Minimal residual disease detected by next-generation sequencing following autologous hematopoietic stem cell transplantation had significant prognostic value among patients with multiple myeloma, according to results of a study published in Annals of Oncology.
“Previous studies in different lymphoid neoplasms have reported a sensitivity difference between the various techniques, with next-generation sequencing-based methods demonstrating greater sensitivity compared [with] flow cytometry and allele-specific oligonucleotide-polymerase chain reaction,” Hiroyuki Takamatsu, MD, associate professor of hematology and respiratory medicine at Kanazawa University Graduate School of Medical Science in Kanazawa, Japan, and colleagues wrote. “Our results support and further expand on these previous findings.”
Autologous HSCT in conjunction with novel therapeutic drugs can dramatically improve response rates and prognoses of patients with multiple myeloma. However, relapse owing to minimal residual disease (MRD) is the main cause of death among these patients.
Because new technologies that assess deeper response are required to detect MRD, researchers compared the prognostic value of MRD detected by next-generation sequencing with allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR).
The sensitivity of the next-generation sequencing assay (Adaptive Biotechnologies) was 1 x 10–7 for autograft cells and 1 x 10–6 for bone marrow cells. Sensitivity of immunoglobulin heavy chain (IgH)-based ASO-PCR (TaqMan) was 10–4 to 10–5.
The retrospective analysis included autograft and bone marrow samples from 125 newly diagnosed Japanese patients with multiple myeloma who underwent high-dose melphalan plus autologous HSCT.
Median follow-up for survivors was 3.5 years (range, 0.5-10.5 years).
Researchers first assessed diagnostic samples using the next-generation sequencing-based assay. They detected at least one clonal sequence in 100% (n = 31) of fresh/frozen bone marrow samples and 91% (n = 82 of 90) of bone marrow close/smear slide/biopsy samples for an overall clone identification rate of 90% (n = 113).
When assessing IgH clonality for ASO-PCR, researcher prepared primers for 65% (n = 53 of 82) of bone marrow smear/decalcified biopsy slides and 71% (n = 22 of 31) fresh/frozen bone marrow samples, resulting in a 66% identification rate.
According to next-generation sequencing of post-HSCT bone marrow cells in 51 patients, the 26 patients found to be MRD negative — defined as less than 10-6 — demonstrated significantly better 4-year PFS (96%; P = .0004) and OS (100%; P = .04) than the 25 MRD-positive patients.
After restricting the analysis to 39 patients with complete responses, the 24 with MRD-negative disease also showed significantly better PFS than the 15 MRD-positive patients (P = .02). Because only one death occurred among these patients, there was no significant difference in OS.
Then researchers conducted autograft MRD assessment using the next-generation sequencing-based platform in 43 patients who did not receive post-HSCT treatment. The 10 patients with MRD negativity — defined as less than 10–7 — in the autograft had better PFS (P = .002) and demonstrated a trend toward better OS than the 33 MRD-positive patients.
MRD assessment of 58 patients who did receive post-HSCT treatment showed a similar pattern.
Researchers then compared treated and untreated patients to determine whether post-HSCT treatment alters clinical outcomes in patients with MRD-positive autografts by next-generation sequencing. Results showed the 49 MRD-positive patients who received post-HSCT treatment had significantly better PFS (P = .001) and a trend toward better OS than the 33 untreated patients.
Researchers evaluated 68 autografts and 25 bone marrow samples by both next-generation sequencing and ASO-PCR. Thirty-five samples were MRD positive by next-generation sequencing but negative by ASO-PCR, “which is consistent with the higher sensitivity afforded by the next-generation sequencing platform,” the researchers wrote.
Seven patients with MRD-negative autografts by next-generation sequencing showed significantly better PFS than 11 patients with MRD-positive disease by next-generation sequencing undetected by ASO-PCR (P = .018). This trend persisted in bone marrow samples.
“The association between MRD status and clinical outcome may reflect that the presence of MRD positivity means that there are contaminating myeloma cells in the product that will be infused back into the patient,” Takamatsu and colleagues wrote. “Alternatively, the presence of MRD in the autograft can simply indicate that a substantial number of myeloma cells remain in the patient’s body and the homogenous nature of the mobilized autograft relative to the focal nature of myeloma in bone marrow might provide a better sample to assess MRD.”
Limitations of the study included its relatively small sample size and its retrospective nature, researchers noted.
“Low-level MRD detected by next-generation sequencing-based platform, but not ASO-PCR, has significant prognostic value when assessing either the autograft product or bone marrow cells post-autologous [HSCT],” Takamatsu and colleagues wrote. “These findings, particularly regarding the significance of MRD negativity in autograft, should be confirmed in prospective studies.” – by Chuck Gormley
Disclosures: Adaptive Biotechnologies, Grant-in-Aid for Scientific Research, Hokkoku Foundation for Cancer Research, International Myeloma Foundation Japan and Mitsui Life Social Welfare Foundation funded this study. Takamatsu reports research funding from Takeda and Fujimoto and honoraria from Celgene and Janssen. Please see the full study for a list of all other authors’ relevant financial disclosures.