Introduction

Multiple myeloma (MM) is an incurable malignancy of clonal plasma cells. Incorporation of the monoclonal antibody daratumumab (dara) has improved treatment outcomes in newly diagnosed and relapsed/refractory MM (RRMM). The addition of low-dose, metronomic cyclophosphamide (cyclo) promotes dara-mediated NK cell cellular cytotoxicity and cellular phagocytosis in preclinical studies. We hypothesized that cyclo in combination with pomalidomide (pom), dexamethasone (dex) and dara could be effective in RRMM and we herein report the primary analysis from the multi-centre, Phase 1b Cyclophosphamide, Pomalidomide, Dexamethasone and Daratumumab (CPD-DARA) CTRIAL-IE-19-17(NCT04667663).

Methods

Patients with RRMM after 2-5 prior lines, including a proteosome inhibitor and immunomodulatory agent, received 28-day cycles of cyclo 50mg orally daily, subcutaneous dara 1800 mg weekly for 2 cycles, fortnightly for 4 cycles and on day 1 thereafter, dex 40mg orally weekly (20mg if ≥70 years), and pom orally, started at 4mg on days 1-21 per cycle. Patients were enrolled by a 3+3 algorithm, with dose de-escalation and determination of the maximum tolerated dose (MTD) based on occurrence of dose limiting toxicities (DLTs) during cycle 1. Treatment continued until intolerance, progressive disease (PD) or death. The primary end-point was to determine the MTD of pom in combination with cyclo, dex and dara. Adverse events (AEs) were graded using the US National Cancer Institute Common Terminology Criteria for Adverse Events V5. Patient reported outcomes (PRO) were assessed using FACT-G and MyPOS surveys. Study was supported by research funding from Johnson & Johnson Innovative medicine Ireland, Bristol Myers Squibb, Friends of Cancer Trials Ireland, Health Research Board and Irish Cancer Society.

Results

16 patients were enrolled. Median age was 67.5 years (range 46-77), 69% male,100% Caucasian, with a median 3 prior lines (1-5). 38% had received previous dara, 31% pom, 94% lenalidomide, 94% were double-class exposed, 38% triple-class exposed and 19% penta-class exposed. 38% had high-risk disease (ISS stage III or deletion of 17p, t(14;16) and/or t(4;14)).

No DLTs occurred and MTD was determined as 4mg of pom. Median duration of exposure to therapy was 11.7 mons (0.2 - 33.8). At time of analysis, 14 patients had discontinued treatment (6 PD, 3 investigator decision, 4 AEs, of which 2 were deemed treatment-related, and 1 death) and 2 remain on treatment. Of the 14 patients, 8 completed study as per protocol and 6 have withdrawn (1 withdrew consent and 5 deaths).

Treatment emergent adverse events (TEAEs) occurred in 100% (grade ≥3 94%). Haematologic grade ≥3 TEAEs included neutropenia (56%), lymphopenia (50%), anaemia (25%), leucopoenia (19%), and thrombocytopenia (19%). Other Grade ≥3 TEAEs occurring in ≥10% of participants were infection (19%), atrial fibrillation (13%), Covid-19 (13%), back pain (13%), diarrhoea (13%) and syncope (13%). Despite frequent grade ≥3 neutropenia, febrile neutropenia only occurred in 13% (all grade ≥3) and grade ≥3 pneumonia in 6%.

Serious adverse events (SAEs) occurred in 81%, with infection and Covid-19 (19% each) the most common. One SAE resulted in death due to an acute myocardial infarction, unrelated to study treatment. The other 4 deaths were due to PD. MyPOS scores increased slightly from baseline to end of treatment (EOT), with a mean change from baseline (SD) of 4 (13.75).

75% of patients (95% CI 51-90) achieved ≥stable disease after cycle 6 and 50% (27-73) at EOT. Median time to response was 12.1 weeks (4.0-29.1). After 6 cycles, 38% were in ≥VGPR, 13% in CR, and 19% were MRD negative. Median progression free survival (mPFS) was 15.0 months (median follow-up 22.7). PFS was 75% (46-90) at 6 mons and 44% (18-67) at 18 mons. Overall survival (OS) was 88% (59-97) at 6 mons and 67% (41-86) at 18 mons. Patients with high-risk disease (n = 6) had less favourable outcomes, with a median PFS of 7 mons compared with 15 mons in non-high risk patients.

Conclusions

CPD-DARA is an active regimen, with MRD-negative durable responses seen in RRMM. Safety is similar to other dara and pom-based combinations, with comparable rates of neutropenia and infection despite the addition of cyclo. CPD-DARA appears to be tolerable, with reassuring PRO data and few discontinuations due to AEs. These findings support further evaluation of CPD-DARA in larger trials as an active, cost-effective, regimen.

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2025
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