Early relapse following ASCT a hallmark of high-risk myeloma
Individuals with myeloma who relapse within a year (ie, progression-free survival [PFS] <12 months) after receiving autologous stem cell transplant (ASCT) may have high-risk disease, suggesting poor survival rates, according to the results of the MYELOMA XI* trial presented at ASH 2018.
This phase III, multicentre trial included 4,420 individuals who were initially randomized to receive induction therapy comprising CTD** or RCD***. Participants who failed to achieve very good partial response# with either regimen were then randomized 1:1 to consolidation treatment with or without CVD##. Transplant-eligible patients (n=1,274) proceeded to receive ASCT. Of these, 52 percent received maintenance therapy using a lenalidomide-based regimen. [ASH 2018, abstract 122]
Fourteen percent of ASCT recipients relapsed within 12 months of the procedure (arm A), while the rest progressed beyond 12 months (arm B).
Compared with arm B, patients in arm A had a lower baseline haemoglobin concentration (mean, 104.6 vs 111.9 g/L; p<0.0001), a higher baseline plasma cell percentage in the bone marrow (mean, 45.9 percent vs 36.7 percent; p<0.0001), and were more likely to have ISS### stage 3 disease (28.7 percent vs 20.3 percent; p=0.0068). There were also more patients who were lambda light-chain (LC) restricted (43.3 percent vs 33.6 percent; p=0.0145) in arm A vs arm B.
“Lambda [LC] patients have a greater degree of immunoparesis. [This] can be associated with a shorter PFS due to [the reduced] immunosurveillance, which is one mechanism to resist disease progression,” explained study author Dr Ceri Bygrave from the University Hospital of Wales in Cardiff, UK. “Lambda LC patients often have higher [serum-free] LC levels, [which] can lead to a lower estimated glomerular filtration rate and a higher beta-2 microglobulin and ISS stage.”
The association between lambda LC subtype and inferior survival is interesting and needs further evaluation, added Bygrave, citing similar results from a previous trial demonstrating poorer overall survival (OS) among lambda-restricted vs kappa-restricted myeloma patients (2.0 vs 2.4 years; p<0.007). [Blood 2006;108:2013-2019]
Arm A also included more patients with high-risk (33 percent vs 31 percent; p=0.00001) and ultra-high-risk (31 percent vs 9 percent; p=0.00001) lesions than arm B. Nonetheless, patients with standard-risk (SR) genetics can still exhibit early disease progression, Bygrave pointed out. “Sixty-four percent of patients [in arm A] had SR genetics. Forty-eight patients progressed within 100 days of transplant, which … is very shocking.”
Continued PFS evaluation showed further inferior outcomes in arm A vs arm B (median PFS, 28 vs 67 months; p<0.00001), translating to a markedly shorter 3-year OS (28 percent vs 53 percent; p<0.00001). Moreover, 75 percent of patients in arm A died within 3 years of study entry. “This is a statistic that we need to improve on,” said Bygrave.
Despite strategies identifying myeloma risk (ie, staging, clinical features, patient factors), there remains a lack of consensus regarding the appropriate treatment of high-risk disease, noted Bygrave. “It is impossible to recognize all high-risk patients at diagnosis … because the features of high-risk disease are sometimes subtle … [The] timing of first relapse [may define] risk for some patients. However, by then, it may be too late to intervene.”
“Early relapse can be used as a marker of high-risk disease, which represents a large unmet need,” said Bygrave. “Response to standard therapies and timing of first relapse [are] additional phenotypic definitions of high risk that need to be examined in more detail ... [While] this group of patients may benefit from early use of novel immunotherapies, dedicated studies [are warranted] … to better characterize and identify this group and develop treatments to improve their outcomes.”