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Carfilzomib in a patient with R/R MM intolerant of other therapies

Prof. Eric Tse
Department of Medicine
University of Hong Kong
03 Aug 2020
History and presentation

The patient is a 62-year-old male with no prior history of diabetes, hypertension, or renal dysfunction. He developed deep vein thrombosis (DVT) 2 years ago after prostate surgery.

He initially presented with frothy urine. Urinalysis showed mild proteinuria of 0.2 g/day. Immunoglobulin (IG) assay showed elevated IgG kappa paraprotein level of 27.5 g/L, while serum beta-2 microglobulin was 2.1 mg/L. Bone marrow (BM) biopsy revealed 15 percent plasma cells. Chest X-ray was normal, while blood tests showed normal levels of serum albumin, creatinine and haemoglobin. Since the patient was asymptomatic, he was diagnosed with smouldering myeloma and was observed for 2 years with no treatment.1

There was mild deterioration in the patient’s kidney function after 2 years (creatinine level, 160 µmol/L), at which point treatment was initiated.

Treatment and response

The patient received 10 cycles of thalidomide and dexamethasone, which resulted in a decrease of IgG kappa paraprotein to 2.8 g/L. He was maintained on thalidomide monotherapy and was referred for an autologous stem cell transplantation (ASCT). (Table 1)

While awaiting ASCT, the patient’s IgG kappa paraprotein increased to 11.8 g/L. He received five cycles of bortezomib, cyclophosphamide and dexamethasone, which led to a decrease in IgG kappa paraprotein to 4 g/L. He underwent ASCT after receiving melphalan 200 mg/m2 as standard conditioning for the procedure.Following ASCT, his IgG kappa paraprotein decreased to 2.6 g/L.

Lenalidomide was not preferred due to past medical history of DVT.3 The patient instead received bortezomib 1.3 mg/m2 every 4 weeks as maintenance therapy. However, treatment was discontinued after five cycles due to grade 3 peripheral neuropathy. Serum protein electrophoresis showed weak oligoclonal bands, and the patient was put on observation without any further treatment.

Three months after receiving bortezomib, paraprotein increased to 2 g/L. The patient refused BM biopsy. Under the assumption that he was experiencing a biochemical relapse, the patient was treated with lenalidomide and low-dose dexamethasone as well as rivaroxaban for DVT prophylaxis. Lenalidomide treatment was discontinued after 4 cycles due to haemoperitoneum.

After 8 months, the patient’s IgG kappa paraprotein increased to 14.8 g/L. BM biopsy showed 30 percent abnormal plasma cells. MRI and PET-CT scan showed no bone lesions. There was slight deterioration of renal function (serum creatinine, 140 μmol/L).

Since the patient was unable to tolerate further bortezomib therapy and with treatment cost taken into consideration, he was treated with biweekly carfilzomib at a fixed dose of 30 mg/day for 3 consecutive weeks (days 1, 2, 8, 9, 15 and 16 of a 28-day cycle) and biweekly dexamethasone at 20 mg/day for 4 consecutive weeks (days 1, 2, 8, 9, 15, 16, 22 and 23 of a 28-day cycle) per cycle, which was a modified dosing regimen in the ENDEAVOR (Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone for Patients with Relapsed or Refractory Multiple Myeloma) trial.4 He also received intravenous hydration with 250 mL normal saline before each carfilzomib infusion during cycle 1 for tumour lysis prophylaxis.5

After three cycles of carfilzomib, the patient developed hypertension (systolic blood pressure, 150 mm Hg), which was well managed with amlodipine 5 mg/day.

After eight cycles of carfilzomib, the patient’s IgG kappa paraprotein decreased to 3.9 mg/L. BM biopsy revealed very few plasma cells. Serum creatinine slightly increased to 150 μmol/L. Blood pressure remained controlled with amlodipine therapy; the last ECG was normal; heart failure symptoms were absent. There was no evidence of neuropathy or thrombocytopaenia. The patient remained on carfilzomib plus dexamethasone maintenance as of May 2020.

AMG-152mo_01

Discussion

Relapse and treatment resistance are common in patients with multiple myeloma (MM), which limits subsequent-line options.6 The first-in-class proteasome inhibitor bortezomib, together with dexamethasone, has emerged as the standard treatment option for relapsed/refractory (R/R) MM due to its proven survival benefits.4,7-9 However, bortezomib therapy is associated with an increased risk of significant peripheral neuropathy, which may lead to treatment discontinuation.4,8-10

The irreversible and selective proteasome inhibitor carfilzomib was an appropriate later-line treatment option for this patient since it is approved for the treatment of R/R MM patients who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, such as lenalidomide, with demonstrated disease progression on or within 60 days of completing the last treatment cycle.5 In the ENDEAVOR trial, carfilzomib was associated with significantly improved progression-free survival (PFS) vs bortezomib in patients with R/R MM who had received one to three previous treatments, including carfilzomib or bortezomib.4

The randomized, open-label, phase III ENDEAVOR study was one of the first head-to-head trials that compared the survival benefits between the two proteasome inhibitors in R/R MM. Patients received carfilzomib (20 mg/m² on days 1 and 2 of cycle 1; 56 mg/m² thereafter) on days 1, 2, 8, 9, 15 and 16, and dexamethasone (20 mg) on days 1, 2, 8, 9, 15, 16, 22 and 23 of a 28-day cycle, or bortezomib (1.3 mg/m²) on days 1, 4, 8 and 11, and dexamethasone (20 mg) on days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21-day cycle, with both combination treatments given until disease progression.4

A significantly higher objective response rate was attained with carfilzomib vs bortezomib (77 percent vs 63 percent; odds ratio [OR], 2.03; 95 percent confidence interval [CI], 1.52 to 2.72; p<0.0001). The rate of complete response or better was also significantly higher in the carfilzomib vs bortezomib group (13 percent vs 6 percent; p=0.0010).4

More importantly, the improved response rates associated with carfilzomib translated into survival benefits. Carfilzomib treatment was associated with a longer median PFS of 18.7 months vs 9.4 months with bortezomib (hazard ratio [HR], 0.53; 95 percent CI, 0.44 to 0.65; p<0.0001).4 (Figure) In the interim overall survival (OS) analysis of ENDEAVOR, median OS was 47.6 months (95 percent CI, 42.5 to not evaluable) in the carfilzomib group vs 40.0 months (95 percent CI, 32.6 to 42.3) in the bortezomib group (HR, 0.791; 95 percent CI, 0.648 to 0.964; one-sided p=0.010).11

AMG-152mo_02

Our patient received a modified 30 mg/day biweekly dosing schedule of carfilzomib due to cost considerations. Dosing is flexible for carfilzomib, as demonstrated in the randomized, open-label, phase III ARROW (Once Weekly Versus Twice Weekly Carfilzomib Dosing in Patients with Relapsed and Refractory Multiple Myeloma) trial. In this trial, once-weekly carfilzomib (70 mg/m2) was associated with a median PFS of 11.2 months (95 percent CI, 8.6 to 13.0) vs 7.6 months (95 percent CI, 5.8 to 9.2) attained by patients on twice-weekly carfilzomib (27 mg/m2) (HR, 0.69; 95 percent CI, 0.54 to 0.83; p=0.0029). Overall safety was comparable between both groups.6

Carfilzomib has no absolute contraindications; however, its use is not recommended in patients with uncontrolled hypertension, untreated arrhythmia and recent myocardial infarction (within 6 months prior to commencing treatment). Any pre-existing cardiovascular (CV) conditions, such as mild heart failure, should be stabilized before commencing carfilzomib and cardiac function should be monitored closely (eg, by ECG and exercise tolerance testing) during treatment, with any arising complications requiring prompt management, especially in patients with CV disease or risk factors, such as diabetes.5

Although CV adverse events (AEs) such as hypertension and heart failure were more common among Asian patients in the ENDEAVOR and ARROW trials vs the overall population, the total number of Asian patients who received carfilzomib in both trials was relatively small vs the global population to ascertain a significant difference (n=55 in ENDEAVOR; n=45 in ARROW).4,6,12 (Table 2) While a number of patients develop hypertension while on carfilzomib in clinical practice, it is usually of low grade and easily controlled with medication; furthermore, no patients in our practice have been hospitalized for heart failure due to carfilzomib to date.  

Both ENDEAVOR and ARROW trials showed improved outcomes with carfilzomib plus dexamethasone, with an acceptable safety profile among Asian patients, demonstrating a favourable benefit-risk profile with various dosing regimens.4,6,12 Overall, the agent is well tolerated by Hong Kong Chinese patients, including the elderly.

HK-AMG-152mo_r

Instances of tumour lysis syndrome (TLS) following carfilzomib administration have been reported in the literature; however, this has not been observed in Hong Kong. Hydration with 250–500 mL of normal saline or other appropriate intravenous fluids before the first dose of carfilzomib can help prevent TLS, and can be discontinued thereafter in the absence of any AEs.4-6 Overhydration should be avoided, especially in patients at increased risk of cardiac AEs, such as heart failure.4,5

This case illustrates tha carfilzomib plus dexamethasone is a viable option in R/R MM patients, such as ours, who tolerated the treatment well and achieved a very good response in spite of multiple prior lines of therapy.


 

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