Vaccinating Against Mutated RAS in Multiple Myeloma: The Phase I/II TG01/QS-21 Study
Authors: Norseth Hanne Marie , Monsen Hedda Berg , Remen Nora , Inderberg Else Marit , Vålerhaugen Helen , Bergly Laila Helene , Lysén Anna , Abrahamsen Ingerid Weum , Schjesvold Fredrik 
Published: December 2024

Background: RAS mutations are among the most frequent mutations in multiple myeloma (MM) found in approximately 50% of newly diagnosed patients with increasing prevalence as the disease progresses (Lionetti M et al, 2015). Several studies have found that RAS mutations may be present already at the smoldering stage and some genomic studies suggest that MM may be driven by mutations within the RAS signaling cascade (Boyle EM et al, 2021). The clinical relevance of RAS mutations is however still unclear.

TG01 is an injectable antigen-specific cancer immunotherapy consisting of a mixture of seven different synthetic peptides that mimic fragments of mutant forms of the human RAS protein. The peptides that make up TG01 are identical to peptides derived from single-base substitutions on codons 12 or 13 commonly found in MM patients. TG01 has previously been tested in phase I/II studies in patients with pancreatic cancer with a very tolerable safety profile and high levels of immunological responses (Palmer DH et al, 2020). TG01 is administered with QS-21 as an adjuvant.

Aims: The study (NCT05841550) is evaluating vaccination with TG01/QS-21 as single agent treatment in patients with KRAS or NRAS codon 12/13 mutation and either MM following at least one previous line of therapy or high-risk smoldering MM (HR SMM). The primary endpoint is safety and tolerability of TG01/QS-21. Secondary endpoints include response according to IMWG criteria, immunological response to the vaccine defined by the TG01- specific cytokine production as well as the size of the RAS-mutated clone (as estimated by variant allele frequency by next generation sequencing) before and after completing study treatment and/or at progression.

Methods: The TG01 study is an academic, single arm, open-label, phase I/II study. 20 patients will be included and receive TG01/QS-21 0,7 mg SC Q2W for the first 12 weeks followed by Q2M until week 52 for a total of 12 doses. Patients will be screened for RAS mutations with a PCR based method (Biocartis IdyllaTM system) and only included if they have one of the seven mutations that are targeted by the TG01 vaccine.

Results: As of July 01, 2024, 39 patients have been screened and 10 patients have been included from the time of study initiation May 31, 2023. The first 7 patients were included in a safety cohort and followed for a minimum of 30 days from treatment initiation before enrollment could continue. Baseline characteristics and safety summary of evaluable patients (n=10) are as follows: Median age: 73 years (range 59-81); Male: 70% (7/10)/Female: 30% (3/10); ISS stage I: 40% (4/10)/II: 30% (3/10)/III: 30% (3/10); HR SMM: 40% (4/10)/MM with prior treatment: 60% (6/10).

There has been a total of 22 AEs since first treatment administration. Three patients have had an AE considered definitely related to study medication, including local skin reaction (n=2) or pain in arm (n=1) around the site of vaccine administration, all grade 1. One patient developed chills considered possibly related to study medication, also grade 1. No patients have developed &gt; grade 3 adverse events (AEs).

Four patients are still on study and have stable disease with a median of 6 treatment cycles started (range 1-10). 6/10 patients have progressed with a median PFS of 3 months as of July 01, 2024.

Conclusion: Preliminary data suggest that TG01/QS-21 has a very tolerable safety profile. No objective responses have so far been observed, but 4/10 subjects remain on treatment with stable disease and enrollment is ongoing. The first analyses of the immunological responses are being performed and will be presented at ASH.