(PA-236) Longitudinal Analysis of Clonal Hematopoietic Mutations (CHIP) in Transplant Eligible Multiple Myeloma (MM) Patients: Trends From Pre-Transplant to 1 year.

Introduction:  CHIP mutations (mtns) are common in MM patients (pts) at time of diagnosis (dx), and may impact survival, but there is limited data around clonal evolution trends. We are expanding on previous results (ASH 2024) of prospective analysis of CHIP mtns in a uniformly treated cohort of 173 IMID naïve MM pts at therapy-related time-points (TPs), including pre-transplant (tx) after non immunodulatory agent (IMID)-containing induction (TP1, 173 pts), 3 months (mos) post-tx using high-dose melphalan (prior to IMID start, TP2, 103 pts), and 1 year post-tx, TP3 (56 pts).

Methods:   CHIP was identified using single-molecule molecular inversion probes (SmMIP) next generation sequencing to a minimum depth of 4000x, with threshold variant allele frequency (VAF) of 1% (for previously unidentified mtns); calls were subjected to filters to reduce false positives.

Results:   Baseline characteristics of the 173 pts were as expected, with median age at dx of 66 years, 59% male, 58.4% IgG sub-type, 24% ISS stage 3 and 24% high risk cytogenetics. 94% of pts received proteasome-inhibitor based induction. 92% of those starting maintenance (60% of overall cohort) received IMID.
At TP1, 63/173 (36%) pts had at least 1 CHIP for a total of 83 mtns, with 14/63 (22%) having co-mtns. DNMT3 accounted for 37/83 (44.5%) mtns, followed by TET2 (15/83, 18%) and PPM1D (8/83, 10%).
At TP2, 36/103 pts (35%) had 54 mtns, with co-mtns in 12 (33%). As in TP1, most common mtns were DNMT3a (29/54, 53%), TET2 (10/54, 18%) and PPM1D (4/54, 7%).
At TP3, 26/56 pts (46%) had 43 mtns, with co-mtns in 7/26 (27%). DNMT3a accounted for 18/43 (42%). Prevalence of TP 53 mtns increased, at 7/43 (16%) at TP3, compared to 5/83 (6%) at TP1, and 4/54 (7%) at TP2.
Next we tracked the fate of 83 mtns in 63 pts seen at TP1. Of these, at least 1 further time-point data (TP2 or 3 or both) was available for 56 mtns (40 pts) of which 3 TP data was available for 25 mtns (18 pts). Of the 56 TP1 mtns, 15 (26%) were non-recurring at any TP, and 41 were recurring. Of 41 recurring mtns, 8/41 (20%) were only detected on lookback analysis after being identified at later TPs, initially being below cut-off VAF.
DNMT3a comprised a minority (2/15, 13%) on non-recurring mtns, despite higher prevalence (25/56, 45%) at TP1. Tet2 accounted for 6/15 (40%) of non-recurring mtns (baseline prevalence (12/56, 21%)).
The mean VAF at TP1 was 6.6, and remained stable from TP1 to TP2, and TP2 to TP3. A few mtns (DNMT3a, PPM1D, ASXL1) in individual pts showed greater VAF variations than expected.

Conclusions:   In this longitudinal study, the overall incidence of CHIP mutations is stable from non-IMID induction through high dose melphalan and 1 year of IMID maintenance.  However, individual mutations can expand (TP53) or be lost (TET2), though many new mutations can be found at baseline at very low VAF. Clinical correlates and longer follow-up for evolution patterns is ongoing.