The Co-Occurrence of 1q21+/1q23+ and t(4;14) Abnormalities with Specific Clone Size Is Predictive of Shorter Response to Transplant in Patients with Multiple Myeloma

Introduction: The presence or absence of recurrent chromosomal abnormalities (CA) as detected by karyotype and/or fluorescence in-situ hybridization (FISH) has emerged as one of the most clinically relevant prognostic factors for patients with newly diagnosed multiple myeloma (MM). The Revised-International Staging System (R-ISS) defined high-risk disease as the presence of at least one of the following: deletion(17p), translocation t(4;14)(p16;q32), or translocation t(14;16)(q32;q23). Amplification or gain of chromosome 1q (1q21+/1q23+) has also been growing in its clinical relevance, with 1q21+ found in approximately 35-40% of patients. As a result, this study evaluated differences in survival outcomes and disease characteristics in patients with both 1q+ (1q21+ or 1q23+) and t(4;14), compared to those patients with only 1q+ or t(4;14).

Methods: A retrospective chart review was performed on 243 newly diagnosed MM patients with the cytogenetic abnormalities of interest obtained from established FISH data from bone marrow aspirate samples at diagnosis. Primary endpoints were Progression-Free Survival (PFS) and Overall Survival (OS) after autologous stem cell transplant (ASCT), and Kaplan Meier methods were used to calculate PFS and OS. Secondary endpoints included the identification of disease characteristics between single CA and combined abnormalities. To specifically analyze the quantitative CA cutoff values and the correlation of clone size to survival outcomes, we established subgroupings with positivity defined as 1q21+ or 1q23+ present in more than 20% of cells and t(4;14) present in more than 30% of cells. Patients who satisfied both cutoff criteria were labeled as 'double-hit', and patients with CA present, but clone sizes less than the prespecified cutoffs for both CA, were denoted as 'CA(low)'. All tests were two-sided with p-values <0.05 considered statistically significant.

Results: The median age at diagnosis was 61.5 years, 54% were male, and 84% of patients identified as non-Hispanic White. Of the total cohort and independent of quantitative CA cutoff, 1q+ (1q21+ or 1q23+) only was the most prevalent CA in 198 (81%) of patients, t(4;14) only in 13 (5%) patients, and both 1q+ (1q21+ or 1q23+) and t(4;14) in 32 (13%) patients. One hundred seventy (70%) patients underwent ASCT, followed by maintenance therapy in 85% of them. Pre-transplant best hematologic responses did not differ amongst CA groups. There was no difference in baseline hemoglobin, serum creatinine, calcium, albumin, lactate dehydrogenase, or beta-2 microglobulin amongst the CA groups. No differences in outcomes were noted without including size clone cutoffs. There was a statistically significant difference in univariable analysis in PFS and OS from ASCT in patients with 1q21+ and t(4;14) 'CA(low)’ (n=76, 31%) having better survival outcomes compared to the corresponding 'double-hit’ group (n=25, 10%) (PFS: HR=0.52, 95% CI: 0.30-0.92, p=0.025; OS: HR=0.41, 95% CI: 0.21-0.81, p=0.010). This pattern in PFS and OS after ASCT was also seen in patients with 1q23+ and t(4;14) 'CA(low)’ (n=119, 49%) faring better compared to its 'double-hit’ group (n=19, 8%) (PFS: HR=0.47, 95% CI:0.26-0.83, p=0.009; OS: HR=0.34, 95% CI:0.18-0.66, p=0.001). Patients with t(4;14) only (>30%) (n=19, 8%) within the 1q23+ cohort also demonstrated longer PFS and OS after ASCT as compared to its 'double-hit’ group (PFS: HR=0.42, 95% CI:0.20-0.91, p=0.027; OS: HR=0.38, 95% CI:0.15-0.94, p=0.037). After adjusting for age and R-ISS staging, the difference between 1q23+ and t(4;14) 'CA(low)’ vs 'double-hit’ and t(4;14) only within the 1q23+ cohort vs 'double-hit’ remained significant in multivariable analysis in PFS after ASCT ('CA(low)’ group: HR=0.50, 95% CI:0.25-0.99, p=0.048; and t(4;14) only group: HR=0.41, 95% CI:0.18-0.98, p=0.045).

Conclusion: Our findings reveal the differences seen in MM patients with single CA compared to the combined high-risk aberrations with both 1q21+/1q23+ and t(4;14). The effects of quantitative clone sizes on survival outcomes were displayed as patients with smaller clone sizes (i.e. 'CA(low)’ subsets) had superior survival outcomes than those patients with 'double-hit’ 1q21+ (or 1q23+) >20% and t(4;14) >30%. It is thus imperative for clinicians to be mindful of not only the presence of high-risk CA but also the size of the aberrant clone influencing subsequent MM disease characteristics.

Bumma:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Ad Board; Sanofi, Genzyme: Other: Ad Board, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Rosko:Genentech: Research Funding; Pfizer: Research Funding; Merck Foundation: Research Funding. Khan:Secura Bio: Consultancy, Research Funding; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Janssen: Honoraria.