Introduction

The introduction of immunomodulatory agents and proteasome inhibitors (PIs) has transformed multiple myeloma (MM) therapy over the past decades, with significant improvement in response rates, progression-free survival (PFS) and overall survival (OS).1, 2 However, relapse is inevitable in almost all patients, and recurrence of MM is typically more aggressive with each subsequent relapse, justifying the development of new combinations mainly in MM-refractory disease.3

In preclinical studies, the immunomodulatory agents thalidomide and lenalidomide were each shown to potentiate the activity of bortezomib in combination with dexamethasone.4, 5 Results from clinical studies confirmed the antimyeloma activity of the combination of lenalidomide and bortezomib in patients with MM.6, Table 1).

Table 1 Baseline patient demographic, disease and treatment characteristics
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Of the study patients, 59 were male and 56 and 44% had an Eastern Cooperative Oncology Group performance status of 0 and 1, respectively (Table 1). Median patient age was 58.5 years (range, 36–76 years). The median time from initial diagnosis was 3.4 years (range, 0.7–12.1 years); in the MTD groups with IV bortezomib and MTD groups with SC bortezomib, it was 4.2 years (range, 1.5–8.2 years) and 2.0 years (range, 0.7–9.1 years), respectively. All patients were refractory to lenalidomide, and all were exposed to a prior PI (97% bortezomib; 6% ixazomib). All patients had progressive disease after the last myeloma regimen, and the majority (91.2%) had progressed ⩽60 days after the last regimen. Twenty-three patients (68%) underwent prior stem cell transplant (SCT). The median number of prior lines of antimyeloma therapy received was 2 (range, 1–4). Compared with the IV bortezomib cohort, fewer patients in the SC bortezomib cohort received ⩾2 prior lines of antimyeloma treatment and prior transplant. At screening, 14 patients had peripheral sensory neuropathy, 11 of whom had a grade 1 event.

At the time of data cutoff (2 April 2015), all patients had discontinued study treatment (Table 2). The most common reason for treatment discontinuation was PD in 22 patients (65%): 9 (75%) in the dose-escalation cohort and 6 (60%) and 7 (58%) in the MTD cohorts with IV and SC bortezomib, respectively. One patient discontinued pomalidomide treatment due to metastatic pancreatic cancer diagnosed 1.1 months after study treatment initiation, and 3 patients discontinued because they went on to receive SCT. As of November 2016, 13 patients are in long-term follow-up.

Table 2 Patient disposition
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Treatment exposure and safety

The median duration of treatment was 6.2 months (range, 1.2–27.6 months), and the median number of treatment cycles received was 9 (range, 2–36) for all treated patients (Table 3). Patients in the MTD IV bortezomib cohort received a median of 11 (range, 2–19) and patients in the MTD SC bortezomib cohort received a median of 8 (range, 3–15) cycles of treatment. The median relative dose intensity was 0.9 for pomalidomide throughout the study and 0.9 for bortezomib during the first 8 cycles of treatment. The incidences of dose interruptions and reductions due to TEAEs were 79 and 38% for pomalidomide and 74 and 44% for bortezomib, respectively. The number of dose interruptions was similar regardless of method of bortezomib administration. However, the number of reductions of pomalidomide and bortezomib dose due to TEAEs was slightly less frequent in the IV (40 and 30%, respectively) vs SC (50 and 58%, respectively) bortezomib cohort. Neutropenia was the most common TEAE leading to pomalidomide dose reductions (9%). Infections (47%), neutropenia (26%), pneumonia (9%), peripheral sensory neuropathy (9%), dizziness (9%) and fatigue (9%) were common TEAEs (⩾3 patients) leading to pomalidomide dose interruptions. Peripheral sensory neuropathy (12%) was the most common TEAE (⩾3 patients) leading to bortezomib dose reductions, whereas interruptions were primarily due to infections (44%), neutropenia (21%), pneumonia (12%) and fatigue (9%).

Table 3 Treatment exposure, dose interruptions and dose reductions
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All of the 34 patients included in the safety population had ⩾1 TEAE; 29 (85%) had ⩾1 grade 3/4 TEAE (Table 4). Neutropenia and thrombocytopenia were the most common grade 3/4 TEAEs. The incidence of these events was higher in the IV bortezomib cohort (80 and 40%, respectively) compared with the SC bortezomib cohort (25 and 17%, respectively). Eighteen patients (53%) had treatment-emergent peripheral neuropathy, with 6 out of 12 (50%) in the escalation cohort, 3 out of 10 (30%) in the IV bortezomib cohort and 9 out of 12 (75%) in the SC bortezomib cohort; none of the events were grade 3/4. Treatment-emergent deep vein thrombosis was uncommon (6%); no patients experienced a grade 3/4 event. One death occurred during treatment cycle 3 as a result of cardiac arrest unrelated to study drugs.

Table 4 Grade 3/4 TEAEs occurring in ⩾5% of all patients
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Efficacy

All 34 patients were evaluable for tumor response (Figure 2). Disease control with at least stable disease was reported for all patients. The ORR (better than or equal to PR) for all treated patients was 65%. One patient in the MTD IV bortezomib cohort had a stringent complete response (sCR) and 2 patients in the MTD SC bortezomib cohort had a CR. Patients with sCR/CR received 1 or 2 prior lines of therapy (Table 5). ORR was 59% for all patients treated at the MTD: 70 and 50% in the IV and SC bortezomib cohorts, respectively. For all responding patients (n=22), the median TTR was 1.0 months (range, 0.7–5.1 months) and the median DOR was 7.4 months (95% CI, 4.4–9.6 months). This was similar for the patients treated at the MTD: median TTR of 0.9 months (range, 0.7–3.1 months) and median DOR of 7.4 months (95% CI, 4.1-not estimable).

Figure 2
figure 2

Response outcomes. All treated patients were evaluated for response (better than or equal to PR). TTR and DOR were reported for patients who achieved response. BORT, bortezomib; CR, complete response; sCR, stringent complete response; VGPR, very good PR.

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Table 5 Response outcomes by number of prior lines of therapy
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Discussion

Preclinical and clinical studies have proven the clinical benefit of combination therapy with an immunomodulatory agent and a PI for the treatment of patients with RRMM.4, 5, 6, 7 In this phase 1 trial, we demonstrated that triple therapy with pomalidomide, bortezomib and LoDEX was highly active, resulting in an ORR of 65% and disease control in 100%, despite all patients being refractory to lenalidomide and nearly all having prior exposure to bortezomib. Responses were durable, lasting a median of 7.4 months. The MTD of the combination regimen was established at the MPD of pomalidomide 4 mg, IV or SC bortezomib 1.3 mg/m2 and LoDEX 20 mg (10 mg for patients aged >75 years). At this therapeutic dose level, 3 patients achieved sCR/CR.

The regimen of pomalidomide, bortezomib and LoDEX was well tolerated, and toxicities proved manageable, regardless of mode of bortezomib administration. Patients were able to receive a median of 9 cycles of therapy, and no patients discontinued treatment due to a treatment-related event. The incidences of dose interruptions and reductions for pomalidomide and bortezomib were consistent with those of prior studies.13, 19 There were also no reports of grade 3/4 peripheral neuropathy, deep vein thrombosis or other toxicities sometimes associated with immunomodulatory agents and/or PIs.10, 21, 23, 24 Consistent with the findings of the SC vs IV bortezomib phase 3 noninferiority trial, grade 3/4 TEAEs were less frequent with SC vs IV bortezomib administration.19 However, this finding may have been influenced by fewer patients receiving ⩾2 prior lines of antimyeloma treatment and prior transplant in the SC vs IV bortezomib cohorts. Patients in the SC cohort also received fewer cycles of treatment, which may have influenced the incidence of TEAEs. The finding that patients received fewer cycles of SC vs IV bortezomib may be due to the timing of when patients discontinued treatment for SCT; 1 patient in the IV group and 2 patients in the SC group went on to receive SCTs.

In studies of pomalidomide plus LoDEX, approximately one-third of patients with advanced RRMM achieved a tumor response (better than or equal to PR).25 As demonstrated in this trial and others, the addition of PIs to IMiD combinations has the potential to lead to deeper and more durable responses.26, 27, 28, 29, 30 Preliminary results of a phase 1/2 trial of once-weekly bortezomib with pomalidomide and LoDEX demonstrated a response rate of 85, with 19 and 45% of patients achieving sCR/CR and at least very good PR, respectively.29 Responses were durable, lasting a median of 13.7 months. This patient population differed somewhat because <30% of patients had refractory disease and just over one-half had prior exposure to bortezomib. In another phase 1 trial with the PI carfilzomib, given in combination with pomalidomide and LoDEX, the ORR was 50%, with a clinical benefit rate of 66%.28 Similar to data from the phase 1 trial presented here, all patients were refractory to lenalidomide, although the patients were more heavily pretreated (median 6 prior regimens (range, 2–12)) and nearly all were refractory to bortezomib. Results of the phase 1 portion of the Alliance A061202 study of an oral PI, ixazomib, given in combination with pomalidomide and LoDEX, demonstrated an ORR of 55% in patients with RRMM who had received a median of 3 prior lines of therapy (range, 2–10) and who were refractory to lenalidomide and a PI.26

Pomalidomide-based triple therapy combination regimens with other drug classes have also demonstrated high antimyeloma activity in patients with RRMM, including the triple therapy regimens of pomalidomide plus dexamethasone in combination with cyclophosphamide (ORR, 65–67%),31, 32 the monoclonal antibodies anti-CD38 (daratumumab; ORR, 71%)33 and anti–programmed cell death protein 1 (pembrolizumab; ORR, 60%)34 and a histone deacetylase inhibitor (ACY-241; ORR, 46%).35 Taken together, these studies demonstrate the utility of pomalidomide and dexamethasone as a platform for combining novel agents.

In conclusion, the MTD of pomalidomide 4 mg, bortezomib 1.3 mg/m2 and LoDEX 20 mg (10 mg for patients aged >75 years) was well tolerated and highly active in patients with RRMM who were refractory to lenalidomide and had been previously exposed to bortezomib. These findings support further evaluation in clinical trials and suggest that pomalidomide, bortezomib and LoDEX may be an important new treatment option for patients with RRMM. A large randomized, multicenter, international, phase 3 trial, MM-007 (OPTIMISMM), to confirm these findings is currently ongoing and is close to completing enrollment (ClinicalTrials.gov NCT01734928).

Future directions include the addition of other novel agents to this platform, such as the monoclonal antibodies discussed previously, as well as histone deacetylase inhibitors and other promising next-generation small molecules.36, 37, 38