Secondary Monoclonal Gammopathy of Undetermined Significance after Allogeneic Stem Cell Transplantation in Multiple Myeloma

Background In the course of multiple myeloma (MM), patients may develop monoclonal bands of different isotypes than the original myeloma M-protein. Several terms have been used to describe this phenomenon, including abnormal protein band, oligoclonal protein bands, transient mono- or oligoclonal gammopathy, oligoclonal humoral response, atypical serum immunofixation pattern, and in myeloma patients, as we will use in this study, secondary MGUS (sMGUS). There are currently no data available regarding the frequency of sMGUS and its prognostic significance in MM patients who underwent allogeneic stem cell transplantation (allo-SCT). Here, we describe the occurrence of sMGUS and its association with response, progression-free survival (PFS), and overall survival (OS) in this group of patients.

Study design We included a total of 138 patients who underwent 139 allo-SCTs (39.6% in the upfront setting and 60.4% for relapsed multiple myeloma). All patients received their allo-SCT in the University Medical Center Utrecht. Secondary MGUS was defined as appearance of a protein band on immunofixation or electrophoresis that is different from the original myeloma M-protein in heavy-chain or light-chain isotype, or in its migration pattern.

Results Sixty-seven (48.2%) patients developed at least one sMGUS after allo-SCT with a median latency of 6.9 months. Twenty-five patients had only one new protein band (18.0%), 9 (6.5%) had 2 bands, 8 (5.8%) had 3 bands, and 25 (18.0%) had four or more. The median duration of all sMGUS cases was 4.47 months (range 0.0-74.5 months). There was no progression of sMGUS to MM or other lymphoproliferative diseases. Secondary MGUS occurred more often in patients who achieved at least very good partial response after allo-SCT, compared to partial response or less (54.8% vs 26.5%, P=0.005). The incidence was also higher in the upfront setting as compared to patients with relapsed disease (60.0% vs 40.5%; P=0.037), or with a sibling donor compared to matched unrelated donor (57.0% vs 36.7%, P=0.026), but less often after T cell depletion (39.3% vs 61.8%, P=0.025). Importantly, development of post-transplant MGUS as a time-dependent variable, independently predicted for superior PFS and OS (median PFS: 37.5 vs 6.3 months, P<0.001; median OS: 115.3 vs 31.0 months, P=0.004). Since most TRM occurred in the first 6 months after allo-SCT (12 out of 15 TRM cases; 80%), we also performed a landmark analysis at this time-point. PFS and OS remained significantly superior in patients with sMGUS (n=100 patients; median PFS: 31.5 vs 4.9 months, P<0.001; median OS: 109.3 vs 57.3 months, P=0.015). Importantly, development of sMGUS was associated with improved PFS and OS both in patients who received allo-SCT as part of first-line treatment and in patients with relapsed MM. In addition, emergence of sMGUS predicted for enhanced PFS and OS in patients who achieved at least VGPR and also in patients who achieved less than VGPR after allo-SCT.

Conclusions This is the first study that evaluates the significance of sMGUS in MM patients treated with allo-SCT. Development of sMGUS after allo-SCT was associated with a better quality of response, as well as significantly improved PFS and OS, both in patients transplanted in the upfront setting and at the time of relapse. Clinicians should be aware of the benign nature of this phenomenon, and sMGUS should not be confused with relapse or progression of disease.