Prognostic Value of Translocation 11;14 in Patients with Relapsed/Refractory Myeloma Receiving Anti-CD38 Therapy

Introduction: The translocation t(11;14) is present in ~15% of patients newly diagnosed MM and is associated with a unique clinical and pathological phenotype, despite still being classified as standard risk MM. Ex-vivo studies have also suggested that CD38 expression is decreased in patients with MM that harbors t(11;14), and hence there is a need for real-world data that compares the efficacy of anti-CD38 therapy for patients with and without t(11;14). We used clinical and cytogenetic data from a large, group of real-world patients with relapsed/refractory MM. We hypothesized that CD38 expression would be sufficient in those with t(11;14) to permit activity of anti-CD38 antibodies and that amongst patients receiving anti-CD38 therapies, outcomes would be similar in patients with t(11;14) when compared to those without the translocation.

Methods: We conducted a retrospective cohort study using the Flatiron Health electronic health record (EHR)-derived database. We evaluated data from relapsed/refractory MM patients initiating treatment including anti-CD38 therapy in their 2^nd or later line of therapy between November 2015 and December 2021. Patients were also required to have documented cytogenetic testing by FISH for high-risk cytogenetic abnormalities (HRCAs) and t(11;14). Presence of t(11;14) and HRCAs defined as deletion 17p, amplification or gain 1q21, t(4;14), t(14;16) and t(14;20) was determined from FISH testing. Our primary outcomes of interest were progression-free survival (PFS) and overall survival (OS). We used the Kaplan-Meier product limit estimator to calculate survivor functions for PFS and OS and compared equality of survivor functions between groups stratified by t(11;14) and HRCA status using log-rank tests. A multivariate analysis was done adjusting for age, sex, functional status, ISS Stage, eGFR and autologous stem cell transplant receipt. Separate analysis was performed for patients with just t(11;14) and no other HRCA, as well as those without (t11;14) and no HRCA (defined as wildtype).

Results: An overall cohort of 1,685 patients with MM initiating anti-CD38 therapy as 2^nd or later treatment with a median follow up of 22.6 months was identified. Patient characteristics are listed in Table 1.

In the overall study sample, patients with and without t(11;14) had a similar median PFS, 16.6 months and 15.0 months respectively (Figure 1, p = 0.24). Median PFS was also similar when comparing patients with t(11;14) and no HRCAs (19.9 months) to wild-type patients (19.6 months) (p = 0.59). Similar associations were observed for these comparisons in OS. Median OS for patients with and without t(11;14) was 49.8 months and 31.9 months respectively (p = 0.07). In multivariable models comparing PFS in patients with t(11;14) to patients without t(11;14), we observed similar risks (HR 1.07, 95% CI 0.80-1.44, p = 0.65) after adjustment for confounders and presence of other HRCAs. When comparing PFS in patients with t(11;14) and no HRCAs to wildtype patients, no statistically significant differences were observed (HR 1.27, 95% CI 0.84-1.94, p = 0.26). In multivariable models comparing OS in patients with t(11;14) to patients without t(11;14), we observed similarly not significant risks (HR 0.82, 95% CI 0.56-1.20, p = 0.31) after adjustment for confounders and presence of other HRCAs. When comparing OS in patients with t(11;14) and no HRCAs to wildtype patients, we also observed similar risks of overall mortality (HR 0.90, 95% CI 0.50-1.61, p = 0.72).

Conclusion: In this large real-world study of outcomes of anti-CD38 therapy with relapsed/refractory MM, no significant difference in outcomes were observed between those who had t(11;14) compared to those who did not. This study has important implications as t(11;14) is increasingly recognized as a unique subset of MM with different biology, treatment response rates, and prognosis. As targeted therapies specific to patients with t(11;14) such as venetoclax are increasingly utilized in this patient population, it is important to recognize that anti-CD38 therapy should remain an important part of the treatment landscape for these patients, and that synergistic strategies incorporating bcl-2 inhibition and anti-CD38 targeting should be explored further in clinical trials.

Chakraborty:Janssen, Sanofi Pasteur, Adaptive Biotech: Consultancy; Genentech Inc.: Research Funding. Rubinstein:Janssen: Consultancy; Sanofi: Consultancy; Roche: Consultancy; EUSA: Consultancy. Tuchman:Janssen: Honoraria; Prothena: Honoraria; Shattuck Labs: Honoraria. Costa:Adaptive Biotechnologies: Consultancy, Honoraria; Genentech: Research Funding; AbbVie: Research Funding; Sanofi: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Giri:Pack Health: Research Funding; CareVive: Honoraria, Research Funding; OncLive: Honoraria. Mian:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Fonseca:Adaptive Biotechnologies: Divested equity in a private or publicly-traded company in the past 24 months; Adaptive Biotechnologies, Caris Life Sciences, OncoMyx and OncoTracker: Other: Scientific Advisory Board; AbbVie, Amgen, Bayer, BMS/Celgene, GSK, H3 Therapeutics, Janssen, Juno, Karyopharm, Kite, Merck, Novartis, Oncopeptides, OncoTracker, Pfizer, Pharmacyclics, Regeneron, Sanofi, Takeda: Consultancy; Adaptive Biotechnologies, Caris Life Sciences, Oncomyx and OncoTracker: Membership on an entity's Board of Directors or advisory committees; Amgen, BMS, Celgene, Takeda, Bayer, Janssen, Novartis, Pharmacyclics, Sanofi, Merck, Juno, Kite, Aduro, OncoTracker, GSK, AbbVie, Pfizer, Karyopharm.: Consultancy; Genentech, Pfizer, Sanofi: Honoraria, Research Funding; FIH prognostication in myeloma: Patents & Royalties. Sborov:Pfizer: Consultancy; Bioline: Consultancy; BMS: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees.