06)	<.001
Delayed phase†	19 (50)	9 (12.9)	6.78 (2.63–17.45)	<.001
PR of vomiting, N (%)
Acute phase	6 (15.8)	11 (15.7)	1.01 (0.34–3.00)	0.992
Delayed phase	14 (36.8)	13 (18.6)	2.56 (1.05–6.25)	0.039
ORR of vomiting, N (%)	28 (73.7)	17 (24.3)	8.73 (3.53–21.59)	<.001

CI = confidence interval, CR = complete response, HDM = high-dose melphalan, NEPA = netupitant/palonosetron, OR = odds ratio; ORR = objective response rate, PR = partial response.

^*Acute phase, the first 24 h following treatment with HDM conditioning.

^†Delayed phase, 24–168 h following treatment with HDM conditioning.

Figure 1.

Subgroup and multivariable logistic regression analyses of complete response rates of acute and delayed phases. (A) Subgroup analysis of the CR rate in the acute (0–24 h) and delayed (24–168 h) phases. (B) Multivariable logistic regression analysis of CR rates in the acute and delayed phases. ASCT = autologous stem cell transplantation, BMI = body mass index, CI = confidence interval, CR = complete response, HCT-CI = hematopoietic cell transplantation–comorbidity index, NEPA = netupitant/palonosetron, OR = odds ratio.

In the delayed phases, the NEPA group had a higher PR rate than the control group, but no significant differences were found in PR rates in the acute phase. Subgroup analysis showed that most factors did not significantly affect PR rates in either phase (Supplement Figure 1, https://links.lww.com/BS/A144). Additionally, the multivariable analysis indicated that NEPA use was independently associated with higher delayed phase PR rates (Supplement Figure 2, https://links.lww.com/BS/A144).

Regarding the ORR rate, the NEPA group exhibited a significantly higher rate compared to the control group, although the ORR rate was not stratified by phase (Table 2). Subgroup analysis showed that most of the subgroups benefited from NEPA-based treatment (Fig. 2A). Multivariable analysis (Fig. 2B) identified NEPA and male sex as independent factors associated with a higher ORR.

Figure 2.

Subgroup and multivariable logistic regression analyses of complete response rates of overall response rate. (A) Subgroup analysis of the ORR based on baseline characteristics. (B) Multivariable logistic regression analysis of ORR. ASCT = autologous stem cell transplantation, BMI = body mass index, CI = confidence interval, HCT-CI = hematopoietic cell transplantation–comorbidity index, NEPA = netupitant/palonosetron, OR = odds ratio, ORR = overall response rate.

3.3. Breakthrough vomiting

Breakthrough vomiting occurred in 10/28 (35.7%) patients in the NEPA group and 53/70 (75.7%) patients in the control group. The volume of emesis in the NEPA group was significantly lower than that in the control group (207.5 mL [range: 110.0–306.3] vs 1155.0 mL [range: 515.0–1935.0]; p < .001). The frequency of vomiting was also significantly decreased in the NEPA group compared to the control group (1 [range: 1–2.5] vs 6 [range: 3–10]; p < .001). No significant differences were observed between groups in terms of high-frequency vomiting days (p = 0.077) or the number of rescue treatments (p = 0.639) (Supplement Table 1, https://links.lww.com/BS/A144).

3.4. Nutritional status

Nutritional status was assessed by measuring the decline in serum albumin levels and the median duration of parenteral nutrition required throughout the hospitalization period for ASCT. Compared to the baseline, albumin levels markedly decreased in all patients. At discharge, the reduction in albumin levels was milder in the NEPA group than in the control group, although this difference was not statistically significant (22.47% vs 20.76%; p = 0.632). A comparable percentage of patients received parenteral nutrition in the NEPA group and the control group (7.9% vs 11.4%; p = 0.744). The duration of parenteral nutrition was shorter in the NEPA group (median, 2 days [range: 1–2]) than in the control group (median, 3 days [range: 3–5.75]; p = 0.046).

3.5. Hematopoietic engraftment

The median time to neutrophil engraftment (absolute neutrophil count ≥ 0.5 × 10⁹/L) was 11 days for both groups. Platelet engraftment (platelet count ≥ 20 × 10⁹/L without the need for transfusion) occurred at 15 days for the NEPA group and at 16 days for the control group without significant differences (p = 0.361).

3.6. Adverse events

Constipation (31.6%), insomnia (31.6%), and diarrhea (18.4%) were the most frequently reported adverse events in the NEPA group. The risk of adverse events was comparable between the NEPA and control groups (Table 3).

Table 3.

Adverse events occurring in ≥5% patients in the NEPA and control groups.

Adverse events	NEPA, n (%)	Control, n (%)	p Value
Constipation	12 (31.6)	16 (22.9)	0.323
Insomnia	12 (31.6)	15 (21.4)	0.245
Diarrhea	7 (18.4)	11 (15.1)	0.719
Perianal pain	4 (10.5)	2 (2.9)	0.181
Gingival pain	3 (7.9)	2 (2.9)	0.342
Axial pain	1 (2.6)	5 (7.1)	0.328
Stomach ache	2 (5.3)	0 (0)	0.122

NEPA = netupitant/palonosetron.

4. DISCUSSION

This study demonstrated that the NEPA-based antiemetic regimen was more effective than a 5-HT₃RA-based regimen in patients undergoing HDM conditioning and subsequent ASCT. The NEPA regimen exhibited significantly higher CR rates in the acute (65.8%) and delayed phases (50%). Additionally, the overall response rate in the NEPA group was notably higher than that in the control group, reaching 73.7%. Additional analyses showed consistent benefits across nearly all predefined subgroups. Moreover, patients receiving NEPA exhibited decreased vomiting volume, decreased number of vomiting episodes, and a shorter duration of parenteral nutrition.

Melphalan is the standard conditioning regimen for ASCT in patients with plasma cell dyscrasia.⁸ The latest NCCN guidelines have reclassified melphalan as HEC. It is now recommended that patients should receive HDM in combination with a triplet antiemetic regimen, including a 5-HT₃ receptor antagonist, an NK₁ receptor antagonist, and dexamethasone. Studies administering 5-HT₃RA-based regimens have reported CR rates, defined as no vomiting and no need for rescue therapy, ranging from 20% to 32% among patients undergoing HDM conditioning and HSCT.^16,17 The addition of NK₁ receptor antagonists, such as aprepitant or fosaprepitant, improved the CR rates to approximately 58%.¹² However, CINV in HDM settings remains a significant challenge. Clark et al¹⁸ and Musso et al⁹ reported that CINV prevention in patients undergoing BEAM or HDM before HSCT was notably ineffective, with CR rates ranging from 12.5% to 24%.

NEPA has emerged as a highly effective antiemetic agent for CINV in patients undergoing chemotherapy.¹⁹ A phase III randomized trial reported a remarkable CR rate of 81% in the first cycle of chemotherapy, with this efficacy being maintained in subsequent cycles.²⁰ Another phase III trial demonstrated that NEPA, when administered with dexamethasone, outperformed palonosetron plus dexamethasone in patients who were chemotherapy-naïve and received moderately emetogenic chemotherapy, with higher CR rates in the acute phase (88.4% vs 85.0%), delayed phase (76.9% vs 69.5%), and overall phase (74.3% vs 66.6%).²¹

Nevertheless, there are only a few small-sized efficacy studies in preventing CINV among patients receiving HDM conditioning before ASCT. Loteta et al¹⁵ conducted a prospective, single-center study with 106 patients who received HDM (200 mg/m²) and ASCT. They observed a high overall CR rate of 94% with a dexamethasone-free NEPA regimen. In the prospective observational study conducted by Apolito et al,²² the CR rate in the overall phase reached 56% among patients receiving HDM, with 85% of patients experiencing no episodes of emesis, which aligns with our findings. However, their studies on the efficacy of NEPA for CINV in HDM conditioning lacked control groups, multivariable analyses, and comprehensive quantitative endpoints, making it challenging to generalize the results to Asian populations.

Although nutritional outcomes were an exploratory outcome, this study is the first to suggest a potential association between the administration of NEPA and the need for parenteral nutrition. High-dose chemotherapy before transplantation was associated with significant changes in physical function, and this impairment may be exacerbated by inadequate dietary intake.²³ Previous studies have emphasized the association between the effective control of CINV and nutritional support. For instance, Flank et al²⁴ demonstrated that enhanced management of CINV is associated with a reduced duration and extent of parenteral nutrition in pediatric patients undergoing conditioning for HSCT. Prolonged total parenteral nutrition was associated with hepatic dysfunction in this population.²⁵ Our results revealed that the duration of parenteral nutrition was significantly shorter in the NEPA group with better vomiting control.

The observed difference in reinfused CD34+ cell counts may correspond to the higher prevalence of prior chemotherapy in the NEPA cohort. However, this difference is unrelated to the mechanisms of antiemetic efficacy and therefore does not affect the study’s endpoints. Although there was an imbalance in prior chemotherapy cycles between the 2 groups, several studies have reported no significant association between chemotherapy cycles and CINV risk.^26,27 Our multivariable analysis also found no independent effect of prior cycles on CINV.

A limitation of this study is the lack of an randomized controlled trial design, which makes it hard to establish a causal relationship and avoid selection bias. Furthermore, the small sample size reduced statistical power. Finally, the single-center design limited the generalizability of our findings.

In conclusion, our study suggests that the NEPA-based antiemetic regimen can effectively prevent both acute and delayed phase CINV in patients receiving melphalan before ASCT and supports its adoption as a standard component of supportive care during melphalan conditioning before ASCT.

ACKNOWLEDGMENTS

This work was supported by the Beijing Natural Science Foundation (Z230016), the National Key Research and Development Program of China (No. 2022YFA1103300 and 2022YFC2502606), the Major Program of the National Natural Science Foundation of China (No. 82293630), the Peking University Medicine Fund for World's Leading Discipline or Discipline Cluster Development (No.71003Y3035), Plan Project of Tongzhou Municipal Science and Technology (No. KJ2024CX045), the National Natural Science Foundation of China (No. 82170208), and the Fundamental Research Funds for the Central Universities.

The authors would like to express their gratitude to EditSprings (https://www.editsprings.cn) for the expert linguistic services provided.

ETHICAL APPROVAL

The study protocol was approved by the Ethics Committee of Peking University People’s Hospital (2025PHB299-002).

AUTHOR CONTRIBUTIONS

L.-Q.C., J.D., T.W., and B.-N.L. contributed equally to this study. L.-Q.C. and X.-D.M. conceived and designed the study. D.-X.D. and Y.L. were responsible for patient recruitment. T.W. collected the data. Y.-Y.W., Q.-L.F., R.-Y.G., Y.Q., Y.-Q.G., X.-X.Q., M.-R.L., X.-J.Q., and Z.-P.F. were responsible for nursing documentation. X.-D.M. and J.D. performed the statistical analysis and drafted the manuscript.

Supplementary Material

bs9-8-e00278-s001.pdf ^{(474.2KB, pdf)}