Early Relapsed Multiple Myeloma With Translocation (11;14)

Presentation

A 62-year-old black male with IgG kappa multiple myeloma with t(11;14) was initially diagnosed in 2019. His treatment history includes lenalidomide, bortezomib, and dexamethasone induction x4 cycles followed by an autologous stem cell transplant (ASCT), resulting in a very good partial remission. He did well on lenalidomide maintenance for about 2 years before he started with a biochemical progression with a slow rise in his IgG paraprotein and free kappa light chain (FKLC), with subsequent development of new lytic disease on PET. His marrow demonstrates 40% plasma cells, flow positive, and fluorescence in situ hybridization (FISH) noting t(11;14) in 42 out of 50 cells. There are no cytogenetic abnormalities. Other comorbidities include hypertension, grade 1 peripheral neuropathy to both feet, and type 2 diabetes mellitus, well controlled. 

Treatment

After discussing all the available options in the early relapse setting with the patient, he decided to participate in M15-654, a phase 1/2 clinical trial evaluating venetoclax, daratumumab, and dexamethasone (VenDd) with or without bortezomib (VenDVd). The patient was randomized to the VenDd arm, with venetoclax at a dose of 800 mg. He was already on an antiviral with valacyclovir, so Pneumocystis jirovecii pneumonia prophylaxis was added, along with zoledronic acid. On day 1 of cycle 1, his M protein was 1.92 g/dL, and his FKLC was 44.4 mg/L with stable counts and renal function. He did well, with a confirmed complete response after 2 cycles.  

The patient developed recurrent upper respiratory infections, and his IgG quantitative level dropped to 345 mg/dL, so monthly intravenous immunoglobulin (IVIG) was initiated. Hypogammaglobulinemia is common in patients with myeloma who are on daratumumab, as the anti-CD38 monoclonal antibody can cause plasma cell death and also targets normal lymphocytes, resulting in an impaired polyclonal response. Monthly IVIG may help in subgroups of myeloma patients, and it is recommended to keep immunoglobulin G levels greater than 600-700 mg/dL depending on your institution’s guidelines. ^1-3 In addition, his dose of venetoclax was reduced to 600 mg due to the recurrent infections as well as fatigue and a slight increase in his peripheral neuropathy. The follow-up bone marrow biopsy results showed <5% plasma cells, flow cytometry negative for myeloma cells, FISH negative, and normal chromosome analysis. The patient continues in stringent complete response and is tolerating his treatment well. 

Discussion

Translocation (11;14) occurs in about 16% to 24% of patients with myeloma and is considered standard risk,^4-9 with black patients having a higher incidence.^10,11 Myeloma cell lines with t(11;14) have a dependence on Bcl-2 ^12,13 for survival, making a Bcl-2 targeted therapy agent a possibility. Venetoclax is a small-molecule oral Bcl-2 inhibitor^14-16 that has been studied as monotherapy as well as in combination with dexamethasone¹⁷and now is being studied in many combinations.  

The M15-654 phase l/2 study of venetoclax plus daratumumab and dexamethasone, with or without bortezomib, in patients with relapsed or refractory multiple myeloma with and without t(11;14), evaluates safety, tolerability, and efficacy in three distinct parts.¹⁸ Our patient went on to receive part 1, VenDd with venetoclax 800 mg. The overall response rate was 96% with VenDd, with the 18-month progression-free survival rate at >90%. The most common adverse events were mild gastrointestinal events and fatigue, as reported with single-agent venetoclax.¹⁷ Increased upper respiratory tract infections were experienced, similar to what has been demonstrated with daratumumab and hypogammaglobulinemia.¹⁹ There was no overall increase in serious side effects. 

According to the NCCN Guidelines,²⁰ there are many treatment options to consider and discuss with patients experiencing early relapse. When discussing new treatment modalities, it is important to consider prior therapies along with any comorbidities or side effects they may have experienced. This case is an example of a shared decision-making opportunity, and a reminder to review all available treatment options, including a clinical trial. As advanced practitioners, we are in the ideal role to be sure our patients feel educated, informed, and part of the decision-making process throughout their cancer journey. 

References

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