Pomalidomide plus dexamethasone for patients with relapsed or refractory multiple myeloma: Final results of the non‐interventional study POSEIDON and comparison with the pivotal phase 3 clinical trials

1 INTRODUCTION

Treatment of multiple myeloma (MM) has changed substantially during the past decade.1-3 The introduction of immunomodulatory drugs (IMiDs®) and proteasome inhibitors (PIs) has resulted in significantly improved outcome of MM patients.2 However, although current treatments are very effective, most MM patients will eventually become refractory to treatment or relapse3-6 and treatment of advanced-stage patients whose disease progressed after several treatment lines remains challenging. Durations of remission have been inversely related to the number of treatment regimens, probably due to acquired drug resistance.4 The prognosis of patients who relapse after or become refractory to PIs such as bortezomib and IMiD agents such as lenalidomide has been assessed to be poor with a median overall survival (OS) of 9 months.7 Pomalidomide (Imnovid®) (POM) is a third-generation IMiD agent with antitumor and immune stimulating properties distinct from those of lenalidomide.8-10 It has been shown to exhibit synergistic responses when used in combination with dexamethasone (DEX)11 and demonstrated efficacy in lenalidomide-refractory patients in clinical trials.11-14 Based on the pivotal phase III (MM-003) trial by San Miguel et al.,12 in which the combination of pomalidomide and low-dose dexamethasone (POM/DEX) resulted in significantly longer survival and a greater number of clinical responses compared to DEX alone, it received approval in 2013 for the treatment of patients with relapsed and refractory MM who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy.15 Efficacy and safety of this combination regimen were further confirmed in a large phase IIIb trial (MM-010) by Dimopoulos et al.14

As published data from clinical trials may not reflect clinical outcomes in real world due to well-known significant differences in multiple aspects, including patient and disease characteristics, treatment-related factors and trial design,16 the assessment of effectiveness and tolerability of POM/DEX in routine clinical practice in a more heterogenous population of patients with relapsed or refractory MM (R/RMM) is of key importance. Thus, the current POSEIDON study aimed to evaluate effectiveness and safety of POM/DEX therapy in Germany in a real-world setting.

2 METHODS 2.1 Study design and setting

POSEIDON (NCT02075996) was a prospective, non-interventional study (NIS) approved by the responsible ethics committees and was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all patients before study entry. Patients were enrolled between 2014 and 2017 at 43 study sites across Germany including hemato-oncologists in hospitals and outpatient clinics, and independent oncology practices. Patients were recruited into two cohorts (I/II) stratified by last prior treatment line. Patients of cohort I had received lenalidomide in the last preceding treatment prior to enrolment, whereas patients of cohort II had received any other prior therapy directly before enrolment, including lenalidomide in earlier treatment lines.

2.2 Patients and treatment

Eligible patients were aged ≥18 years, diagnosed with R/RMM and with decision for treatment with POM/DEX in routine clinical practice. Patients must have received at least two prior therapy lines including both lenalidomide and bortezomib, and patients must have progressed on the last therapy. Further, patients had to fulfill the conditions of the pregnancy prevention program.15

Indication for treatment and decision for therapy with POM/DEX was the responsibility of the treating physician and independent from the decision to include the patient into the study. The treatment observation period comprised patients´ course of POM/DEX treatment until disease progression (PD), death or discontinuation of therapy, however, for a maximum of 12 months. Patients were followed up for assessment of the further course of disease and overall survival according to clinical routine until a maximum of 36 months after end of the treatment observation period of the last patient.

2.3 Study objectives

The primary objective was to assess progression-free survival (PFS), defined as the time from first administration of POM until disease progression or death, whichever came first. Secondary effectiveness objectives included the overall response rate (ORR), according to the International Myeloma Working Group (IMWG) response criteria for MM,17 time to treatment discontinuation (TTD), defined as the time from the first intake of POM until end of POM treatment, time to next treatment (TTNT), defined as the time from first intake of POM until start of a subsequent treatment with any substance other than POM, and OS, defined as the time from first intake of POM until death due to any cause. Effectiveness analyses were performed for predefined subgroups including patients with refractory MM (i.e., patients who had progressed on therapy or within 60 days after completing the last therapy) and patients with relapsed MM (i.e., patients who had progressed later than 60 days after completing the last therapy). Within the subgroup of patients with refractory MM, further subgroup analyses were performed for patients being primary refractory to lenalidomide (i.e., patients who never achieved a minor response (MR) or better with prior lenalidomide therapy) and patients not being primary refractory to lenalidomide. Moreover, analyses were stratified according to patients´ cytogenetic risk profile which was determined based on chromosomal aberrations. Patients who had at least one documented “high-risk” aberration according to the IMWG definition by Sonneveld et al.,18 i.e., gain 1q, gain 1q21, del(13), del(13q), del(13q14), del(17p), del(17p13), hypodiploidy (non-hyperdiploidy), t(4;14), t(14;16) and t(14;20), were assigned to high-risk cytogenetic profile. If none or only “standard risk” aberrations were documented, patients were assigned to standard risk profile. Further study objectives included the safety profile of POM (see Section 2.4), relative dose intensities and patient-reported changes in quality of life (QoL, Section 2.5).

2.4 Adverse events

Any treatment-emergent adverse events (AEs) were recorded from day of first administration of the study treatment until 30 days after the last dose of POM/DEX treatment or end of the 12-months treatment observation period, whatever came first. AEs were graded in accordance with the National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE version 4.03).

2.5 Health-related quality of life

To assess patient's health-related QoL, the EORTC QLQ-C30, with focus on questions 29 and 30, and the EORTC QLQ-MY20 questionnaires were used. Domain scores of the respective questionnaires were averaged and transformed linearly to scores ranging from 0–100. Higher scores in the global health status/functional scales correspond to higher perceived QoL/healthy level of functioning, while higher scores in the symptom scale correspond to a higher level of perceived symptoms. Patients were asked to complete the questionnaires at baseline and every two months thereafter until study treatment discontinuation or latest at end of the 12-month treatment observation period.

2.6 Statistical analysis

All enrolled patients having received at least one dose of POM and at least two prior therapies (including lenalidomide and bortezomib) were included in the full analysis set (FAS). The FAS was used to assess patient and disease characteristics and to analyze effectiveness objectives and QoL. Patients in the FAS for whom data on at least one further post-baseline variable under study treatment were available were included in the safety analysis set (SAF) used for evaluation of safety (AE analysis), exposure and treatment data. All variables were analyzed in a descriptive manner. Continuous variables were listed as number of observations, mean, standard deviation, median, 25%- and 75%-quartile and minimum–maximum. Categorical variables were presented as absolute and relative frequencies within single categories including an individual “missing” category. Subgroup analyses were considered exploratory.

The Kaplan–Meier method19 was used to estimate time-to-event endpoints (PFS, OS and TTNT). The follow-up time (i.e., the treatment observation period plus the follow-up period) was estimated with the reverse Kaplan–Meier method20 and additionally calculated and displayed with descriptive statistics for surviving patients only. Multivariate logistic regression and Cox regression analyses were performed to identify potential factors (age at inclusion, cohort, number of prior therapies, time from diagnosis until start of study treatment), which might have an impact on PFS, OS, TTNT or ORR. All statistical analyses were performed using SAS Version 9.4.

3 RESULTS 3.1 Patient, treatment and tumor characteristics at baseline

Between February 2014 and March 2017, 151 patients in 43 study centers across Germany were enrolled, of whom 79 patients were stratified by prior treatment into cohort I (lenalidomide treatment directly before inclusion) and 72 patients into cohort II (any other prior treatment directly before inclusion). Two patients had been assigned to the corresponding cohort but had no documented treatment start. In total, 144 patients (76 patients of cohort I and 68 patients of cohort II) were included in the FAS (Figure 1).

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Consort diagram. †Patients assigned to the corresponding cohort but without documented treatment start date, ‡Includes only patients who received pomalidomide treatment, §The full analysis set (FAS) consists of all enrolled patients having received at least one dose of pomalidomide. Patients fulfilling at least one off-label criteria (not having received at least two prior therapies, not having received both lenalidomide and bortezomib in previous therapy lines) were excluded from the FAS. Planned observation period (12 months) completed: for these patients no further pomalidomide treatment or incomplete information on pomalidomide treatment was documented in the follow up, and therefore, no reason for end of pomalidomide treatment in the follow up is available

Detailed demographics and clinical characteristics are depicted in Table 1. Data are displayed for patients in total as well as stratified by cohort I/ II and by refractory and relapsed MM; 96 patients were diagnosed with refractory MM (66.7%). Relapsed MM was diagnosed in 40 (27.8%) patients. Eight patients were neither assigned to relapsed nor refractory MM as for them no progress was documented after the last prior treatment and before start of the study treatment. Median age (range) at inclusion was 73.2 years (44.6–86.0) with a median time from initial diagnosis (ID) until start of POM treatment of 4.9 years (0.4–24.2) and a median number of prior therapy lines of 3.0 (2.0–8.0). Most patients presented with an Eastern Cooperative Oncology (ECOG) status of 0 or 1 (61.1%). At the beginning of POM/DEX treatment, most patients had Durie and Salmon stage III (72.9%) and International Staging System (ISS) stage II (29.9%) or III (23.6%). ISS was unknown for 31.3% of patients. The cytogenetic risk group could be determined for 71 patients. Of these, 24 (16.7%) patients were classified into high risk and 47 (32.6%) into standard risk.

TABLE 1. Patient demographics and clinical characteristics at the time of enrolment (FAS: N = 144) Total (N = 144) Cohort I (N = 76) Cohort II (N = 68) Refractory MM (N = 96) Relapsed MM (N = 40) Patient characteristics Age at inclusion [years] (median, range) 73.2 (44.6–86.0) 73.0 (46.6–84.9) 73.6 (44.6–86.0) 72.8 (44.6–84.1) 74.5 (52.6–86.0) Sex Female 63 (43.8) 37 (48.7) 26 (38.2) 41 (42.7) 19 (47.5) Male 81 (56.3) 39 (51.3) 42 (61.8) 55 (57.3) 21 (52.5) Time from ID [years] (median, range) 4.9 (0.4–24.2) 4.5 (0.7–12.6) 6.1 (0.4–24.2) 4.8 (0.4–18.2) 5.7 (1.4–16.7) Performance status ECOG 0–1 88 (61.1) 45 (59.2) 43 (63.2) 60 (62.5) 23 (57.5) ECOG 2–3 29 (20.1) 17 (22.4) 12 (17.6) 19 (19.8) 9 (22.5) Missing 27 (18.8) 14 (18.4) 13 (19.1) 17 (17.7) 8 (20.0) Creatinine clearance ≥60 ml/min 80 (55.6) 47 (61.8) 33 (48.5) 58 (60.4) 20 (50.0) <60 ml/min 92 (63.9) 47 (61.8) 45 (66.2) 61 (63.5) 24 (60.0) Missing 1 (0.7) 1 (1.3) 0 (0.0) 0 (0.0) 1 (2.5) Treatment characteristics Number of prior therapy lines (median, range) 3.0 (2.0–8.0) 2.0 (2.0–7.0) 4.0 (2.0–8.0) 3.0 (2.0–8.0) 3.0 (2.0–6.0) 2 53 (36.8) 47 (61.8) 6 (8.8) 33 (34.4) 18 (45.0) 3 34 (23.6) 14 (18.4) 20 (29.4) 21 (21.9) 11 (27.5) 4 30 (20.8) 9 (11.8) 21 (30.9) 24 (25.0) 5 (12.5) ≥5 27 (18.8) 6 (7.9) 21 (30.9) 18 (18.8) 6 (15) Prior therapies Autologous SCT 51 (35.4) 23 (30.3) 28 (41.2) 31 (32.3) 15 (37.5) Bortezomib 144 (100) 76 (100) 68 (100) 96 (100) 40 (100) Dexamethasone 141 (97.9) 73 (96.1) 68 (100.0) 93 (96.9) 40 (100.0) Lenalidomide 144 (100) 76 (100) 68 (100) 96 (100) 40 (100) Thalidomide 16 (11.1) 7 (9.2) 9 (13.2) 10 (10.4) 6 (15.0) Primary refractorya n.a. n.a. n.a. 14 (14.6) n.a. Primary refractory to lenalidomideb n.a. n.a. n.a. 39 (40.6) n.a. Tumor characteristics ISSc I 22 (15.3) 12 (15.8) 10 (14.7) 13 (13.5) 8 (20.0) II 43 (29.9) 25 (32.9) 18 (26.5) 33 (34.4) 7 (17.5) III 34 (23.6) 18 (23.7) 16 (23.5) 21 (21.9) 12 (30.0) Unknown 45 (31.3) 21 (27.6) 24 (35.3) 29 (30.2) 13 (32.5) Durie and Salmond I 7 (4.9) 3 (3.9) 4 (5.9) 6 (6.3) 1 (2.5) II 29 (20.1) 19 (25.0) 10 (14.7) 17 (17.7) 12 (30.0) III 105 (72.9) 53 (69.7) 52 (76.5) 70 (72.9) 27 (67.5) Unknown 3 (2.1) 1 (1.3) 2 (2.9) 3 (3.1) – A 16 (11.1) 5 (6.6) 11 (16.2) 10 (10.4) 4 (10.0) B 120 (83.3) 69 (90.8) 51 (75.0) 81 (84.4) 33 (82.5) Unknown 5 (3.5) 1 (1.3) 4 (5.9) 2 (2.1) 3 (7.5) Cytogenetic risk groupe High risk 24 (16.7) 10 (13.2) 14 (20.6) 18 (18.8) 5 (12.5) Standard risk 47 (32.6) 29 (38.2) 18 (26.5) 33 (34.4) 12 (30.0) Missing 73 (50.7) 37 (48.7) 36 (52.9) 45 (46.9) 23 (57.5) Note Data displayed with descriptive statistics (median (range) or frequencies (%) for the full analysis set (FAS, n = 144). Cohort I: lenalidomide in last line prior to pomalidomide treatment, Cohort II: no lenalidomide in last line prior to pomalidomide treatment; refractory MM = PD on or within 60 days after last prior therapy, relapsed MM = PD >60 days after last prior therapy; for eight patients an assignment to refractory or relapsed MM was not possible. Abbreviations: ECOG, Eastern Cooperative Oncology Group; ID, initial diagnosis; MM, multiple myeloma; PD, progressive disease; SCT, stem cell transplantation. a Patients with refractory MM who never achieved a minor response or better with any prior therapy. b Patients with refractory MM who never achieved a minor response or better with any prior lenalidomide therapy. c ISS, International Staging System.34 ISS staging at the time of start with pomalidomide therapy. d Staging according to the Durie and Salmon Staging system35 at the time of start with pomalidomide therapy. e Coded by medical experts, patients were classified into cytogenetic risk groups depending on their documented chromosomal aberrations (see Section 2.6). 3.2 Treatment with pomalidomide

The median number (range) of POM treatment cycles was 5.0 (1.0–12.0). The most common reason for end of POM/DEX treatment of 144 patients qualifying for effectiveness analyses was PD, among 57 (39.6%) patients. Further reasons for discontinuation documented among ≥10% of patients were inacceptable toxicity in 27 (18.8%) patients, death in 21 (14.6%) patients and physician´s decision in 15 (10.4%) patients.

Treatment modifications with POM were reported in 120 (82.8%) of 145 patients qualifying for treatment data analysis, thereof 107 (73.8%) therapy breaks and 70 (48.3%) dose reductions. Among the reasons for treatment modifications, 37.2% were treatment related. Other reasons documented were patient´s wish (17.9%), non-compliance (6.9%) and reasons not further specified (64.8%). Median (range) relative dose intensities of POM were 80.6% (16.7–122.6), 82.7% (33.9–122.6) and 80.6% (16.7–101.0) for patients overall, in cohorts I and II, respectively.

3.3 Patient survival and response to therapy 3.3.1 Survival and response to therapy in the total patient population and stratified by cohorts

After a median follow-up of 43.5 months, for the total population, median PFS and OS were 6.3 months [95% confidence interval (CI) 5.2,8.6] and 12.9 months [95% CI 10.6,15.1], respectively (Figure 2A,B).

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Progression-free survival (PFS) and overall survival (OS) of study patients. (A) PFS of the total patient population (FAS), (B) OS of the total patient population (FAS), (C) PFS stratified by cohorts. Cohort I represents patients with lenalidomide in last line prior to pomalidomide treatment and cohort II represents patients with no lenalidomide treatment in last line prior to pomalidomide treatment, (D) OS stratified by cohorts (i.e., cohort I and cohort II as described in C), (E) PFS stratified by refractory vs. relapsed MM. Refractory MM = PD on or within 60 days after last prior therapy; relapsed MM = PD >60 days after last prior therapy; (F) OS stratified by refractory vs. relapsed MM. For eight patients, an assignment to refractory or relapsed MM was not possible. FAS, full analysis set; MM, multiple myeloma; OS, overall survival; PD, progressive disease; PFS, progression-free survival

Median PFS of the cohorts (cohort I: 5.5 months [95% CI 3.8, 9.2]; cohort II: 6.4 months [95% CI 5.3, 8.7]) and median OS (cohort I: 14.1 months [95% CI 10.6, 18.7]); cohort II: 11.7 months [95% CI 8.7, 15.9]) were comparable (Figure 2C,D). Total ORR (complete response [CR]/very good partial response [VGPR]/partial response [PR]) for the total population was 31.9% [95% CI 24.9, 40.0] and 27.6% [95% CI 18.8, 38.6] for cohort I vs. 36.8% [95% CI 26.3, 48.7] for cohort II. 6.3% of patients in the total population (n = 9), 2.6% (n = 2) in cohort I and 10.3% (n = 7) in cohort II achieved CR/VGPR. For 30 (20.8%) patients, no response assessment was documented (Table 2). Median TTD (range) was 4.4 months (0–45.1) for the total population, 4.4 months (0.1–35.7) for cohort I and 4.7 months (0.0–45.1) for cohort II. Median TTNT was 7.7 months [95% CI 6.2–9.6] in total and 7.6 months [95% CI 4.6–11.9] for cohort I compared to 8.3 months [95% CI 6.2–9.2] for cohort II. Multivariate logistic regression analysis for ORR and Cox regression analyses for PFS and OS did not indicate statistically significant impacts of age, lenalidomide in last prior treatment, number of prior therapies and time from diagnosis to start of treatment on the respective effectiveness outcomes in the total patient population.

TABLE 2. Responses under pomalidomide treatment (FAS: n = 144) Total (N = 144) Cohort I (N = 76) Cohort II (N = 68) Refractory MM (N = 96) Relapsed MM (N = 40) Overall response rate n (%) [95% CI] 46 (31.9) [24.9, 40.0] 21 (27.6) [18.8, 38.6] 25 (36.8) [26.3, 48.7] 27 (28.1) [20.1, 37.9] 16 (40.0) [26.3, 55.4] Complete response 2 (1.4) 2 (2.6) 0 (0.0) 0 (0.0) 2 (5.0) Very good partial response 7 (4.9) 0 (0.0) 7 (10.3) 5 (5.2) 2 (5.0) Partial response 37 (25.7) 19 (25.0) 18 (26.5) 22 (22.9) 12 (30.0) Minor response 12 (8.3) 7 (9.2) 5 (7.4) 9 (9.4) 3 (7.5) Stable disease 37 (25.7) 23 (30.3) 14 (20.6) 28 (29.2) 8 (20.0) Progressive disease 10 (6.9) 7 (9.2) 3 (4.4) 8 (8.3) 1 (2.5) Unknown 9 (6.3) 4 (5.3) 5 (7.4) 6 (6.3) 2 (5.0) No assessment available 30 (20.8) 14 (18.4) 16 (23.5) 18 (18.8) 10 (25.0) Note Data displayed with frequencies (%) and with 95% confidence intervals (CIs) for overall response rate (ORR). Analyses based on the full analysis set (FAS, n = 144); Cohort I: Lenalidomide in last line prior to pomalidomide treatment, Cohort II: No lenalidomide in last line prior to pomalidomide treatment; refractory MM = PD on or within 60 days after last prior therapy; relapsed MM = PD >60 days after last prior therapy; for eight patients an assignment to refractory or relapsed MM was not possible. ORR is defined as the proportion of patients responding to the treatment (i.e., patients with complete, very good partial and partial response) during the treatment observation period, assessed in accordance with the International Myeloma Working Group (IMWG) criteria.17 Response information was available for 114 patients (79.2% of the analysis population). Patients without response information (n = 30 (20.8%)) are considered non-responders. Abbreviations: MM, multiple myeloma; PD, progressive disease. 3.3.2 Survival and response to therapy stratified by subgroups Refractory vs. relapsed MM

For patients with refractory MM, median PFS was 5.5 months [95% CI 3.8, 7.4], for patients with relapsed MM, 8.8 months [95% CI 5.2, 12.1]. Median OS of patients with refractory MM vs. relapsed MM was 10.6 [95% CI 7.6, 13.8] and 23.3 months [95% CI 12.9–39.0], respectively (Figure 2E,F). The ORR among patients with refractory MM was 28.1% [95% CI 20.1, 37.9] compared to 40.0% [26.3, 55.4] among patients with relapsed MM (Table 2). Median TTD (range) and TTNT [95% CI] were 4.4 (0.0–45.1) and 6.5 months [95% CI 4.7, 8.6] among patients with refractory MM as compared to 4.7 (0.1–29.6) and 8.9 months [95% CI 6.7, 13.1] among patients with relapsed MM, respectively.

Primary refractory to lenalidomide vs. not primary refractory to lenalidomide

Of the 96 patients diagnosed with refractory MM, 42 (43.8%) patients were classified as not primary refractory to lenalidomide, while 39 (40.6%) patients were classified as primary refractory to lenalidomide. For 15 (15.6%) patients, response to prior lenalidomide therapy was not available. Median PFS was 4.6 [95% CI 3.2, 6.7] for patients not primary refractory to lenalidomide and 5.5 months [95% CI 3.0, 8.8] for patients primary refractory to lenalidomide, while OS was 10.6 [95% CI 6.1, 14.1] and 8.0 months [95% CI 5.1, 14.9], respectively (Figure S1). ORRs of patients not primary refractory to lenalidomide vs. patients primary refractory to lenalidomide were 28.6% [95% CI 17.1, 43.7] vs. 20.5% [95% CI 10.5, 35.8] (Table S1). TTD and TTNT of patients not primary refractory to lenalidomide vs. patients primary refractory to lenalidomide were 4.4 (0.2–31.3) and 6.0 months [95% CI 2.9, 8.4] vs. 3.5 (0.0–28.9) and 5.4 months [95% CI 4.1, 9.7], respectively.

Cytogenetic risk group

Considering patients´ cytogenetic risk profile, median PFS and OS of high-risk patients vs. standard risk patients were 5.9 [95% CI 3.2, 7.3] vs. 5.5 months [95% CI 3.8, 8.8] and 11.2 [95% CI 6.4, 18.3] vs. 11.4 months [95% CI 6.9, 15.9], respectively (Figure S1). ORRs of high- and standard-risk patients were 20.8% [95% CI 8.8, 40.9] and 34.0% [95% CI 22.1, 48.4] (Table S1). Median TTD (range) and median TTNT of high-risk vs. standard-risk patients were as follows: TTD: 4.7 (0.2–17.3) vs. 4.3 months (0.0–31.3) and TTNT: 6.5 [95% CI 3.8, 9.2] vs. 6.7 months [95% CI 3.7, 9.6].

3.4 Quality of life

At baseline, the questionnaire return rate was 85.4%. Based on patient-reported outcomes, QoL maintained stable in POM/DEX treated patients. As shown in boxplots in Figure 3, Global Health Status/QoL was not significantly affected and functional scales (body image, future perspective) as well as symptom scales (disease symptoms, side effects) displayed hardly any changes over time. The greatest change from baseline of −15.2 (±29.5) points was observed after 10 months in the mean (SD) subscale score for body image. Details on changes of questionnaire scores from baseline are depicted in Table S2.

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Changes from baseline in patient-reported quality of

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