Introduction:The overall survival (OS) for patients with multiple myeloma (MM) continues to improve with advances in therapies such as second-generation proteasome inhibitors (PI), immunomodulatory agents (IMiDs) and monoclonal antibodies. Advanced therapeutics (eg chimeric antigen receptor (CAR-T) cells), immunotherapies and 3rd generation agents are also under evaluation. Therefore, interest in Phase 1 clinical trials has increased as patients may benefit from exposure to a novel therapy. Also, increasingly data has been used to obtain breakthrough designation from regulatory authorities as part of accelerated approvals. However, these therapies have unproven efficacy, may cause potentially severe toxicities and patients may receive sub-optimal doses. We therefore analysed the outcomes of our patients and to complement this performed a meta-analysis of publicly available Phase I MM trials.

Methods: This was a retrospective review of patients with MM enrolled onto phase I and I/II trials at the NIHR/UCLH Clinical Research Facility, London, UK. Patients received at least one dose of study drug, AEs were graded by CTCAE 4.0 and response criteria evaluated as per protocol. Individual-patient survival data were analysed using the Kaplan-Meier method and survival curves compared with the log-rank test. A meta-analysis using Medline, EMBASE and was performed to identify abstracts/papers reporting phase I trials from January 2016 to December 2017. Data was extracted by two independent reviewers using the same inclusion and exclusion criteria with significant overlap to ensure inter-observer consistency. Meta-analyses of Overall Response Rate (ORR) were performed using random-effect models.

Results: 50 patients were enrolled onto 7 phase I or I/II clinical trials between March 2012 to June 2018 at the NIHR/UCLH Clinical Research Facility. 6 participated in 2 trials (each trial entry considered a separate event). IMPs were: monoclonal antibody (Mab) (1), HDAC inhibitor (1), immune-modulator (1), proteasome pathway inhibitors (2), kinase pathway inhibitor (1), epigenetic modifier (1). 3 trials were monotherapy and 4 as combinations. The median age was 54 years (33-73), 46% were female. The median time from diagnosis to trial entry was 58.5m (IQR 36-104.5) and median prior lines of therapy was 3 (0-7). Patients received a median of 10 cycles (1-34) over a median duration of 176 days (IQR 112-425). Study withdrawal was due to progressive disease (50%), autograft (16.1%), toxicity (12.5%), completion of study (12.5%) and other (3.6%) (Table 1).

30.4% of patients experienced G3-4 toxicity and 28.6% had dose interruptions of ≥7 days. The overall response rate (≥PR) was 55.3%, ≥VGPR: 26.7% (see Table 1).The median PFS was 14.2 m (95% CI:7.6-15.9) and OS 37.3m (95% CI:29.2-not reached) with a median follow-up of 26.5m. Median OS for those with < 4 prior lines was better (48.1m) vs those ≥ 4 prior lines (30.6m, p-value log-rank test=0.03). Those with adverse risk cytogenetics appeared to do worse vs standard risk: PFS 14.2 vs 7.6m (log rank not significant); OS 37.3 vs 30.6m (log rank: not significant). Most patients (80.3%) received further treatment after trial (12.5% received another trial, 46.4% chemotherapy; 21.4%: autograft). 8.9% were managed expectantly and 5.4% palliated.

110 trial abstracts & publications were selected for meta-analysis that included 3222 patients with a median age of 64 years (30-75), 42% female, median 4 prior lines. 64.6% of reports were combination studies. 17% targeted the proteasome, 17% were MAbs, 10.9% were epigenetic modifiers, 5.5% were cellular therapies and 24.6% were other small molecule inhibitors (Table 2).

The overall response rate across all studies was 52.2% (95% CI 46-58.2). Higher responses were described for immunotherapy studies: BCMA CAR-T cells, 74.2% (95%CI 42.3- 91.8) and monoclonal antibodies, 64.2% (95% CI 56.2- 71.4). PFS and OS was not consistently reported across studies.

Conclusions: Patients derive benefit from phase 1 trials with clinically significant responses reported from this single centre and meta-analysis. Additionally, most received further treatment after. The best responses were reported for immunotherapy studies. Despite this, in our data there was an overall trend for worse outcomes for adverse risk cytogenetics and for those treated later in their disease course.


Townsend:Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Yong:Takeda: Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau. Popat:Amgen: Honoraria.

Author notes


Asterisk with author names denotes non-ASH members.