Carfilzomib, bendamustine, and dexamethasone in patients RRMM

The survival of patients with multiple myeloma (MM) has been improving over the last two decades, and many patients can now reach an overall survival (OS) of 10 years. MM is still incurable, despite the introduction of immunotherapy, and treatment options are limited for patients who experience disease progression after treatment with first-generation novel agents such as bortezomib, lenalidomide, and thalidomide.

Carfilzomib, a second-generation irreversible proteasome inhibitor, has demonstrated efficacy in patients who were refractory to bortezomib with a good safety profile. Carfilzomib was first approved in combination with lenalidomide plus dexamethasone in the relapsed and/or refractory MM (RRMM) setting and at a different dosing regimen with dexamethasone alone.

Bendamustine, a bifunctional chemotherapeutic agent with alkylating and antimetabolite properties, can improve complete response (CR) rate, time to treatment failure when combined with prednisone, and quality of life. It is approved by the European Medicines Agency for patients with MM and severe renal impairment. Although bendamustine has safety issues with peripheral neuropathy, it showed promising efficacy in patients with advanced MM when combined with bortezomib.

There is an unmet need for new therapeutic options that are immunomodulatory drug-free for patients who have also been exposed to bortezomib. Thus, Francesca Gay et al. published a multicenter dose-escalation phase I/II study in Cancer (NCT02056756), which was conducted within the European Myeloma Network as EMN09, to evaluate the maximum tolerated dose (MTD), the safety, and the efficacy of carfilzomib, bendamustine, and dexamethasone (KBd) in patients with RRMM.¹

Study design

Patients were eligible if they had

• previously received ≥2 lines of therapy;
• measurable disease;
• Karnofsky performance status ≥60%; and
• creatinine clearance ≥15 mL per minute.

Patients with Grade >2 peripheral neuropathy or a left ventricular ejection fraction <40% were excluded.

The primary objective of the phase I part of the study was to define the MTD of KBd, while the primary objective of the phase II part was to establish the rate of very good partial responses (VGPRs). The secondary endpoints were to determine the overall response rates, progression-free survival (PFS), OS, and conduct subgroup analyses of prognostic factors.

Dosing regimen

All patients were given 20 mg dexamethasone orally on Days 1, 2, 8, 9, 15, 16, 22, and 23. After prehydratation, carfilzomib was administered intravenously for >30 minutes on Days 1, 2, 8, 9, 15, and 16 in a 28-day cycle.

• In the phase I part, carfilzomib was started at 27 mg/m² (dose level 0), then escalated to 36 mg/m² (dose level +1), and up to 45 mg/m² (dose level +2). A fixed dose of 70 mg/m² bendamustine was administered intravenously on Days 1 and 8 in a 28-day cycle.
• In the phase II part, patients were given KBd at the determined MTD. This KBd regimen was given for eight cycles; then carfilzomib maintenance was administered at the MTD on Days 1, 2, 15, and 16, along with 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 in a 28-day cycle until progressive disease or intolerance.

Results

From April 2014 to February 2017, 13 patients were enrolled in the phase I dose-escalation part of the study, and 50 patients were enrolled in the phase II part. Patients in this study had received a median of three previous lines of therapy before KBd. Key patient characteristics are shown in Table 1.

Table 1. Patient characteristics*

Patient characteristics

ASCT, autologous stem cell transplantation; IQR, interquartile range. *Adapted from Gay, et al.1 †High-risk disease includes deletion 17p (del[17p]), or translocation (4;14) (t[4;14]), or translocation (14;16) (t[14;16]). ‡The proportions of those with refractory disease were based on the number of patients who received the drug. §Seventeen patients received pomalidomide.
Characteristic, % (unless otherwise stated)	Total (N = 63)
>65 Median age (range), years	66 (37–79)
>65 years	57
Male	59
International Staging System
I	52
II	30
III	17
High-risk cytogenetics†	48
Performance status
0	41
≥1	56
Disease status
Primary refractory	5
Relapsed	65
Relapsed and refractory	30
Median time from diagnosis to study entry (IQR), years	5.2 (2.7–8.2)
Number of previous lines of therapy
2	38
3	16
4	16
≥5	30
Previous therapy
ASCT	75
Refractory‡	21
Bortezomib	87
Refractory‡	33
Immunomodulators§	86
Lenalidomide	76
Refractory‡	60

Results of phase I

The KBd regimen at dose level 0 was effective but led to three of six patients experiencing Grade 4 lymphopenia. At dose level +1, a third of patients had Grade 4 thrombocytopenia and Grade 3 febrile neutropenia. After the enrolment of four additional patients at this dose level, the MTD was defined at 36 mg/m² (dose level +1).

Since carfilzomib at 27 mg/m² was better tolerated and achieved similar responses to higher doses, the phase II part of the study evaluated the triplet with carfilzomib at this dose level.

Results of phase II

Efficacy

In an intention-to-treat analysis, 56 out of 63 patients (88.8%) showed a decrease in M protein. KBd achieved an overall response rate of 52%, with 32% of patients at least in VGPR. Table 2 shows the best overall responses of all patients in the study.

Table 2. Best overall response*

CR, complete response; nCR, near complete response; PR, partial response; SD, stable disease; VGPR, very good partial response. *Adapted from Gay, et al.1
Response, %	Total (N = 63)
CR	5
nCR	13
VGPR	14
≥VGPR	32
PR	21
≥PR	52
SD	38

The median PFS was 11.6 months (95% confidence interval [CI], 7.9–15.3 months) and the median OS was 30.4 months (95% CI, 20.5 months to not reached). Patients with standard-risk chromosomal aberrations had significantly better PFS compared with those who were high-risk, with a median PFS of 19.6 vs 7.9 months; hazard ratio, 0.43; 95% CI, 0.21–0.88; p = 0.021.

Despite the small sample size, the subgroup analysis showed that patients with poor prognostic indicators such as deletion 17p (n = 14) were still able to reach a median PFS of 9.4 months. Patients with standard-risk chromosomal aberrations also had a significantly improved OS vs those who were high-risk: the 18-month OS rate was 87% vs 52% (hazard ratio, 0.24; 95% CI, 0.08-0.67; p = 0.007).

There were no clinically significant differences in PFS between patients who relapsed on or were refractory to lenalidomide vs those who relapsed on or were refractory to bortezomib.

Safety

During induction, the following was observed:

• The most frequent Grade 3 and 4 toxicities reported were hematologic (≥20% of events), including lymphopenia, neutropenia, and thrombocytopenia.
• The most frequent Grade 3 and 4 non-hematologic toxicity during induction was pneumonia (13%).
• Of note, venous thromboembolism was experienced by six patients.
• One patient developed hypertension, two patients were diagnosed with acute coronary syndrome, and another two had atrial fibrillation. Five out of 63 (8%) patients had Grade ≥3 cardiac events.
• A total of 13 patients discontinued treatment due to adverse events (AE).

During maintenance therapy, the following was observed:

• The most frequent AE recorded were Grade 1 or 2.
• The most common type of Grade ≥3 toxicities were hematologic.
• A total of three patients discontinued treatment due to AE.

Conclusion

Carfilzomib, at the optimal dose of 27 mg/m², combined with bendamustine and dexamethasone demonstrated clinical efficacy in patients with advanced disease. The safety profile was manageable, with no renal toxicity observed in this study even though patients with moderate renal dysfunction were included.

Overall, in this EMN09 study, the KBd regimen achieved significant rates of ≥VGPR. Patients were able to reach responses rapidly, and the median PFS was 11.6 months.

Treatment with KBd for this advanced stage patient population compares favorably with other regimens, including bortezomib-containing combinations, thus presenting a reasonable alternative. Additionally, as bendamustine has become generic in some countries, it may come at an accessible price, which will help many countries where multiple lines of therapy are needed but not affordable, therefore alleviating a significant financial burden.