# Ultra-Low-Dose Inhalation of Melphalan as an Additional Treatment for COVID-19-Associated Pneumonia

## TL;DR

This study shows that ultra-low-dose melphalan inhalation improves outcomes in patients with COVID-19 pneumonia without causing adverse effects.

## Contribution

The novel use of ultra-low-dose melphalan inhalation as an anti-inflammatory treatment for severe COVID-19 is proposed and tested.

## Key findings

- Patients receiving melphalan inhalations showed significant clinical improvement compared to standard treatment.
- Melphalan reduced dyspnea severity and inflammatory markers like C-reactive protein more rapidly.
- No adverse effects were observed with the ultra-low-dose melphalan treatment.

## Abstract

Background/Objectives: Effective anti-inflammatory treatment for COVID-19 is necessary. It was shown that ultra-low doses (100-fold lower than therapeutic ones) of alkylating drug melphalan (MEL) interact with cytokine cell receptors without DNA damage. A method of treating severe COVID-19 with ultra-low doses of MEL inhalations was proposed. The objective was to study the efficacy and safety of MEL inhalations for COVID-19 pneumonia treatment. Methods: An open-label comparative study (NCT04380376) with 120 patients divided into two groups was conducted. The control group (CG) received standard treatment, and the melphalan group (MG) also received seven daily 0.1 mg MEL inhalations. Changes in clinical improvement, inflammatory markers, and CT lung scan data were primary and secondary endpoints. Results: Patients in the MG showed significantly better clinical outcomes compared to the CG, with improvements in dyspnea according to the WHO Ordinal Scale of Clinical Improvement and the modified Borg Scale, CT scans, and inflammatory markers. No adverse effects (including irritant and bronchoconstrictor effects) possibly related to MEL were reported. Conclusions: This study demonstrated the efficacy of incorporating ultra-low-dose MEL inhalations into the therapeutic regimen for patients with COVID-19-associated pneumonia. This conclusion is supported by a statistically significant improvement in clinical outcomes, as assessed by the OSCI, a more rapid reduction in the severity of dyspnea, and a marked anti-inflammatory effect, evidenced by a faster decline in C-reactive protein levels. No adverse effects were observed with the proposed treatment method. Further large-scale randomized clinical trials are warranted to validate these findings and to evaluate the potential for the implementation of ultra-low-dose MEL inhalation in clinical practice.