High sensitivity of mass spectrometry based M-protein detection

With improved treatment options for patients with Multiple Myeloma (MM), a greater number are achieving a complete response (CR). Measurements of M-protein have enabled doctors to follow CR and subsequent progression, but many of the earlier techniques lack sensitivity. Consequently, there has been a move towards measurement of Minimal Residual Disease (MRD) from bone marrow (BM) aspirates, using either flow cytometry or molecular based methods. MRD measurements from the BM are > 3 times more sensitive than serum measurements and correlate with progression free survival (PFS), although many MRD-negative patients do still progress. However, BM techniques are expensive, time-consuming and uncomfortable for the patient. Therefore, the development of more sensitive serum-based methods that correlate with stringent CR (sCR) would be beneficial.

In a study carried out by researchers at the Department of Pathology and Medicine, Mayo Clinic, Rochester, USA, and published in Blood Cancer Journal, the sensitivity of monoclonal Ig Rapid Accurate Mass Measurements (miRAMM) was tested using serum from MM patients that had achieved a sCR post autologous stem cell transplant (ASCT). This method uses the identification of M-protein from the accurate molecular mass of the light chain component and could be adapted easily for clinical testing.

Key Findings:

• Accurate molecular mass of M-protein light chain (LC) was identified in all samples
• High resolution MS was capable of distinguishing mass differences of 1 Da
• Patients (pts) were included if they had reached sCR at day 100 using conventional testing
• All samples were negative by other serum analysis methods
• When sCR was established at day 100 post-ASCT 16/30 pts could be assessed by miRAMM: M-protein was identified in 13/16 pts (81%); the 3 negative cases were all IgA positive
• When sCR was maintained 6-12 months post-ASCT 25/30 pts could be assessed by miRAMM: M-protein was identified in 15/25 pts (60%)
• miRAMM negativity at 6–12 months post-ASCT: 4/6 (67%) with CR vs 6/19 (32%) for pts without CR
• At 6-12 months, IgG negativity = 38% (6/16) and IgA negativity = 44% (4/9) by miRAMM
• At 100 days post-ASCT 6 months and 12 months, no correlation was found between miRAMM M-protein positivity and PFS
• Change in M-protein intensity was evaluated between the two time points by dividing the change in miRAMM intensity by the time interval between measurements in days
• At day 100 and 6-12 months, 11 pts remained in sCR and were evaluable: 3 reached miRAMM-negativity at the second time point, 1 maintained miRAMM-negative status, 4 had a further reduction in miRAMM M-protein intensity (>40% from day 100 to the second sampling), 2 had miRAMM M-proteins of stable intensity and 1 converted from miRAMM negative to positive
• A longer PFS was observed for the 8pts with continued miRAMM negativity or decreasing M-protein intensity compared with pts that had stable or increasing miRAMM M-protein intensity: 51.6 vs 17.9 months (P < 0.0017)

Conclusion:

This method offers a serum test to measure serum M-proteins, with improved sensitivity over other methods in terms of both cost and ease of use. With such a small sample set in this study, conclusions are limited, but initial data suggests that measurements are indicative of sCR and could be used for meaningful tracking of treatment responses over time. 

Abstract

We assessed the ability of a mass spectrometry-based technique, called monoclonal immunoglobulin rapid accurate mass measurement (miRAMM), to extend the analytical range of M-protein detection in serum samples obtained from myeloma patients in stringent complete response (sCR) post-autologous stem cell transplant (ASCT). To aid the M-protein detection post ASCT, the accurate molecular mass of the M-protein light chain at diagnosis was determined in all patients (N=30) and used to positively identify clones in the sCR serum. Day 100 post-ASCT, sCR samples had miRAMM identifiable M-proteins in 81% of patients. Patients who had achieved only a partial remission (PR) pre-ASCT and those with IgG isotypes serum samples had the highest rate of M-protein detection by miRAMM. miRAMM positivity at single time points (day 100, 6 months or 12 months) did not correlate with progression-free survival (PFS). In contrast, sCR patients who did not decrease their miRAMM M-protein intensities in serial measurements had shorter PFS than those whose miRAMM intensities decreased (median 17.9 months vs 51.6 months; P<0.0017). miRAMM M-protein is a more sensitive blood-based test than traditional M-protein tests and could cost effectively aid in serially monitoring complete remission for continue response or biochemical relapse.