Identifying An Optimally Effective But Tolerable Dose Of Bendamustine In Combination With Thalidomide and Dexamethasone In Patients With Relapsed Or Refractory Multiple Myeloma

Bendamustine has efficacy as first-line treatment in multiple myeloma (MM) (in combination with prednisone), and in refractory patients who have been heavily pre-treated. Dose finding studies have not been performed for bendamustine in heavily pre-treated relapsed/refractory patients. MUK one is a randomised phase II selection trial assessing the activity & tolerability of two doses of bendamustine (B), 60mg/m² vs 100mg/m², in combination with thalidomide (T) & dexamethasone (D) in patients with relapsed/refractory MM.

Patients were randomised to receive B(60)TD or B(100)TD (B days 1 & 8 ; T 100mg od; D 20mg d1, 8, 15 & 22; 28 day cycle). Eligibility was based on confirmed MM with measurable disease, ECOG 0-3, platelets >75x10⁹/L & neutrophils >1.5x10⁹/L at 1st or later relapse. In the initial protocol, patients with lower platelets/neutrophils attributable to myeloma were eligible. Activity and tolerability were joint primary endpoints. The primary activity endpoint was ≥PR within 6 cycles. Tolerability was defined as the ability to receive at least 2 cycles of treatment at full dose with no delays of >2 weeks, without primary growth-factor support. Response rates <20% & tolerability rates <75% were deemed unacceptable based on previous data.

95 patients were randomised: B60TD n=66, B100TD n=29. In the primary analysis population, 56% (25/45, 80% CI [45-66]) of B60TD patients achieved ≥PR, the median progression free survival (PFS) was 8.2 months (95% CI [7.2-10.6]). In the B100TD primary population, 36% (5/14, 80% CI [19-56]) achieved ≥PR, median PFS was 5.1 months (95% CI [2.3-9.0]).

Following an interim analysis the B100TD arm was discontinued due to tolerability. Thereafter, patients were recruited to B60TD arm only, and included only with unsupported neutrophil >1.5x10⁹/L and platelets >75x10⁹/L, regardless of marrow infiltration. Consequently, two analysis populations are defined. (i) Primary analysis population: patients fulfilling amended eligibility criteria without PD after 1 cycle, having ≥1 dose of study drug, (B60TD evaluable n=45; B100TD evaluable n=14). (ii) Combined population: as for (i) but including patients with PD after cycle 1, (B60TD combined n=54; B100TD combined n=20). This group represents an intention to treat population with the amended criteria.

46% (80% CI [37-56]) of patients in the B60TD combined population achieved ≥PR, with a median PFS of 7.5 months (95% CI [5.3-8.7]). In the B100TD combined population 25% (80% CI [13-42]) of patients achieved ≥PR, with a median PFS of 2.6 months (95% CI [1.7-5.6]).

In the assessment of tolerability, 70% (80% CI [59-79]) of B60TD primary patients assessable for tolerability received ≥2 cycles of full-dose treatment with no delay >2 weeks. Median number of B60TD cycles was 6 (range 1-9), with 64% patients receiving ≥6 cycles. 32% patients experienced ≥ grade 3 neutropenia, 25% ≥ grade 3 thrombocytopenia, & 14% ≥ grade 3 anaemia. There was 1 grade 3 neurotoxicity, & no grade 3 nausea or GI disturbance.

Of the B100TD primary patients 71% (80% CI [51-87]) met tolerability criteria. Median number of cycles was 4 (range 1-9), 29% patients receiving ≥6 cycles. 64% patients experienced ≥ grade 3 neutropenia, 21% ≥ grade 3 thrombocytopenia, & 21% ≥ grade 3 anaemia. There were 3 grade 3 neurotoxicities, no grade 3 nausea & 1 grade 3 diarrhoea. Thromboembolism rates with prophylactic anticoagulation was 4% overall.

84% of patients had ≥3 prior therapies, PS 0/1 (85%) & relapsed MM (78%); 37% were ISS 3 at entry, mean b2M=5.6. Most had prior T (90%), Lenalidomide (74%) & Bortezomib (84%); 74% had ≥1 prior autograft.

The combination of BTD shows promising response rates at the 60mg/m² dose, despite only 70% of evaluable patients receiving at least 2 full cycles of bendamustine with ≤2 week delay, in this challenging multi-treated group of patients. The B100TD arm closed to recruitment at interim analysis due to lack of tolerability on the basis of pre-defined stopping rules. Responses were also lower in this arm compared to B60TD arm, which may reflect the ability of patients to receive more cycles of treatment to schedule at 60mg/m² than at 100mg/m². Although not passing the strict pre-specified tolerability boundaries, B60TD appears deliverable beyond 2 cycles in multiply-pretreated MM, with PR in excess of 45%, comparing favourably other novel agent combinations in this heavily pre-treated population.

Schey:Napp: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Cook:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Cavet:Celgene: Consultancy, Research Funding.