Azacitidine (AZA), a ring analogue of pyrimidine nucleoside, cytidine, is a DNA methyltransferase inhibitor and cytotoxic agent with survival benefits in high-risk MDS and AML. In preclinical work, AZA rapidly induces apoptosis of MM cells (HMCL and primary patient samples) and induces synergistic killing of HMCL when combined with lenalidomide (LEN). This, coupled with development of an oral formulation, provides rationale for pursuing this combination in MM.


In relapsed/refractory MM (R/R MM) patients refractory to prior LEN: To determine the maximum tolerated dose (MTD) of oral AZA when administered in combination with fixed dose LEN and dexamethasone (DEX); to characterise safety and tolerability; to assess efficacy: overall response rate (ORR), progression free survival (PFS), overall survival (OS).


Phase Ib, single centre, 3 x 3 paradigm dose escalation study with expansion at MTD. LEN 25mg/d for d1-21/28d cycle and DEX 40mg d1, 8, 15, 22/28 were combined with escalating doses of AZA: initial dose was 100mg for d1-14/28, increasing by either 7 days or 50mg per cohort, to a maximum of 200mg d1-21/28d. Dose limiting toxicity (DLT) was assessed during cycle 1. IMWG uniform response criteria and modified EBMT criteria (minor response, MR) were used. Treatment continued until toxicity/progression. Following review by the independent monitoring committee, an expansion of cohort 2 (100mg d1-21) was undertaken due to the efficacy signal seen in this cohort. This is an interim report.


18 eligible MM patients commenced therapy (7 F, 11 M) at a median age of 64 years (range 50-80 years). Median number of prior lines of therapy was 5 (range 2-8), including 15 patients with prior ASCT (8 with 2 prior ASCT) and 2 patients with prior Allogeneic transplant. All had previously failed LEN (R/R = 15, primary refractory (PrimR) = 3); eight also received pomalidomide (POM) (R/R = 3, PrimR = 5). All had been treated with bortezomib (BTZ) (R/R = 8, PrimR = 8). 16 patients were both BTZ and LEN refractory.

MTD Determination: AZA dose achieved at the time of submission was 150mg d1-21, with no DLTs observed. One patient was not evaluable as they progressed prior to completion of the first cycle.

Safety/tolerability: All grade haematologic toxicity comprised anaemia 5/18 (grade (G) 3/4: 3), neutropenia 6/18 (G 3/4: 5) and thrombocytopenia 9/18 (G 3/4: 3). All non-haem toxicity (>11%) consisted of: nausea 14/18 (G 3/4: 1), vomiting 6/18, constipation 7/18 (G 3/4: 1), fatigue (10, G 3/4: 2), insomnia 3, infection URTI 6/18, LRTI 2, (G 3/4: 2). All but 1 patient required antiemetic therapy to tolerate AZA. Two patients required dose reductions of AZA, two for LEN and three for DEX.

Efficacy: ORR (≥PR) was 39% (7/18): 6 PR, and 1 VGPR. Of the remaining patients, 2 achieved MR, 6 SD, and 3 PD, giving an overall clinical benefit rate (CBR) of 50%. Responses were seen in all but one cohort [100mg d1-14 (3 PR), 100mg d1-21 (1 VGPR, 1 PR), 150mg d1-14 (nil), and 150mg d1-21 (2 PR, 2 MR)]. Time to achieve best response in patients with ≥ MR was 2.7m (1-3.7m). Two of five patients treated with LEN in prior 1-2 treatment lines responded (PR, VGPR), one had SD (duration of response (DoR): 5m). One of eight patients treated with POM in prior 1-2 treatment lines responded (PR), with 2 achieving MR and 3 SD (DoR: 2, 3 and 6m). Median PFS 3.8m, median OS 14.5m. Median time on study was 3.7m (0.3-12.9m). Four patients remain on study.


Oral AZA in combination with LEN and DEX appears to be well tolerated and effective in a group of heavily pre-treated R/R MM patients, including within a subgroup of patients who have recently failed IMiD therapy, suggesting that AZA may overcome drug resistance in R/R MM. The MTD has not yet been determined.


Off Label Use: oral azacitidine in patients with relapsed/refractory myeloma.

Author notes


Asterisk with author names denotes non-ASH members.

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