Clinical Characteristics and Outcomes of Myeloma Patients Exhibiting Translocation (14;16): An Ultra-High-Risk Group of Myeloma Patients

Background

Important advancements in anti-myeloma treatments resulted in significant survival benefits for myeloma patients. While the patients presenting with standard risk cytogenetics have enjoyed these advantages, the outcome of patients exhibiting high-risk cytogenetic abnormalities remains poor. According to IMWG, high risk cytogenetics are defined as the presence of del17p, t(4;14) and t(14;16). The first two abnormalities occur in an appreciable number if patients and have been analyzed in several studies. However, the subgroup of patients harboring t (14;16) has not been well described due to its low incidence, and some prior studies have questioned its prognostic value. We have embarked on describing the clinical presentation and the prognostication of myeloma patients exhibiting t(14;16)

Methods

We performed an IRB-approved outcome analysis of myeloma patients with t(14;16) from the Winship Cancer Institute (WCI) at Emory University, USA and Department of Clinical Therapeutics , National and Kapodistrian University (NKU) of Athens, Greece. The cohort for this analysis consisted of myeloma patients diagnosed with symptomatic myeloma from February 2008 until March 2017. Descriptive information of clinical characteristics and outcomes were analyzed.

Results

In total 47 patients (29 patients from the WCI and 18 patients from NKU) were included in this analysis. The median age at diagnosis was 64 years (range 37-82), 57% had anemia (hemoglobin < 10 gr/dl), 19% had platelets counts <100x109/L, 35% had hypercalcemia (corrected serum calcium ≥11 mg/dl), 31% had serum creatinine ≥2 mg/dl and 32% had elevated LDH (≥ Upper limit of normal) and per ISS stage, 49% were stage 3. Other cytogenetic abnormalities were also present including del17p in 27%, amp1q21 in 55%, del13q in 67%; importantly in 6% a t(4;14) and in 5% a t(11;14) was also present. Post-induction 81% achieved ≥PR (30% sCR/CR, 28% VGPR and 23% PR) ;44% of the patients received ASCT1 in 1st remission, 21% received post-ASCT consolidation and 48% received maintenance after induction or intensification and the best response for all patients was sCR/CR in 43%, VGPR in 23% and PR in 17%. The use of a PI+IMiD combination was associated with higher and deeper response rates (≥VGPR in 68% vs 43%, p=0.025). After a median follow up of 29 months, the PFS1 was 20 months for the entire cohort and the estimated median OS is 46 months.

In univariate analysis, factors associated with poor PFS1 included age >65 years (p=0.024), the presence of amp1q21 (p=0.017), but not of other abnormalities while use of PI+IMiD combination (p=0.043), ASCT at 1^st remission (P<0.001) and the use of maintenance therapy after induction (P=0.007) were associated with longer PFS1. In multivariate analysis for PFS1, transplant in 1^st remission (HR 3.93, 95% CI1.43-10.83, p=0.008) and maintenance (HR 2.4. 95% CI 0.97-5.95, p=0.059) were identified as independent prognostic factors. Interestingly, among the 13 patients that progressed at WCI, 5 patients progressed as extramedullary relapses (3 with CNS involvement). The aggressiveness of the disease relapses precluded further treatments and most patients at time of death were naïve to a multitude of anti-myeloma therapies. Regarding OS, in univariate analysis, the presence of hypercalcemia at diagnosis (p=0.001) and elevated LDH (p=0.004) were associated with poor OS, while, the presence of additional cytogenetic abnormalities (del17p, or del13q or amp1q21) was not associated with survival in this population of patients with t(14;16).

Conclusion

This analysis highlights the poor prognosis of myeloma patients harboring the t (14;16) chromosomal abnormality. Such patients commonly present with poor prognostic features, including hypercalcemia, elevated LDH, increased creatinine, ISS-3 disease and also have increased frequency of other high risk cytogenetic aberrations such as del13q, amp1q21 in more than 50% of patients and del17p in 25% of patients. The use of PI+IMiD regimens probably helps with obtaining deeper responses. The inferior median PFS1 and OS seen in the modern day cohorts and the inability to use the novel regimens in the later course of the disease due to disease aggressiveness prompts us to use active regimens upfront, which can aid in preventing relapse.