Outcomes of triple class (proteasome inhibitor, IMiDs and monoclonal antibody) refractory patients with multiple myeloma

Abstract

TO THE EDITOR: Multiple myeloma (MM) is a genetically heterogenous plasma cell malignancy that is characterized by the accrual of subclonal genetic changes as the disease advances [1]. These subclonal alterations contribute to the development of therapeutic resistance and despite the improvement in the overall survival (OS), MM remains incurable [2]. Proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) had been the backbone of therapeutic regimens in MM until recently [3]. Monoclonal antibodies (mAbs) against CD38 and SLAMF7 can improve outcomes for patients previously treated with PIs and IMiDs [4]. However, patients with diseases that are refractory to PIs, IMiDs, and mAbs have a poor prognosis and are commonly referred to as having a triple class refractory (TCR) disease [5]. Currently, there is no established standard of care for TCR MM with promising treatment options including selinexor, bispecific antibodies, and chimeric antigen receptor T(CAR-T) cell therapies [4, 6, 7]. In this study, we report the outcomes of patients with triple refractory MM and response to therapy post TCR status. Consecutive patients with MM diagnosed between 01/01/2013 and 12/31/2018 and seen at Mayo Clinic, Rochester, MN were included in this study. Refractoriness to therapy was defined as non-responsiveness (failure to achieve at least a minimal response) to therapy or progression on or within 60 days of discontinuation of therapy [8]. Patients meeting the definition for refractory disease for at least one PI, IMiD, and monoclonal antibody (daratumumab, isatuximab or elotuzumab) were considered to have TCR disease. The mSMART 3.0 (www.msmart.org) classification was used to characterize cytogenetic risk using interphase fluorescence in situ hybridization (FISH), with high-risk cytogenetic features including t(4;14), t(14;16), t(14;20), deletion 17p, TP53 mutation and 1q gain. Patients with FISH data available within 6 months of TCR date was utilized for comparison with baseline FISH cytogenetic data at diagnosis of MM. The international myeloma working group (IMWG) criteria were used for response assessment. Between 01/01/2013 and 12/31/2018, out of 1773 patients with MM, a total of 249 patients (14%) were identified to have TCR MM. The median follow-up from diagnosis of MM till the date of the last follow-up was 6.8 years (95% CI: 6.3–7.3 years). The median follow-up from TCR MM till the last follow-up was 1.9 years (95% CI: 1.6–2.4). Characteristics of the cohort are depicted in Table 1. Cytogenetic data were available in 208 patients at diagnosis; 116 (56%) patients harbored high-risk cytogenetics. At TCR status, 110 (44%) patients had FISH data available; 95 patients (87%) had high-risk cytogenetics (Table 1). Among these 110 patients, 91 patients also had FISH data available from the time of diagnosis for comparison. Thirty-one percent (28/91) patients did not demonstrate any new cytogenetic abnormality at TCR status; 31% (28/91) had a new 1q duplication, 25% (23/91) had a new 17p deletion, 24% (22/91) had a new 8q24 deletion, 19 (21%) patients had a near tetraploid clone, 3% (3/91) patients had a new deletion 1p. The median number of lines of therapy for the entire cohort were 8 (range 1–17); the patients were exposed to a median of 5 (range 1–12) lines of therapy prior to TCR status. Details of refractoriness to PIs, IMiDs, and mAbs are outlined in 1b. For the entire cohort, 21 (8%) patients were treated with chimeric antigen receptor T (CAR-T) cell therapy, 34 (14%) received a B-cell maturation antigen (BCMA)-directed antibody (23 received an antibody-drug conjugate and 11 received a T-cell redirecting antibody), 20 (8%) received selinexor-based therapy and 41 (16%) were treated with venetoclax-based combination therapy. With regard to transplant therapies from the diagnosis, 181 (73%) patients underwent 1 autologous stem cell transplant (ASCT), 24 (10%) underwent 2 ASCTs, including tandem (7/24) or for recurrence (17/24), 9 (4%) patients received an allogenic transplant in addition to ASCT while 44 (18%) patients did not receive any form of transplant. The median time to development of triple refractory disease was 2.9 years (95% CI: 2.6–3.2 years) from diagnosis of MM. The