Measurable residual disease (MRD) assessed by mass spectrometry (MS) in peripheral blood versus next generation sequencing (NGS) in bone marrow in multiple myeloma treated on phase II trial of KRd+ASCT.

Abstract

8513 Background: MRD-negativity in multiple myeloma (MM) assessed by NGS in bone marrow (BM) aspirate is associated with longer progression free survival (PFS) and overall survival. MS can detect monoclonal protein at a heightened sensitivity in peripheral blood (PB). We sought to assess the concordance of MS in PB and NGS in BM, comparing outcomes by MRD status. Methods: MRD was tested on paired PB and BM samples from transplant (ASCT)-eligible pts with newly diagnosed secretory MM who received treatment on a phase II clinical trial (NCT01816971) with KRd for 4 cycles, ASCT, KRd for 14 cycles, and lenalidomide maintenance (LM). Both NGS and MS were evaluable in 36 pts after a total of 18 cycles of KRd (C18) and in 24 pts after 1 year of LM. MS signatures were identified in pretreatment PB samples. C18 and after 1 year of LM PB samples were evaluated using both MALDI-TOF and liquid-chromatography-MS (LCMS) by the Binding Site Group. Paired MRD by NGS was performed by ClonoSEQ. 20/60 samples reached the limit of detection for 10−6 and 40/60 for 10−5. Results: There was substantial concordance between NGS and MALDI-TOF among the 60 samples ( κ= 0.667, 83% agreement) and fair concordance between NGS and LCMS ( κ= 0.348, 63% agreement). However, all 22 discordant samples (8 with NGS depth 10−6, 14 with NGS depth 10−5) were NGS−/LCMS+. 4/16 (25%) of these pts converted to NGS+, and 3/16 (19%) clinically progressed. There was stronger concordance between LCMS and NGS 10−6( κ= 0.615) than with NGS 10−5( κ= 0.375). At a median follow-up of 56 months, C18 LCMS−(n = 9) was associated with superior PFS vs all LCMS+(n = 27; p = 0.03) and independently vs NGS—/LCMS+ (n = 14; p = 0.04). There were 10 events (including 4 deaths) in the C18 LCMS+ group vs 0 in the LCMS− group. Conclusions: MRD assessment by LCMS in PB appears to reach and possibly exceed the sensitivity of MRD by NGS in BM at a depth of 10−5-10−6. LCMS positivity predicted conversion from NGS— to NGS+ in 25% of discordant cases, and LCMS negativity was a better predictor of superior PFS than MRD negativity by NGS. These observations need confirmation in larger prospective studies.

Implications of detecting serum monoclonal protein by MASS‐fix following stem cell transplantation in multiple myeloma

“…16 Additionally, data underscoring the profound benefit of attaining a dual-negative state (MRD-negative by NGS and MS) in another study were recently presented. 17 Despite several limitations associated with a retrospective analysis, including lack of post-ASCT serial sampling to overcome the confounding impact of variable half-lives of immunoglobulin subtypes, and a relatively short follow-up (median: 26 months), our study demonstrates that by using a simple, generalizable peripheral blood-based assay, with advantages of high throughput, rapid turnaround time, noninvasive serial sampling and higher analytical sensitivity and specificity compared to traditional IFE, 4,9 we can further risk-stratify patients with MM who are otherwise deemed MRD-negative by bone marrow NGF. In conclusion, the serum MASS-FIX results appear to complement the bone marrow-based NGF findings in accurately prognosticating patients with MM post ASCT.…”

“…In a small study, with a short follow‐up (median: 11 months), only one of 23 patients in CR who were negative by both NGF and MALDI‐TOF‐MS relapsed 16 . Additionally, data underscoring the profound benefit of attaining a dual‐negative state (MRD‐negative by NGS and MS) in another study were recently presented 17 …”

Tumor Reduction in Multiple Myeloma: New Concepts for New Therapeutics

“…New techniques of mass spectrometry (MS) enable the identification of monoclonal proteins with a deeper limit of sensitivity in comparison with EP and IF (85), leading to an increased power to discriminate populations with different survival outcomes. It is still pending validation in large prospective studies, but preliminary data suggest that MS may represent a less invasive alternative than MRD evaluations in bone marrow by NGS or MFC (45,86).…”

New regimens and directions in the management of newly diagnosed multiple myeloma

“…While this approach may overcome the barrier of patchy involvement within the bone marrow, it is fraught with several challenges including dependence of the type of monoclonal protein and the clearance characteristics of different immunoglobulin isotypes which may results in certain subtypes to persist in the blood longer than others resulting in positive MRD 79 while there may be no detectable MRD within the bone marrow similar to the challenge with traditional response assessment where the patient may have low level presence of monoclonal protein by traditional response assessment and no detectable disease within the bone marrow and have comparable outcomes to MRD negative patients in complete remission. However, different techniques including peripheral blood mass spectrometry, 80 cell‐free DNA and circulating plasma cells are being evaluated. These will require further study in the context of prospective clinical trials using cross‐validated approaches before such approaches can become acceptable as mainstream for MRD testing.…”

“…However, different techniques including peripheral blood mass spectrometry, 80 cell-free DNA and circulating plasma cells are being evaluated. These will require further study in the context of prospective clinical trials using cross-validated approaches before such approaches can become acceptable as mainstream for MRD testing.…”