Pomalidomide, dexamethasone, and daratumumab immediately after lenalidomide-based treatment in patients with multiple myeloma: updated efficacy, safety, and health-related quality of life results from the phase 2 MM-014 trial

Abstract

Patients with relapsed/refractory multiple myeloma (RRMM) need proven subsequent therapies after early-line lenalidomide treatment failure. The phase 2 MM-014 trial (NCT01946477) investigated pomalidomide, dexamethasone, and daratumumab after 1 to 2 prior treatment lines (62.5%, 1 prior line) in patients with RRMM and prior lenalidomide (75.0%, lenalidomide refractory). With a median follow-up of 28.4 months, overall response rate was 77.7% (52.7% achieved very good partial response or better) and median progression-free survival was 30.8 months. For patients with lenalidomide-refractory disease, these outcomes were 76.2%, 47.6%, and 23.7 months, respectively. No new safety signals were observed; 64.3% experienced grade 3/4 neutropenia. Health-related quality of life was preserved or trended toward improvement through 12 treatment cycles. Pomalidomide, dexamethasone, and daratumumab given immediately after early-line lenalidomide-based treatment continues to demonstrate safety and efficacy, supporting pomalidomide-dexamethasone as a foundation of combination therapy in RRMM and providing evidence that the immunomodulatory agent class delivers benefit after lenalidomide treatment failure.

Keywords:

• Pomalidomide
• daratumumab
• multiple myeloma
• refractory
• lenalidomide

Introduction

Novel therapies have delivered clinically meaningful improvements in survival outcomes for patients with multiple myeloma (MM). However, MM remains incurable and inevitably progresses to a relapsing-remitting course, with remission periods becoming shorter and outcomes worsening with each relapse [1–5]. Additionally, health-related quality of life (HRQoL) tends to progressively deteriorate throughout a patient’s disease journey due to both disease burden and treatment toxicities [6–8]. As the MM therapeutic landscape has evolved with the introduction of newer therapies and combinations, HRQoL has become a crucial dimension of patient care, with preservation or improvement of HRQoL emerging as a key treatment goal [8]. Early-line relapsed or refractory MM (RRMM) represents a critical juncture in the patient journey: effective treatment to delay relapse at this stage will prolong the need for subsequent lines of therapy and alleviate myeloma symptoms, both of which have considerable impact on HRQoL [4,9,10].

Treatment with the immunomodulatory agent lenalidomide until disease progression is a standard of care for the treatment of newly diagnosed MM and RRMM [11,12]. Therefore, patients with disease that has become refractory to lenalidomide or relapsed during early treatment lines represent an important population in need of effective, proven therapies following disease progression [13]. The benefits of maintaining continuous immunomodulation with pomalidomide following lenalidomide have been demonstrated previously in clinical trials of lenalidomide-exposed patients [14–17]. Pomalidomide has more potent, direct tumoricidal and immunomodulatory effects that are distinct from those of lenalidomide [18–21]; in clinical trials, pomalidomide has demonstrated efficacy and tolerability in patients with prior exposure to lenalidomide, including those with myeloma refractory to lenalidomide [14,22–26]. The anti-CD38 monoclonal antibody daratumumab also exerts direct antitumor and immunomodulatory effects and has demonstrated synergistic immune-enhancing properties in combination with pomalidomide [17,27–31].

In the US, the triplet regimen of pomalidomide, dexamethasone, and daratumumab (intravenous injection) is approved for the treatment of patients with MM who received ≥2 prior therapies including lenalidomide and a proteasome inhibitor [32]. Initial regulatory approval was based on the findings of the phase 1 b EQUULEUS/MMY1001 RRMM study of patients with heavily pretreated RRMM (median, 4 prior lines of therapy) [33]. Overall response rate (ORR) was 60.2%, including an ORR of 57.5% in patients with disease refractory to a proteasome inhibitor and an immunomodulatory agent. Median progression-free survival (PFS) was 8.8 months. Until the MM-014 and APOLLO trials, this regimen had not been extensively studied in earlier lines of therapy or in patients who developed lenalidomide-refractory disease immediately prior to study entry [15,16,34]. Based on the APOLLO trial, a subcutaneous formulation of daratumumab is now approved in the US in combination with pomalidomide and dexamethasone for patients with MM who received ≥1 prior therapy including lenalidomide and a proteasome inhibitor [35].

MM-014, a multicenter, multinational phase 2 study comprising 3 cohorts, was specifically designed to investigate outcomes of sequencing pomalidomide-based therapy immediately following lenalidomide-treatment failure in early treatment lines [15,16]. Initial findings from cohort B, which evaluated pomalidomide, dexamethasone, and daratumumab, were promising, with an ORR of 77.7% and a 1-year PFS rate of 75.1% (median follow-up, 17.2 months) [16]. An immune-profiling analysis of cohort B during the first 2 cycles of treatment further demonstrated that although the combination simultaneously decreased natural killer and B cells, it markedly increased activated and proliferating natural killer and T cells and reduced naïve effector memory compartments [17]. The analysis also showed a depletion of CD38-expressing regulatory T cells with no increase in frequency of total regulatory T cells, consistent with previous observations on the mechanism of action of daratumumab [17,29]. These immune enhancements were also observed in patients with disease refractory to lenalidomide [17]. Here, we report updated efficacy and safety results from cohort B and HRQoL through 12 cycles of treatment.

Materials and methods

Patients and study design

The nonrandomized, multicenter, multinational, open-label, phase 2 MM-014 trial is being conducted in 49 study sites across the US, Canada, and Japan. The study is composed of 3 patient cohorts: cohort A (patients receiving pomalidomide plus dexamethasone after 2 prior lines of antimyeloma therapy) [15], cohort B (patients receiving pomalidomide, dexamethasone, and daratumumab after 1 or 2 prior lines of therapy) [16], and cohort C (only Japanese patients treated with pomalidomide, dexamethasone, and daratumumab after 1 or 2 prior lines of therapy). Details of cohort B of the MM-014 trial have been previously described [16]. In brief, eligible patients had 1 or 2 prior lines of therapy, including lenalidomide-based treatment for ≥2 consecutive cycles as their most recent regimen. Patients must have had documented disease progression during or after their last line of therapy. Patients who relapsed after or had disease refractory (defined as nonresponsive to therapy or disease progression ≤60 days after the last dose) to lenalidomide were also eligible for inclusion.

All patients provided written informed consent, agreed to the publication of data pertaining to themselves, and acknowledged that they cannot be identified via this paper; all patient data were fully anonymized. All mandatory laboratory health and safety procedures were followed in the conduct of the experimental work. The study protocol was approved by the institutional review board or central or local ethics committee at each participating study site. The study conformed to the principles of Good Clinical Practice according to the International Conference on Harmonization requirements and the Declaration of Helsinki. The trial is registered with ClinicalTrials.gov (NCT01946477).

Procedures

Patients received treatment in 28-day cycles until disease progression or unacceptable toxicity. Pomalidomide 4 mg/day was given orally on days 1 to 21; dexamethasone 40 mg/day (20 mg/d in patients aged >75 y) was given orally on days 1, 8, 15, and 22; and daratumumab 16 mg/kg was given intravenously on days 1, 8, 15, and 22 of cycles 1 and 2; days 1 and 15 of cycles 3 to 6; and day 1 of cycle 7 and beyond. At the discretion of the investigator, pre- and post-infusion medications required for daratumumab administration per labeling were allowed [32,36]. All patients received antithrombotic or anticoagulant prophylaxis. Patients were also allowed therapy for myeloma-associated bone disease, unless contraindicated, and hematopoietic growth factor support, including platelet and/or red blood cell transfusions, per the discretion of the investigator.

Outcomes

The primary endpoint was ORR, assessed by investigators using local imaging review and central laboratory results according to modified International Myeloma Working Group criteria. Secondary endpoints included PFS, estimated from time of study enrollment, and safety. Adverse events (AEs) were coded according to the Medical Dictionary of Regulatory Activities (version 20.0) and graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). HRQoL, an exploratory endpoint, was assessed using EuroQoL EQ-5D at baseline, at day 1 of each treatment cycle prior to treatment administration, and at treatment discontinuation. Change from the baseline assessment at each postbaseline time point was measured and analyzed using a paired t test. The proportion of patients who deteriorated, remained stable, or had resolution in EQ-5D domains from baseline to cycle 12 was also calculated.

Statistical analysis

Primary, secondary, and exploratory analyses were conducted in the intention-to-treat (ITT) population, which comprised all enrolled patients. The efficacy-evaluable (EE) population included patients who received ≥1 dose of study treatment and had ≥1 postbaseline assessment and was used for supportive sensitivity analyses for ORR and PFS. The safety population included patients who received ≥1 dose of study treatment. Finally, the HRQoL-evaluable population included patients with a baseline and ≥1 postbaseline HRQoL evaluation. Baseline and demographic characteristics were summarized via frequency tabulations for categorical variables and descriptive statistics for continuous variables. Point estimates of ORR and 95% CI were calculated using normal approximation to the binomial distribution. Kaplan-Meier procedures were used to characterize PFS; medians and 95% CIs were estimated.

Results

Patients

The ITT population included 112 patients [16]. Median age was 66.5 years, all patients had received lenalidomide in the immediately prior line of therapy, and most patients (62.5%) had only 1 prior line of therapy (Table 1). The most common immediately prior lenalidomide dose was ≤10 mg (48.2%; median duration, 25.7 months), followed by 25 mg (31.3%; median duration, 16.6 months). Overall, 28 patients (25.0%) had relapsed disease following lenalidomide, and 84 patients (75.0%) had disease that was refractory to lenalidomide. Baseline characteristics in the lenalidomide-relapsed and -refractory subgroups were similar to those of the ITT population, although Eastern Cooperative Oncology Group performance status of 0 was numerically less common in the lenalidomide-refractory subgroup vs the lenalidomide-relapsed subgroup (35.7% vs 50.0%). Fewer patients who were refractory to lenalidomide had only 1 prior line of therapy vs patients in the lenalidomide-relapsed subgroup (58.3% vs 75.0%).

Table 1. Demographic and baseline characteristics of the ITT population and LEN-relapsed or -refractory subgroups.

Characteristic	ITT Population	LEN Relapsed	LEN Refractory
	(N = 112)	(n = 28)	(n = 84)
Age, median (range), years	66.5 (39.0–83.0)	67.5 (39.0–83.0)	66.0 (43.0–82.0)
>65 years, n (%)	62 (55.4)	17 (60.7)	45 (53.6)
Male, n (%)	76 (67.9)	18 (64.3)	58 (69.0)
ECOG PS, n (%)
0	44 (39.3)	14 (50.0)	30 (35.7)
1	67 (59.8)	14 (50.0)	53 (63.1)
2	1 (0.9)	0	1 (1.2)
Renal function, n (%)
≥30 and <45 mL/min	7 (6.3)	3 (10.7)	4 (4.8)
≥45 and <60 mL/min	12 (10.7)	4 (14.3)	8 (9.5)
≥60 mL/min	79 (70.5)	16 (57.1)	63 (75.0)
Missing	14 (12.5)	5 (17.9)	9 (10.7)
Calculated R-ISS stage, n (%)
I	30 (26.8)	5 (17.9)	25 (29.8)
II	53 (47.3)	12 (42.9)	41 (48.8)
III	8 (7.1)	3 (10.7)	5 (6.0)
NE	21 (18.8)	8 (28.6)	13 (15.5)
Calculated IMWG risk, n (%)
Low	9 (8.0)	1 (3.6)	8 (9.5)
Standard	96 (85.7)	25 (89.3)	71 (84.5)
High	7 (6.3)	2 (7.1)	5 (6.0)
Time from MM diagnosis, median (range), years	3.4 (0.5–11.6)	5.0 (1.6–11.2)	3.3 (0.5–11.6)
Number of prior antimyeloma lines, median (range)	1 (1–2)	1 (1–2)	1 (1–2)
1 Prior line of therapy, n (%)	70 (62.5)	21 (75.0)	49 (58.3)
2 Prior lines of therapy, n (%)	42 (37.5)	7 (25.0)	35 (41.7)
Prior therapies, n (%)
LEN	112 (100)	28 (100)	84 (100)
Proteasome inhibitor^a	89 (79.5)	22 (78.6)	67 (79.8)
BORT	87 (77.7)	21 (75.0)	66 (78.6)
CFZ	11 (9.8)	4 (14.3)	7 (8.3)
IXA	4 (3.6)	1 (3.6)	3 (3.6)
Alkylating agents	89 (79.5)	22 (78.6)	67 (79.8)
SCT	78 (69.6)	19 (67.9)	59 (70.2)
Monoclonal antibodies	4 (3.6)	1 (3.6)	3 (3.6)
Elotuzumab	4 (3.6)	1 (3.6)	3 (3.6)
Other agents	8 (7.1)^b	2 (7.1)^c	6 (7.1)^d
Refractory to most recent prior LEN-containing regimen, n (%)^e	84 (75.0)	0	84 (100)
Duration of most recent prior LEN-containing regimen, median (range), months	23.9 (0.4–116.8)	19.8 (0.4–116.8)	24.3 (2.8–99.6)
Most recent prior LEN dose, n (%)
25 mg	35 (31.3)	11 (39.3)	24 (28.6)
20 mg	4 (3.6)	1 (3.6)	3 (3.6)
15 mg	18 (16.1)	2 (7.1)	16 (19.0)
≤10 mg	54 (48.2)	13 (46.4)	41 (48.8)
Missing	1 (0.9)	1 (3.6)	0
Duration of most recent LEN dose, median, months
25 mg	16.6	5.0	24.0
20 mg	43.2	73.9	39.2
15 mg	20.5	1.7	23.1
≤10 mg	25.7	26.5	24.6

BORT: bortezomib; CFZ: carfilzomib; ECOG PS: Eastern Cooperative Oncology Group performance status; IMWG: International Myeloma Working Group; ITT: intention-to-treat; IXA: ixazomib; LEN: lenalidomide; MM: multiple myeloma; NE: not evaluable; R-ISS: revised International Staging System; SCT: stem cell transplant.

^aPatients may have received >1 proteasome inhibitor. ^bIncluding 1 patient who received doxorubicin, 8 patients who received etoposide, and 3 patients who received cisplatin. Patients may have received >1 of these agents. ^cIncluding 2 patients who received etoposide and 1 patient who received cisplatin. Patients may have received >1 of these agents. ^dIncluding 1 patient who received doxorubicin, 6 patients who received etoposide, and 2 patients who received cisplatin. Patients may have received >1 of these agents. ^eRefractoriness to lenalidomide was defined as being refractory to the lenalidomide-containing regimen immediately prior to study entry.

Patient disposition and treatment exposure

With a median follow-up of 28.4 months, 31 patients (27.7%) remained on treatment at data cutoff (March 24, 2020; Table S1). Among the 81 patients (72.3%) who had discontinued treatment, the most common reasons for discontinuation were progressive disease (n = 46), withdrawal by patient (n = 19), AEs (n = 7), transition to another commercially available treatment (n = 2), death (n = 2), and other reasons (n = 3); the reason for discontinuation was missing for 2 patients. Median duration of treatment was 15.9 months with pomalidomide, 13.9 months with dexamethasone, and 16.0 months with daratumumab (median, 17, 15, and 17 cycles of therapy, respectively; Table S2). Median relative dose intensity of pomalidomide, dexamethasone, and daratumumab was 0.9, 0.8, and 1.0, respectively.

Efficacy

ORR was 77.7%, with very good partial response (VGPR) or better reached by 59 patients (52.7%) in the ITT population (Table 2). The median time to response from the first dose date was 1.0 month (range, 0.8–4.8 mo). Responses deepened from the initial analysis, in which 57 patients (50.9%) achieved VGPR or better [16]. With longer follow-up, 29 patients reached VGPR, including 2 patients who shifted from partial response to VGPR. These 2 patients achieved VGPR (best response) in 20.0 and 22.3 months; median duration of treatment was 30.5 months. Three of 30 patients shifted from VGPR to complete response. The time for these patients to achieve complete response (best response) was 7.3, 10.8, and 12.9 months; median duration of treatment was 26.7 months. ORR among patients who had relapsed after lenalidomide (82.1%) and those who were refractory to lenalidomide (76.2%) was similar to that reported in the ITT population. VGPR or better was achieved by 19 patients (67.9%) in the lenalidomide-relapsed and 40 (47.6%) in the lenalidomide-refractory subgroups (p = 0.369). ORR was 78.6% in patients with 1 prior line of therapy (n = 70) and 76.2% in patients with 2 prior lines of therapy (n = 42); the percentage of patients achieving VGPR or better was 60.0% and 40.5%, respectively (p = 0.311). In patients who received prior lenalidomide and a proteasome inhibitor (n = 89), ORR was 78.7%, and 55.1% of patients had VGPR or better. In the EE population (n = 109), ORR was 79.8%; 59 patients (54.1%) achieved VGPR or better. Median duration of response was 29.9 months (95% CI, 17.5-not estimable [NE]) in lenalidomide-refractory patients, 29.9 months (95% CI, 12.0-NE) in patients with 2 prior lines of therapy, and not yet reached in the ITT and EE populations and other subgroups.

Table 2. Response by mIMWG criteria in the ITT population and LEN-relapsed or -refractory subgroups.

Response, n (%)	ITT Population	LEN Relapsed	LEN Refractory
	(N = 112)	(n = 28)	(n = 84)
CBR	96 (85.7)	25 (89.3)	71 (84.5)
ORR	87 (77.7)	23 (82.1)	64 (76.2)
CR	30 (26.8)	12 (42.9)	18 (21.4)
VGPR	29 (25.9)	7 (25.0)	22 (26.2)
PR	28 (25.0)	4 (14.3)	24 (28.6)
MR	9 (8.0)	2 (7.1)	7 (8.3)
SD	8 (7.1)	1 (3.6)	7 (8.3)
PD	5 (4.5)	1 (3.6)	4 (4.8)
NE	2 (1.8)	1 (3.6)	1 (1.2)
Missing	1 (0.9)	0	1 (1.2)

CBR: clinical benefit rate; CR: complete response; ITT: intention-to-treat; LEN: lenalidomide; mIMWG: modified International Myeloma Working Group; MR: minimal response; NE: not estimable; ORR: overall response rate; PD: progressive disease; PR: partial response; SD: stable disease; VGPR: very good partial response.

Median PFS was 30.8 months (95% CI, 19.3-NE) in both the ITT (Figure 1(A)) and EE populations; 1-year PFS rates were 74.1% and 74.8%, respectively. In patients with disease that relapsed after lenalidomide, median PFS was not yet reached (95% CI, 18.2-NE; Figure 1(B)) and the 1-year PFS was 83.2%. In those with lenalidomide-refractory disease, median PFS was 23.7 months (95% CI, 14.0-NE) and the 1-year PFS rate was 70.9%. No significant difference was observed in median PFS between those patients who relapsed after lenalidomide vs those with lenalidomide-refractory disease (p = 0.315). Median PFS was not yet reached (95% CI, 19.3-NE) and 19.4 months (95% CI, 12.7-NE) in patients with 1 and 2 prior lines of therapy, respectively, with no significant difference between these subgroups (p = 0.368) (Figure 1(C)). In patients who had prior exposure to both lenalidomide and a proteasome inhibitor (n = 89), median PFS was not yet reached (95% CI, 18.2-NE), with a 1-year PFS rate of 74.1%. In patients with low (n = 9, International Staging System I/II, absence of t[4;14], 17p13 del, and +1q21, and age <55 y), standard (n = 96; not low or high), and high (n = 7; International Staging System II/III and presence of t[4;14] or 17p13 del) calculated International Myeloma Working Group risk, median PFS was 18.3 months (95% CI, 8.1-NE), not yet reached (95% CI, 19.4-NE), and 10.4 months (95% CI, 1.0–24.1), respectively (1-year PFS rates, 75.0%, 76.9%, and 42.9%). Median PFS was 23.5 months (95% CI, 13.6-NE) in the 79 patients with creatinine clearance ≥60 mL/min (1-year PFS rate, 67.5%) and not yet reached (95% CI, 24.6-NE) in the 19 patients with creatinine clearance <60 mL/min (1-year PFS rate, 88.5%). Overall survival data to estimate the median were not yet mature at the time of this analysis. The 1-, 2-, and 3-year overall survival rates for the ITT population were 90.8%, 72.1%, and 64.7%, respectively.

Figure 1. Kaplan-Meier estimates of PFS in the ITT population (A), by lenalidomide-relapsed or -refractory status (B), and by prior line of therapy (C). ITT: intention-to-treat; NE: not estimable; PFS: progression-free survival.

Safety

At least 1 treatment-emergent AE (TEAE) was experienced by 109 patients (97.3%). Infections (79.5%) and neutropenia (67.0%) were the most common TEAEs. Infusion-related reactions occurred in 34 patients (30.4%) and were predominantly grade 1 or 2, with 1 patient experiencing a grade 3/4 event (Table 3). Neutropenia was the most common hematologic grade 3/4 TEAE (64.3% of patients). Grade 3/4 febrile neutropenia was observed in 9.8% of patients. Other common grade 3/4 hematologic TEAEs were anemia (17.9%), thrombocytopenia (14.3%), and leukopenia (8.9%). Grade 3/4 infections were noted in 36.6% of patients, including 16.1% with grade 3/4 pneumonia. Of the 112 patients enrolled in the study, 103 (92%) of patients used an anti-infective agent as a concomitant medication (73 different antibiotics were taken by 1 or more patients concomitantly with treatment). Infection development appeared to be consistent over the course of the study, with a mean (±SD) of 3.6% ± 2.5% of patients reporting ≥ grade 3 infections per cycle (Figure S1). Pomalidomide was discontinued in 7 patients because of a TEAE, including 2 patients with infection and 1 each with leukopenia and thrombocytopenia, breast cancer, lymphocytic leukemia, basal ganglia infarction, and pulmonary embolism. Nine patients discontinued daratumumab. Except for breast cancer, 6 patients discontinued daratumumab for the same reasons listed for pomalidomide, and 1 patient each discontinued because of febrile neutropenia, hypersensitivity, and an infusion-related reaction.

Table 3. Select grade 3/4 TEAEs in the safety population.

TEAEs, n (%)^a	Safety population
	(N = 112)
≥1 Grade 3/4 TEAEs	109 (97.3)
Grade 3/4 hematologic TEAEs^b
Neutropenia	72 (64.3)
Febrile neutropenia	11 (9.8)
Anemia	20 (17.9)
Thrombocytopenia	16 (14.3)
Leukopenia	10 (8.9)
Grade 3/4 nonhematologic TEAEs^b
Infections and infestations	41 (36.6)
Pneumonia	18 (16.1)
Influenza	5 (4.5)
Sepsis	5 (4.5)
Parainfluenza virus	5 (4.5)
Pneumocystis jirovecii pneumonia	4 (3.6)
Back pain	7 (6.3)
Fatigue	6 (5.4)
Hypertension	6 (5.4)
Insomnia	6 (5.4)
Chronic obstructive pulmonary disease	6 (5.4)
Hyperglycemia	6 (5.4)
Hypokalemia	6 (5.4)
Atrial fibrillation	5 (4.5)
Cataract	5 (4.5)
Dyspnea	5 (4.5)
Diarrhea	4 (3.6)
Hyponatremia	4 (3.6)
Hypophosphatemia	4 (3.6)
Pulmonary embolism	4 (3.6)
Syncope	4 (3.6)

TEAE: treatment-emergent adverse event.

^aTEAE severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.

^bReported in ≥3% of the safety population.

HRQoL

Mean changes from baseline in the EQ-5D index (Figure S1(A)) and visual analog scale health score (Figure S1(B)) were stable through 12 cycles of treatment. At cycle 12, 26.1% and 38.2% of patients achieved minimum clinically important improvements in the EQ-5D index (≥0.1) and the visual analog scale health score (≥6), respectively. Stable EQ-5D index scores were observed across most patient subgroups (Figure 2). Most patients experienced stable scores in the individual EQ-5D domains, with trends toward improvement in usual activities, pain/discomfort, and anxiety/depression (Figure 3).

Figure 2. Mean change from baseline in EQ-5D at cycle 12. ECOG PS: Eastern Cooperative Oncology Group performance status; IMWG: International Myeloma Working Group; LCL: lower confidence limit; LEN: lenalidomide; R-ISS: revised International Staging System; SCT: stem cell transplant; Tx: treatment; UCL: upper confidence limit.

Figure 3. Resolution and deterioration of EQ-5D domains at cycle 12.

Discussion

As novel triplet therapy combinations for RRMM have emerged onto the treatment landscape, choosing the optimal regimen after lenalidomide treatment failure and in early lines of therapy is at the forefront of current clinical decisions. Pomalidomide-based triplet regimens show promising efficacy, safety, and sustainment of QoL in the lenalidomide-relapsed and -refractory disease setting, including in early lines of therapy [14,16,26]. In this updated analysis of the MM-014 phase 2 trial, pomalidomide, dexamethasone, and daratumumab continued to demonstrate efficacy immediately following first- or second-line lenalidomide treatment failure. With a median follow-up of 28.4 months, ORR was 77.7%, with more than half of all patients achieving VGPR or better. The rate of VGPR or better was higher than previously reported, as 5 patients improved their response with longer treatment. Notably, the median PFS of 30.8 months observed is the longest reported to date with a triplet regimen in a patient population with predominately lenalidomide-refractory disease [14,33,37–43].

Although there appeared to be a trend for improved PFS and a better VGPR rate in patients who were relapsed post lenalidomide vs those who were lenalidomide refractory, the differences between these groups were not statistically significant. Similarly, there were no significant differences in PFS or VGPR rate between those patients with 1 prior line or 2 prior lines of therapy.

These data confirm that class-switching away from lenalidomide may not be needed because there is a benefit of maintaining continuous immunomodulation with pomalidomide, particularly when combined with anti-CD38 therapy, immediately following lenalidomide treatment failure. The toxicity findings were consistent with the prior analysis, with 64.3% of patients experiencing grade 3/4 neutropenia and no new safety signals noted. HRQoL parameters were stable or demonstrated trends toward improvement. Given the oral nature of pomalidomide, the availability of a SC formulation of daratumumab and the increased interval of daratumumab infusion after cycle 2, the regimen is convenient to administer. Taken together, these results demonstrate the benefit of the combination of pomalidomide and daratumumab in early lines of therapy in RRMM.

Pomalidomide-based triplet regimens have recently been investigated in other clinical trials of patients with predominately lenalidomide-refractory disease, including the phase 3 APOLLO (pomalidomide, dexamethasone, and subcutaneous daratumumab) [34], OPTIMISMM (pomalidomide, bortezomib, and dexamethasone) [14], and ICARIA-MM (pomalidomide, dexamethasone, and isatuximab) [44] trials and the phase 2 ELOQUENT-3 trial (pomalidomide, dexamethasone, and elotuzumab) [38]. In each of these trials, all patients had prior exposure to lenalidomide, and the proportion of patients with lenalidomide-refractory disease ranged from 69.9% to 92.5%. Median prior lines of therapy ranged from 2 to 3, indicating that these trials included more heavily pretreated patients than the MM-014 cohort B trial. ORR with pomalidomide-based therapy ranged from 53.3% in ELOQUENT-3 to 82.2% in OPTIMISMM. Median PFS ranged from 10.3 months in ELOQUENT-3 to 12.4 months in APOLLO. Subanalyses of the OPTIMISMM and ICARIA-MM trials confirmed the benefit of pomalidomide-based therapy in the second line and in lenalidomide-refractory patients [26,43]. Although cross-trial comparisons must be interpreted cautiously due to differences in trial design and patient populations, the updated findings with pomalidomide, dexamethasone, and daratumumab in cohort B of MM-014 compare favorably and add to the growing body of evidence demonstrating the efficacy of pomalidomide-based therapy in patients after first relapse and with disease that is refractory to lenalidomide.

Until the MM-014 and the APOLLO trials, daratumumab-based triplets in lenalidomide-refractory disease and after first relapse had not been well studied. For the phase 3 CASTOR trial, a median PFS of 27.0 months was reported in 122 patients with 1 prior line of therapy who subsequently received daratumumab, bortezomib, and dexamethasone compared with 7.9 months in patients who received bortezomib and dexamethasone alone (n = 113) [40]. Less than half of the patients (42%) in the CASTOR trial had prior exposure to lenalidomide, and 28% had lenalidomide-refractory disease. In the phase 3 CANDOR trial, median PFS with daratumumab, carfilzomib, and dexamethasone was not reached at a median follow-up of 16.9 months for PFS; 42% had prior exposure to lenalidomide and 33% had lenalidomide-refractory disease [45]. Longer follow-up of the CANDOR trial is needed to determine the extent to which daratumumab, carfilzomib, and dexamethasone will benefit patients with lenalidomide-refractory disease and/or 1 prior line of therapy.

Patient HRQoL is adversely impacted throughout the disease course of MM due to both symptom burden and drug toxicities, particularly with combination regimens and in later lines of therapy as the disease progresses and treatment toxicities accumulate [46]. In the era of novel combination therapies, HRQoL has emerged as a critical treatment goal in the context of promising survival improvements [8]. Importantly, HRQoL was maintained or trended toward improvement with pomalidomide, dexamethasone, and daratumumab, a combination of agents with 3 distinct toxicity profiles. As assessed by mean change in EQ-5D index score and visual analog scale health score through 12 cycles of treatment, HRQoL was stable, including in most assessed subgroups. The EQ-5D domains of usual activities, pain/discomfort, and anxiety/depression demonstrated trends toward improvement by cycle 12. These findings are also in accordance with a recent HRQoL subanalysis of the phase 3 OPTIMISMM trial by Weisel et al. [47]. Between the pomalidomide, bortezomib, and dexamethasone arm and the bortezomib and dexamethasone arm, mean score changes were generally stable for global QoL, physical functioning, fatigue, adverse effects of treatment domains, and EQ-5D-3L index, indicating that the addition of pomalidomide to bortezomib and dexamethasone did not negatively impact QoL.

Patients in cohort B of MM-014 received daratumumab intravenously, but a subcutaneous formulation has recently been approved in the US with indications for both newly diagnosed MM and RRMM [35]. The subcutaneous formulation was used in the phase 3 APOLLO trial, with only 5% of patients experiencing an infusion-related reaction (all grade 1 or 2) [34]. In general, subcutaneous injections may be preferred over intravenous infusions by patients and their providers and are not likely to negatively impact QoL compared with intravenous infusions [48,49].

In conclusion, these updated findings in over 100 patients from cohort B of MM-014 reaffirm the benefit of combination pomalidomide, dexamethasone, and daratumumab in patients with early-line RRMM who have had prior lenalidomide, even in those with lenalidomide-refractory disease at first relapse. The median PFS of 30.8 months observed in this study is the longest reported to date for a triplet regimen in a population of predominately lenalidomide-refractory patients [14,33,37–43]. HRQoL was maintained or trended toward improvement over the course of 12 months. These findings continue to demonstrate that it is not necessary to switch away from the immunomodulatory agent class following lenalidomide treatment failure and support the use of pomalidomide as a foundation for combination therapy in RRMM.

Acknowledgments

The authors thank Faiza Zafar for her support and contributions to the study while employed at Celgene, a Bristol-Myers Squibb Company, and Mihaela Marina of MediTech Media, Ltd, for medical writing assistance in the preparation of this manuscript, which was sponsored by Bristol Myers Squibb.

Data availability statement

BMS policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.

Additional information

Funding

This study was sponsored by Celgene, a Bristol-Myers Squibb Company.