The combination of venetoclax, daratumumab and dexamethasone for the treatment of refractory primary plasma cell leukemia
Authors: Sos Nalghranyan, Amrit P. Singh, Carolina Schinke
Journal: American Journal of Hematology (2019)

To the Editor: Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) characterized by the presence of ≥20% circulating plasma cells in the peripheral blood. While the advances of novel treatments have significantly improved clinical outcomes in non-pPCL MM, survival remains still poor for patients with pPCL emphasizing the need for better therapeutic options in this particular patient group.1 Up to 60% of pPCL patients present with a translocation t(11;14), which has been associated with high bcl-2 expression.2 Venetoclax, an oral bcl-2 inhibitor, has demonstrated promising results in non-pPCL MM,2 and few reports have shown its efficacy in pPCL.3, 4 Here we report on a novel combination regimen consisting of venetoclax and daratumumab that led to rapid tumor reduction in a pPCL patient who presented with translocation t(11;14) and poor risk bi-allelic TP53 inactivation and who was refractory to initial chemo-induction therapy with VDT-ACE (bortezomib on days 1, 4, 8, and 11, dexamethasone 40 mg p.o. daily days 1-4, thalidomide 100 mg p.o. daily days1-21, doxorubicin 10 mg/m2 daily on days 1-4, cyclophosphamide 400 mg/m2 daily on days 1-4, and etoposide 40 mg/m2 daily on days 1-4). A 74-year-old male was admitted to the UAMS inpatient service with complaints of generalized malaise and fatigue, and decreased urine output. Complete blood count revealed severe anemia with a hemoglobin level of 7.7 g/dL, and a creatinine level of 4.7 mg/dL, with a Glomerular Filtration Rate of 12.2 mL/min/1.73 m2. Peripheral smear showed circulating plasma cells, Figure 1A. This was further confirmed by flow-cytometry (54% circulating plasma cells in peripheral blood). Additional work up revealed markedly elevated lambda light chains of 1800 mg/dL. Bone marrow (BM) biopsy revealed 90% plasma cells positive for CD138, Figure 1B,C. Flourescence in situ hybridization was positive for translocation t(11:14) (95%) and a deletion 17p in 25%. His immunoglobulins, including IgG, IgA and IgM were all suppressed, and immunofixation in the serum and urine was positive for lambda light chains. The patient presented with 8 g proteinuria, which was predominantly due to increased urinary light chain excretion (Urine M-protein = 7.4 g/dL), suggestive for light chain cast nephropathy as a cause of the patient's renal compromise. The patient's albumin at presentation was 3 g/dL with a Beta2-Microglobulin of 25.9 mg/L, classifying him as stage 3 within the International Staging System (ISS). Whole exome sequencing of the patients isolated CD138+ cells revealed a TP53 mutation (234Y > H) in 75% of his plasma cells, with a concurrent copy number deletion of TP53. This bi-allelic TP53 inactivation on the background of an ISS 3 has been recently termed as "double-hit", and MM patients presenting with this constellation have been shown to have an extremely poor outcome.5 In order to rapidly reduce the patient's MM burden and to salvage his renal function, we promptly initiated combination chemotherapy consisting of VDT-ACE. After 3 weeks of therapy initiation, the patient's light chain burden had only responded marginally, and the patient's renal function remained severely compromised, Figure 1D. Given the patient's known translocation t(11;14), we then initiated therapy with a combination of venetoclax 300 mg p.o. daily, daratumumab at the standard dose of 16 mg/kg and dexamethasone 20 mg p.o. weekly. This regimen drastically reduced the patient's tumor burden, which in turn lead to an improved renal function. Remarkably, the patient achieved a stringently defined complete remission (sCR) two months after the initiation of venetoclax/daratumumab/dexamethasone, and also had no evidence of minimal residual disease at 1 myeloma cell in 105 cells, measured by eight color flow-cytometry as previously reported,6 4 months into therapy, Figure 1E and F. He continues to be in a sCR after 10 months of therapy. Primary plasma cell leukemia remains one of the most aggressive hematologic cancers with poor clinical outcome. In particular elderly patients, such as the one in this report, have limited therapeutic options as their age, and often performance status make them unfit for aggressive therapy including stem cell transplantation. In addition, renal compromise, which is evident in up to 50% of pPCL patients, precludes the use of various anti-MM therapies which further narrows down possible treatment options. In this presented case, the combination chemotherapy consisting of VDT-ACE did not yield a deep enough response to significantly lower the tumor burden and improve renal function. In contrast, a relative low dose of venetoclax in combination with daratumumab and dexamethasone was highly effective and well tolerated in this elderly patient. Apart from his translocation t(11;14), the patient also harbored a bi-allelic inactivation of TP53, a very poor prognostic marker. Given our experience and few other case reports,3, 4 a venetoclax based regimen should be further explored in pPCL patients with translocation t(11;14) that have acquired poor prognostic secondary genetic events.