Could bendamustine plus dexamethasone be a viable treatment option for R/R systemic light-chain amyloidosis?

Systemic light-chain (AL) amyloidosis is a condition associated with underlying plasma cell dyscrasia. Characterizing the disease is notoriously difficult due to its range of manifestations, and there is a  lack of treatments for patients with AL amyloidosis. This is highlighted by the lack of any approved regimen for AL amyloidosis by the U.S. Food & Drug Administration (FDA).^1,2 The main feature of AL amyloidosis is the production of abnormal immunoglobulin (Ig) light chains by a plasma cell clone, resulting in an abundance of free light chains (FLCs) which misfold and aggregate into amyloid fibrils. Deposition of these toxic proteins in target organs leads to organ dysfunction and ultimately results in death. Despite the severity of the disease, there remains no standard of care (SoC).²

Several treatments for relapsed/refractory AL amyloidosis (RRAL) are under investigation. The TOURMALINE-AL1  (NCT01659658) trial investigated the combination of ixazomib plus dexamethasone (ixa-dex) for the treatment of RRAL. This study was the first phase III trial in patients with RRAL to show a significant improvement on clinical outcomes. Despite the trial not meeting the first primary endpoint of hematologic overall response rate (ORR), ixa-dex treatment resulted in an improved complete response (CR) rate and duration of response (DoR).³ Read a summary of the data here.

Bendamustine is a unique chemotherapeutic agent with both alkylating and antimetabolite activity, which mutually targets apoptotic and non-apoptotic cytotoxic pathways. ^4,5 The multi-functional activity of bendamustine may explain why it is efficacious in patients with R/R disease, and a number of late phase trials have investigated bendamustine either alone or as part of a combination regimen for the treatment of previously untreated or R/R multiple myeloma (MM; RRMM).² The studies have uncovered the favorable safety profile and potency of bendamustine as an anti-plasma cell therapy. Results from a phase III study, investigating the safety and efficacy of bendamustine plus prednisone versus melphalan plus prednisone, demonstrated that bendamustine prolonged time to treatment failure as well as increased complete response (CR) rates.⁶ Data from this study resulted in the European Medicines Agency (EMA) approving bendamustine for the treatment of adult patients with previously untreated MM in 2010.⁶

Due to the positive outcomes accomplished with bendamustine in MM, a phase IIa multicenter study (NCT01222260) was conducted to determine the efficacy and safety of bendamustine plus dexamethasone (ben-dex) in patients with persistent or progressive AL amyloidosis after one or more prior therapy. Suzanne Lentzsch and Galina G. Lagos, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, US, and colleagues recently published the results in the Journal of Clinical Oncology and we hereby present a summary.² An interview with Professor Lentzsch about how to treat  AL amyloidosis, is available below.

Study Design

Patient eligibility

• Adult patients with RRAL (N = 31) were enrolled from six sites across the United States
• Patients had received one or more prior therapy and had measurable disease defined as ≥ one of:
  • Serum monoclonal protein ≥ 0.5 g/dL
  • Urine monoclonal protein > 200 mg/dL
  • Bone marrow clonal plasma cell population
  • Abnormal FLC ratio
• Patients with symptomatic MM were excluded

Treatment

• Ben-dex was administered in 28-day cycles:
  • Bendamustine intravenously on Days 1 and 2 based on creatinine clearance (CrCl):
    • CrCl ≥ 60mL/min: 100 mg/m²
      • Dose escalation to 120 mg/m² was available for patients who tolerated the treatment and had both a favorable performance status
    • CrCl 59–30mL/min: 90 mg/m²
    • CrCl 15–30 mL/min: 70 mg/m²
  • Dexamethasone (40 mg) orally on Days 1, 8, 15 and 22
• Patients received a median of four cycles (range, 2–12; n = 29)
• Treatment continued until disease progression or for up to six cycles after achievement of hematologic CR

Experimental endpoints

• Primary endpoint: ≥ partial response (PR) rate
• Secondary endpoints: hematologic CR and very good partial response (VGPR) rates, organ response rate, progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs; AEs)

Results

Patient characteristics

• Patient characteristics are illustrated in Table 1

Table 1. Patient characteristics

Auto-SCT, autologous stem cell transplant; dFLC, difference in free light chain; ECOG, Eastern Cooperative Oncology Group; eGFR, estimated glomerular filtration rate; GI, gastrointestinal
Baseline characteristics	Patients (N = 31)
Median age, years (range) Male, % ECOG performance status, n (range) Light-chain type: lambda, % Median dFLC, mg/dL (range) Relapsed hematologic disease at trial enrollment, % Median time since diagnosis, months (range)	65 (42–78) 71 1 (0–2) 68 12.2 (0.2–442.9) 65 31.0 (3.0–167.2)
Organ involvement, %
Number of organs involved (range) Cardiac Renal Neurologic GI Hepatic ≥ 2 organs involved	2 (1–4) 58 52 26 29 13 58
Prior treatment
Median No. of prior therapies (range) Median time since last therapy, months (range) Auto-SCT, %	2 (1–5) 4.4 (0.5–110.3) 45

Efficacy

• 29 patients completed ≥ two cycles of treatment and were eligible for response assessment
• The overall hematologic response rate was 57%
  • Median time to best hematologic response: 2.8 months (range, 0.9–7.5)
  • Hematologic responses to ben-dex is shown in Table 2
• Of 24 patients with measurable organ disease, seven had an organ response (29%) at a median of 2.8 months (range, 1.9–6.0)
  • 10 patients had organ progression
  • Most patients with organ progression never achieved hematologic response
• At a median follow-up of 14.9 months (range, 3.0–59.8)
  • Median OS: 18.2 months (95% CI, 11.3–43.8)
    • Median OS was significantly prolonged in patients achieving a CR, VGPR, or PR compared to patients without hematological responses after two cycles: not reached vs5 months (p = 0.0291)
  • Median PFS: 11.3 months (95% CI, 5.0–15.4)

Table 2. Hematologic responses to ben-dex

CR, complete response; NA, not available; NR, no response; PR, partial response; VGPR, very good partial response * One patient was enrolled based on bone marrow involvement without detectable serum monoclonal protein or a dFLC > 40 mg/L and did not undergo repeat bone marrow biopsy at the end of the study. He could not be evaluated for a hematologic response but was assessed for organ response
Hematologic response (n = 28)*	Patients, n (%)	Median months until response (range)
≥ PR	16 (57)	2.8 (0.9–7.5)
CR	3 (11)	4.7 (2.0–7.5)
VGPR	5 (18)	3.5 (0.9–6.0)
PR	8 (29)	1.8 (0.9–4.0)
NR	10 (36)	NA
Progression during treatment	2 (7)	2.7 (1.9–3.5)

Safety

• AEs are shown in Table 4
• No treatment-related, Grade 5, serious AEs (SAEs) were observed
• Twenty patients (65%) had ≥ 1 Grade 3–4 TRAE
• Leukopenia (26%), fatigue (19%), renal dysfunction (13%), rash (6%), and mood symptoms (6%) were the most commonly observed Grade 3 and 4 AEs
• SAEs due to treatment were observed in 32% of patients
• Discontinuations occurred due to AEs (n = 8), lack of response (n = 5), organ disease progression (n = 3) and hematologic disease progression (n = 2)
• Dose reductions of bendamustine were necessary in 9 patients and for dexamethasone in 15 patients

Table 4. AEs observed in patients receiving ben-dex

AE, adverse event; SAE, serious adverse event; WBC, white blood cells
AE	Patients (n = 31)
	Grade 3 or 4 AE	SAE
Fatigue	6	1
Anemia	1	0
Decreased WBC count	8	0
Nausea/vomiting	1	0
Diarrhea	1	1
Mood symptoms	2	0
Renal dysfunction	4	2
Infection	1	1
Rash	2	1
Infusion-related reaction	1	1
Fever/chills	0	2
Dehydration	1	0

Concluding remarks

• Ben-dex significantly prolonged the OS of patients who achieved a hematologic response
• The ben-dex regimen demonstrated a favorable safety profile in patients with RRAL
• Despite the small cohort size, data from this study suggest that ben-dex could be an effective therapy for patients with AL amyloidosis after first and secondary relapse to emerging front-line treatments