Secondary plasma cell leukaemia treated with single agent venetoclax

Abstract

Patients with multiple myeloma (MM) are at risk of developing secondary Plasma Cell Leukaemia (sPCL), with associated hyperviscosity. In such patients combination therapies for MM are associated with a short median overall survival of just 1·3 months.1 Translocation (11;14) is reported in 33% of sPCL and involves the immunoglobulin heavy chain locus on 14q32.2 Selective inhibition of Bcl-2 with venetoclax has shown single agent activity in MM patients harbouring this translocation, however, single agent activity has not been reported in sPCL. We demonstrate a rapid and deep haematologic response with reversal of symptomatic hyperviscosity in sPCL with single agent venetoclax treatment. Plasma cell leukaemia occurs in the setting of pre-existing multiple myeloma (sPCL) or arises as a de novo aggressive haematological malignancy characterized by circulating plasma cells > 2 × 109/l in peripheral blood.3 sPCL has a dismal prognosis with no standard or effective therapy available. In recent years the frequency of sPCL has increased,1 likely explained by improved overall survival in MM, leading to a higher prevalence of the disease, and development of clonal evolution in patients who are treated with multiple novel agents. sPCL occurs in 1·8–4% of MM patients and is associated with immunoglobulin heavy chain (IgH) translocations on locus 14q32 in 80% of cases, the most common being t(11;14), seen in 25–65% of patients.1 Bcl-2 family proteins are critical regulators of apoptosis with anti-apoptotic (Mcl-1, Bcl-2, Bcl-xL), multidomain pro-apoptotic (Bax, Bak) and BH3-only members (Bim, Noxa, Bad).4 MM cells that harbour t(11;14) express high levels of Bcl-2 relative to Bcl-xL and Mcl-1.5 Venetoclax, a first in class oral BH3 mimetic, which selectively inhibits Bcl-2 but not Bcl-xL or Mcl-1, has shown single agent activity in MM.5 BH3 profiling has previously correctly identified Bcl-2-dependent leukaemias; in this case we apply this method to sPCL.6, 7 Single agent activity of venetoclax has not been reported for primary or secondary plasma cell leukaemia, although, given the rate of t(11;14) translocations in this disease it follows that clinical responses may be achieved and successful combination therapy with venetoclax in primary PCL has been reported.8 A 73-year-old woman with a history of IgG kappa MM presented with bilateral visual disturbance. She had a two-year history of MM and was receiving therapy with daratumumab. The patient was refractory to bortezomib, carfilzomib, lenalidomide and ixazomib combination therapies. Her peripheral blood smear was consistent with sPCL with circulating plasma cells > 5 × 109/l Fig 1. Ophthalmic examination demonstrated bilateral macular and optic disc oedema with retinal haemorrhages and a central retinal vein occlusion. Restaging of MM was undertaken and the patient had an urgent plasma viscosity measured. IgG paraprotein was 99 g/l with kappa light chains of 200 mg/l and a kappa:lambda ratio of 250. Haemoglobin was 8·1 g/dl with creatinine of 139 μmol/l. Plasma viscosity returned > 5 mPas and emergency plasmapheresis was performed. Cytogenetic analysis of CD138+ selected bone marrow plasma cells revealed a t(11;14) translocation. Following written informed consent of the patient BH3 profiling was performed on CD138+ cells, which revealed selective Bcl-2-dependent sensitivity to ABT-199 (venetoclax). Ex vivo treatment showed sensitivity to ABT-199 at very low concentrations compared to other BH3 mimetics tested. Western blot analysis confirmed high BCL-2 expression in the patient compared to MM cell lines. The patient was commenced on venetoclax 50 mg and the dose was escalated to 400 mg over a three-week period, with excellent tolerability of dose escalation and no evidence of tumour lysis syndrome. Plasma viscosity rapidly reduced from 4 mPas to 1·1 mPas (normal range 1·1–1·4 mPas) coincident with a rapid normalization of the light chain ratio and 93% reduction in IgG paraprotein to 7.3 g/l, consistent with a very good partial response (VGPR) by International Myeloma Working Group (IMWG) response criteria.9 Indeed the response in terms of hyperviscosity reversal was comparable to plasmapheresis in terms of rapidity and was better sustained. Rapid complete resolution of symptomatic hyperviscosity, recovery of visual acuity, resolution of anaemia and restoration of normal renal function occurred. The patient continues on treatment in VGPR at the time of reporting, nine months following initiation of venetoclax. This case demonstrates single agent activity of venetoclax in t(11;14) sPCL refractory to proteasome inhibitors, immunomodulatory drugs and daratumumab. Venetoclax induced a rapid haematologic and clinical response in a patient with hyperviscosity syndrome that would otherwise have undoubtedly been rapidly fatal. Our preclinical data generated using CD138+ plasma cells isolated from the patient’s bone marrow, demonstrates direct toxicity of MM/PCL cells to BCL-2 inhibition ex vivo with enhanced sensitivity compared to other BH3 mimetics (Fig 2). This ex vivo response was mimicked in vivo in this bench to bedside case. Genetic studies of sPCL have demonstrated this disorder to be genomically distinct from MM with 82% of patients having translocations involving IgH 14q32 in some studies and a propensity toward hypodiploidy.10, 11 This may indicate that IgH translocations act as an early clonal driver event in sPCL, which is supported by data that indicate that transformation to sPCL from MM is not necessarily a late or ‘end stage’ event as traditionally assumed. The median time to leukaemic progression from MM is midway in disease evolution at 20·8 months,1 and this case demonstrates effective molecularly targeted treatments can induce rapid and deep responses at this stage. This may also point to a clinically and clonally distinct subset of MM patients, who develop sPCL and have a propensity for lytic bone disease and renal impairment according to published clinical studies.1 The present case demonstrates clinical efficacy of single agent venetoclax in inducing a rapid and deep remission of t(11;14) sPCL with hyperviscosity and highlights the potential utility of BH3 profiling and ex vivo BH3 mimetic treatments as potential biomarkers. The identification of an actionable target was critical in this case and has resulted in a nine-month progression-free survival. This case highlights a novel space of therapy for patients with plasma cell dyscrasias on the MM/sPCL spectrum, where more clinical data are needed to facilitate an effective personalized approach for therapy.12 The authors acknowledge funding from Abbvie for preclinical studies as part of an investigator-initiated agreement. The authors have no conflicts of interest to disclose. SVG was involved in the clinical case, preclinical studies and wrote the manuscript, TNC supervised and performed preclinical studies and wrote the manuscript and figures, LF and RB performed preclinical studies. JQ and PM were involved clinically in the case and edited the manuscript and figures.

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