melphalan

A variety of factors led to clonal diversification and increased tumor mutation burden, such as MAPK-Ras mutations and incremental changes related to chromosomal bands 1 and 17, while mutational signature analyses revealed that APOBEC activity and melphalan treatment leave a distinct impact on the clonal composition in MM genomes. To capture and dissect tumor heterogeneity, our review suggests combining methods or using technical approaches with high resolution to assess the impact of clonal evolution.

P2, N=88, Completed, Radboud University Medical Center | Active, not recruiting --> Completed

P2, N=36, Not yet recruiting, Washington University School of Medicine

P2, N=215, Recruiting, Memorial Sloan Kettering Cancer Center

P3, N=660, Completed, Fondazione EMN Italy Onlus | Active, not recruiting --> Completed | Trial completion date: Nov 2024 --> Jul 2024

P1, N=22, Recruiting, University of Wisconsin, Madison | Suspended --> Recruiting | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

Background: High dose melphalan and ASCT, followed by lenalidomide (len) maintenance, improves progression-free survival (PFS) in MM but is generally not curative. In newly-diagnosed MM patients with <CR after induction, belamaf every 3 months in conjunction with ASCT and len maintenance appears feasible (at 1.9 mg/kg starting dose), with expected reversible ocular toxicities, and so far has promising rates of sCR, MRD-negativity, and PFS. Accrual and follow-up are ongoing.

We recently demonstrated that INO can be added safely to a non-myeloablative conditioning of bendamustine, fludarabine, and rituximab in patients with indolent lymphoid malignancies who required an allogeneic hematopoietic transplantation (HCT) (Am J Hematol 2024)...Patients who received transplants from MUDs received an additional dose of methotrexate 5 mg/m2 on day +11 and 1 mg/kg of rabbit anti-thymocyte globulin IV on days -1 and -2 before HCT...The patient who was in CR2 at transplant had Ph+ ALL and was maintained on ponatinib after HCT. Key prior therapies in ALL patients included blinatumomab (n=5) and INO (n=5)... Our conclusions are limited by the small number of patients due to slow accrual. However, our data suggest that INO is safe when combined with a melphalan plus fludarabine HCT conditioning regimen. The survival outcomes are encouraging and need to be validated in a larger number of patients.

NPM1 MRD positive patients receiving nonmyeloablative conditioning or reduced-intensity conditioning (RIC) without melphalan (mel) had increased risk of relapse or death compared to patients receiving myeloablative conditioning or RIC with mel, regardless of FLT3-ITD co-mutational status (3yrs: relapse 87% vs 55%, P=0.006; OS 15% vs 42%, P=0.013). In patients with NPM1 mutated AML from the Pre-MEASURE study, we show that detection of residual NPM1 variants in pre-transplant blood during CR1 using a highly sensitive DNA-based assay is associated in a dose-dependent manner with a significantly increased risk of relapse and death after allo-HCT, which can be mitigated in part by conditioning regimen. In patients co-mutated for both FLT3-ITD and NPM1 at diagnosis, NPM1 should be prioritized as a target for NGS-MRD if only one test is available.

Several patients with prior melphalan exposure have SBS99 evident in several biopsies, consistent with single cell expansion from MM cells surviving transplant and subsequently seeding in multiple sites... PMD and EMD demonstrate multiple features of genomic complexity when compared with BM-based myeloma, which include emerging copy number aberrations, mutational burden and complex structural variants. EMD are more complex in general than PMD, while IMD shows only trends to increased genomic aberration compared with BM. Ongoing analyses include an expansion in WGS samples, and correlation of genomic features with clinical response to therapy.

P1, N=33, Recruiting, City of Hope Medical Center | Initiation date: Sep 2024 --> May 2024

P3, N=389, Completed, Fondazione EMN Italy Onlus | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Jul 2024

P2, N=59, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

P1, N=22, Active, not recruiting, City of Hope Medical Center | Recruiting --> Active, not recruiting | N=16 --> 22

P1/2, N=0, Withdrawn, GlyPharma Therapeutics | Phase classification: P1b/2a --> P1/2

P2, N=66, Not yet recruiting, Ruijin Hospital

P2, N=42, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

P=N/A, N=30, Recruiting, McMaster University | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jul 2024 --> Jul 2025

P2, N=63, Recruiting, Thomas Jefferson University | Trial completion date: Oct 2024 --> Apr 2025 | Trial primary completion date: Oct 2024 --> Apr 2025

P1, N=22, Suspended, University of Wisconsin, Madison | Recruiting --> Suspended

Methods Patients diagnosed with myeloma and concomitant dialysis-dependent renal dysfunction were admitted for ASCT after achieving at least partial response with bortezomib-based induction therapy. For both patients, mobilization consisted of granulocyte colony stimulating factor for 5 days and CD34 directed Plerixafor on Day 1...Use of reduced dose melphalan, pre-emptive dialysis after 24 hours and monitoring for acidosis and symptoms of uraemia to identify acidosis at an early stage allows safe administration of high dose chemotherapy. A major proportion of patients can potentially achieve reduction or freedom from dialysis support post-transplant.

P2, N=120, Recruiting, Université de Sherbrooke | Initiation date: Sep 2024 --> Dec 2024

P2, N=50, Active, not recruiting, University of Arkansas | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

P2, N=170, Active, not recruiting, St. Jude Children's Research Hospital | Recruiting --> Active, not recruiting | N=52 --> 170

Moreover, treatment with AA but not 12-HETE partially abrogated the inhibitory effect of palmitic acid on MΦ-mediated MM cell survival in response to bortezomib or melphalan. Overall, we identified palmitic acid as a factor that inhibits MΦ-mediated resistance to bortezomib and melphalan in MM, which may have clinical significance.

P3, N=706, Completed, Janssen Research & Development, LLC | Active, not recruiting --> Completed

P2, N=401, Active, not recruiting, Stichting European Myeloma Network | Trial completion date: Feb 2025 --> Feb 2026 | Trial primary completion date: May 2024 --> Jun 2025

P3, N=126, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

P2, N=12, Active, not recruiting, Catherine Bollard | Recruiting --> Active, not recruiting

P2, N=22, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Jun 2024 --> Jun 2025

P1, N=50, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jul 2024 --> Jun 2028 | Trial primary completion date: Jul 2024 --> Jun 2028

P4, N=42, Not yet recruiting, Meishan City Peoples Hospital; Meishan City Peoples Hospital

P2, N=34, Not yet recruiting, Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

Five of the eight BRCA2 PGV carriers exhibited tumor-specific copy number loss in BRCA2, suggesting somatic loss of heterozygosity. PGV-As were associated with younger age at diagnosis, personal or familial cancer history, and longer progression-free survival after upfront high-dose melphalan and autologous stem cell transplant (p<0.01).

They find an association of patients with PGVs and previous family or personal history of cancer and that these patients are diagnosed slightly earlier than those without PGVs. Patients with PGVs had a longer progression free survival than those without PGVs when they received high dose melphalan and autologous stem cell transplant, providing a therapeutic rationale for diagnostic germline testing in myeloma.

P3, N=172, Not yet recruiting, Augusta University

P2, N=20, Recruiting, Fred Hutchinson Cancer Center | Trial primary completion date: Aug 2024 --> Aug 2026

P2, N=28, Not yet recruiting, Masonic Cancer Center, University of Minnesota | Initiation date: Aug 2024 --> Dec 2024

P1, N=4, Terminated, Roswell Park Cancer Institute | Trial completion date: Jan 2027 --> Jun 2024 | Active, not recruiting --> Terminated; Lack of funding

Several melphalan-exposed patients had SBS99 evident in the phylogenetic tree trunk of multiple biopsies, consistent with single cells surviving transplant and subsequently seeding in multiple sites. PMD and EMD demonstrate multiple features of genomic complexity when compared with BM-based myeloma, including emerging copy number aberration, mutational burden, and complex structural variants. Ongoing studies include expanding the WGS dataset, and correlation of genomic features with clinical response to therapy.

P2, N=1, Terminated, M.D. Anderson Cancer Center | N=40 --> 1 | Trial completion date: May 2025 --> Aug 2024 | Active, not recruiting --> Terminated | Trial primary completion date: May 2025 --> Aug 2024; PI Request

Our real-world analysis demonstrates that MEL140 yields similar deep post-transplant remissions as MEL200, translating to improved PFS for patients achieving MRD negativity, regardless of the dose used.