Venetoclax in Combination With Carfilzomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma Harboring t(11,14)(q13;q32)

Two Case Reports and a Review of the Literature

Khadega A. Abuelgasim; Noha Alherz; Ayman Alhejazi; Moussab Damlaj


J Med Case Reports. 2020;14(54) 

In This Article

Case Presentations

Patient 1

A 50-year-old Saudi man who was diagnosed with International Staging System (ISS) stage III kappa light chain MM presented with acute kidney injury (serum creatinine 309 μmol/L), hypercalcemia (corrected serum calcium 3.15 mmol/L), and anemia (hemoglobin 119 g/L) in July 2013. The results of serum and urine protein electrophoresis were both negative for M protein spike. Serum free light chain showed kappa of 1830 mg/L and lambda of 10.1 mg/L with a kappa/lambda (K/L) ratio of 180.7. Bone marrow aspiration and biopsy (BMBx) showed diffuse infiltration by kappa restricted PCs; bone marrow cytogenetics were consistent with normal male karyotype. The result of fluorescence in situ hybridization (FISH) for MM recurrent alterations, including t(11,14)(q13;q32), was negative.

The patient was initially treated with bortezomib/thalidomide/dexamethasone (VTd) for a total of five cycles, and he achieved a complete response (CR). He underwent autologous hematopoietic stem cell transplant (auto-HSCT) with 140 mg/m2 melphalan conditioning due to his dialysis-dependent end-stage renal disease. Three months following auto-HSCT, two cycles of consolidative VTd were given, followed by maintenance lenalidomide 5 mg orally every other day. He came off of dialysis 1 year after undergoing auto-HSCT.

Two years following auto-HSCT, he presented with bony pain. His serum kappa was 1000 mg/L and lambda was 19.9 mg/L, with K/L ratio of > 19.9. Positron emission tomography with computed tomography (PET/CT) revealed multiple new bony lesions. The result of BMBx was consistent with 32% kappa restricted PCs, all collectively consistent with progressive disease (PD). He was salvaged with three cycles of carfilzomib/lenalidomide/dexamethasone (KRd). He was refractory to KRd because he presented with bony pain and rising kappa 31,840.00 mg/L and lambda 5.00 mg/L, with K/L ratio of 6368 and evidence of new lesions seen by PET/CT. Due to multiple vertebral compression fractures and intractable pain, he underwent vertebroplasty in October 2016, and his therapy was switched to bortezomib/cyclophosphamide/dexamethasone, and he received a total of three cycles, achieving very good partial response (VGPR) with kappa 1250.00 mg/L and lambda 156.41 mg/L with a K/L ratio of 157.23.

To deepen his response in preparation for a second auto-HSCT, he was started on 25% dose-reduced bortezomib/dexamethasone/cisplatin/doxorubicin/cyclophosphamide, achieving VGPR after two cycles with less than 5% PCs in BMBx; negative PET/CT results; and serum kappa 302.00 mg/L, lambda 2.16 mg/L, with K/L ratio 139.81.

He subsequently underwent a second auto-HSCT 1 year following his first relapse. Assessment on day + 90 after auto-HSCT showed kappa 63.70 mg/L, lambda 13.70 mg/L, with K/L ratio of 4.6. The result of PET/CT was negative for active disease. He was started on bortezomib maintenance therapy every other week.

In March 2018, he presented with biochemical relapse while receiving bortezomib maintenance therapy with kappa 17,400.00 mg/L, lambda 20.40 mg/L, with K/L ratio of 85.29, but no evidence of active disease on a PET/CT scan. His estimated creatinine clearance was < 30 mmol/L, so he was considered ineligible for allogeneic stem cell transplant and therefore was started on elotuzumab/lenalidomide/dexamethasone, of which he received a total of five cycles until July 2018. On August 18, 2018, he presented with bony pain and was found to have multiple new lytic lesions and multiple pathological fractures with kappa 9650.00 mg/L, lambda 9.78 mg/L, with K/L ratio > 986.7 consistent with PD; therefore, he was started on daratumumab/vincristine/dexamethasone for a total of six cycles. Evaluation after the sixth cycle showed kappa 565.00 mg/L, lambda 5.92 mg/L, with K/L ratio of 954.39. BMBx showed cellularity 20% with only 5% PCs, but with newly acquired t(11,14)(q13;q32).

On March 16, 2019, he was started on venetoclax/carfilzomib/dexamethasone (VenKd). The dose of carfilzomib was 56 mg/m2 on days 1, 8, and 22; dexamethasone 40 mg weekly; and venetoclax was started at 50 mg per day, escalated to 200 mg per day over a period of 2 months. However he required multiple dose adjustments due to myelosuppression. Assessment after three cycles of VenKd included BMBx, which showed 40–50% cellularity with 1% PCs and serum kappa 492.50 mg/L, lambda 7.21 mg/L, with K/L ratio of 68.1. PET/CT showed no evidence of PET/CT-avid lesions consistent with VGPR. A repeat PET/CT scan after six cycles of VenKD was consistent with PD because it showed multiple new avid lesions and serum kappa 580.00 mg/L, lambda 7.38 mg/L, with K/L ratio of 78.59. The patient was started on cyclophosphamide/carfilzomib/dexamethasone and has received three cycles thus far. The evolution of therapy in patient 1 is shown in Table 1.

Patient 2

A 48-year-old Saudi man was diagnosed with ISS stage III immunoglobulin G kappa MM in May 2017 when he presented with bony pain and was found to have multiple lytic lesions by PET/CT. His BMBx revealed 80% PCs, and FISH analysis showed isolated t(11,14)(q13;q32). His serum kappa was 584.00 mg/L, lambda was 2.54 mg/L, and K/L ratio was 229.92.

He was started on bortezomib/lenalidomide/dexamethasone (VRd). Lenalidomide was replaced by thalidomide (VTd) due to his severe allergic reaction in the first cycle. Assessment after four cycles of VTd showed serum kappa 9.58 mg/L, lambda 11.00 mg/L, and K/L ratio of 0.87, and BMBx showed PCs of < 1%, consistent with stringent complete remission. On October 11, 2017, he underwent auto-HSCT. Assessment on day + 90 after auto-HSCT showed morphological remission in bone marrow and serum kappa 13.00 mg/L, lambda 8.32 mg/L, and K/L ratio of 1.56, consistent with maintained response. Three months after auto-HSCT, he was started on thalidomide maintenance due to lenalidomide allergy. He developed grade 3 neurotoxicity despite dose adjustments; therefore, thalidomide was discontinued after 8 months.

On November 25, 2018, he presented with clinical PD in the form of extramedullary plasmacytomas in the left thumb and middle finger and serum kappa of 285.00 mg/L, lambda of 8.63 mg/L, and K/L ratio of 32.80. His PET/CT scan showed new active bony lesions consistent with PD. He was started on Kd, which was complicated by intensive care unit admission due to respiratory failure and acute kidney injury requiring hemodialysis.

On February 11, 2019, he was started on daratumumab/pomalidomide/dexamethasone; he received a total of two cycles with evidence of PD with worsening of plasmacytomas in his fingers as well as a new nasal mass associated with pain and epistaxis. Because the patient had t(11,14)(q13;q32), he was shifted to VenKD on April 8, 2019. Venetoclax was dosed at 400 mg per day, then escalated to 600 mg per day over a period of 1 month; carfilzomib was dosed at 56 mg/m2 on days 1, 8, and 22 and dexamethasone at 40 mg weekly. Marked initial clinical response was observed. However, on June 8, 2019, after the third VenKd cycle, he presented with generalized body weakness, and his creatinine increased to 449 μmol/L from baseline of 69 μmol/L; his white blood cell count increased to 34,000 × 109/L from a baseline of 7.41 × 109/L; his blood smear showed 30% PCs; and BMBx showed hypercellularity of 90% with diffuse infiltration of PCs consistent with PC leukemia. His PET/CT scan showed multiple new active bony lesions consistent with PD. His general condition rapidly deteriorated, and ultimately he died of multiorgan failure on June 27, 2019. The evolution of therapy in patient 2 is shown in Table 2.