Pomalidomide in multiple myeloma

KEYWORDS:

• Pomalidomide
• multiple myeloma
• therapy
• IMiDs

1. Introduction

The recent introduction of novel agents (thalidomide, lenalidomide, and bortezomib) has impacted favorably on the survival of multiple myeloma (MM) patients. However, prognosis is poor for those who relapse or are refractory (RR) to lenalidomide and bortezomib [1]. Pomalidomide, a third-generation IMiD, was approved in 2013 by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in combination with low-dose dexamethasone for MM patients who have received at least two prior therapies, including both lenalidomide and bortezomib, and whose disease progressed after the last treatment. Herein, we review the current knowledge regarding the clinical use of pomalidomide in MM (Tables 1 and 2).

Table 1. Pomalidomide phase I and, I and II trials in multiple myeloma.

Authors	Population	No of patients	Schedule	ORR	Median PFS
Phase I tials
Schey et al. [2]	Relapsed/refractory	24	MTD Pom 2 mg 28/28	54%	39 weeks
Streetly et al. [3]	Relapsed	20	MTD Pom 5 mg every other day ± dexa	50%	10.5 months
Richardson et al. [4]	Relapsed/refractory	38	MTD Pom 4 mg 21/28 ± dexa	21%	4.6 months
Shah et al. [5]	Relapsed/refractory	32	MTD carfilzomib 20/27 mg/m^2 days 1, 2, 8, 9, 15, 16, pom 4 mg 21/28, dexa 40 mg weekly	50%	7.2 months
Richardson et al. [6]	Relapsed/refractory to lena	34	MTD pom 4 mg on days 1–14, bort 1.3 mg/m^2 on days 1, 4, 8, 11, and dexa 20 mg (10 mg for patients aged >75 years) on days 1, 2, 4, 5, 8, 9, 11, and 12	65%	Not reported
Shah et al. [7]	Relapsed/refractory	31	MTD oprozomib 210 mg on days 1, 2, 8, 9, 15, 16, 22, 23, pom 4 mg 21/28, dexa 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23	57%	Not reported
Chari et al. [8]	Relapsed/refractory	77	Daratumumab 16 mg/kg weekly for 2 cycles, then every 2 weeks for 4 cycles, and every 4 weeks until progression, pom 4 mg 21/28, dexa 40 mg weekly (20 mg for patients >75 years).	58.5%	Not reported
Phase I and II trials
Larocca et al. [9]	Relapsed/refractory to lena	24 (phase I) 55 (phase II)	MTD Pom 2.5 mg/day 28/28, cyclo at 50 mg every other day, prednisone at 50 mg every other day	51%	10.4 months
Lacy et al. [10]	Relapsed/refractory to lena	9 (phase I) 47 (phase II)	MTD Poma 4 mg 21/28 + bortezomib 1.3 mg/m^2 on days 1, 8, 15, 22 IV or SQ and + dexa 40 mg weekly	81% (44 evaluable patients)	17.7 months
Voorhees et al. [11]	Refractory to lena and PI	17	MTD Poma 4 mg 21/28 + ixazomib 4 mg on days 1,8,15 + dexa 40 mg weekly	62% (13 evaluable patients)	Not reported

Bort: bortezomib; Cyclo: cyclophosphamide; dexa: dexamethasone; IV: intavenously; lena: lenalidomide; MTD: maximum tolerated dose; ORR: overall response rate; PI: proteasome inhibitor; PFS: progression free survival; Pom: pomalidomide; SQ: subcutaneously.

Table 2. Pomalidomide phase II and III trials in multiple myeloma.

Authors	Disease status	No. of patients	Schedule	ORR	Median PFS
Phase II trials
Richardson et al. [12]	Relapsed/refractory	221 113	Pom 4 mg 21/28 + dexa 40 mg weekly versus Pom 4 mg 21/28	33% 18%	4.2 months 2.7 months
Lacy et al. [13]	Refractory to lena and bort	35 35	Pom 2 mg 28/28 + dexa 40 mg weekly versus Pom 4 mg 28/28+ dexa 40 mg weekly	25% 29%	6.5 months 3.2 months
Leleu et al. [14]	Refractory to lena and bort	43 41	Pom 4 mg 21/28 + dexa 40 mg weekly versus Pom 4 mg 28/28 + dexa 40 mg weekly	35% 34%	TTP: 5.8 months 4.7 months
Baz et al. [15]	Relapsed/refractory to lena	36 34	Pom 4 mg 21/28 + dexa 40 mg weekly versus Pom 4 mg 21/28 + dexa 40 mg weekly + Cyclo 400 mg on days 1, 8, 15	38.9% 64.7%	4.4 months 9.5 months
Badros et al. [16]	Relapsed/refractory	24	Pom 4 mg 21/28 + dexa 40 mg weekly + pembrolizumab 200 mg IV every 2 weeks	36.4%	Not reported
Phase III trials
San Miguel et al. [17]	Relapsed/refractory who have failed bort and lena	302 153	Pom 4 mg 21/28 + dexa 20 mg vs. dexa 40 mg on days 1–4, 9–12, 17–20	31% 10%	4 months 1.9 months
Dimopoulos et al. [18]	Relapsed/refractory who have failed bort and lena	682	Pomalidomide 4 mg 21/28 + dexa 40 mg (20 mg for patients aged >75 years) on days 1, 8, 15, and 22	32.6%	4.6 months

Bort: bortezomib; Cyclo: cyclophosphamide; dexa: dexamethasone; lena: lenalidomide; ORR: overall response rate; PFS: progression free survival; Pom: pomalidomide; TTP: time to progression.

2. Mechanism of action

The glutamic acid derivative pomalidomide (4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione) is a novel third-generation IMiD that is more potent and less toxic than thalidomide and lenalidomide. Pomalidomide is rapidly absorbed orally and predominantly undergoes liver metabolism [1].

Pomalidomide inhibits the cell cycle and induces apoptosis in MM cells. Pomalidomide treatment downregulates pro-inflammatory cytokines, VEGF (an important prosurvival factor for MM cells), and enhances natural killer cell cytotoxicity. Cereblon, a molecular target of IMiDs [1], is expressed at very low levels in plasma cells from patients resistant to IMiDs (including pomalidomide). Pomalidomide through the downregulation of the transcription factor PU.1 allows reduction of bone resorption [1].

3. Phase I clinical studies

Three phase I studies, investigating the maximum tolerated dose (MTD) of pomalidomide, were conducted in relapsed/refractory MM (RRMM) patients [2–4]. In the first trial, pomalidomide was tested using a continuous scheme (daily for 28 days). The MTD was 2 mg per day. Dose-limiting toxicities (DLTs) were neutropenia and deep vein thrombosis (DVT) [2]. The second study explored an alternate day escalation-schedule of pomalidomide (1, 2, 5, and 10 mg). The MTD was 5 mg. DLTs were neutropenia [3]. Lastly, the MM-002 trial investigated a dose-escalation of pomalidomide given for 21 of 28 days per cycle. The MTD was 4 mg/day and the overall response rate (ORR) was 21% [5]. Again DLTs included neutropenia. In the three studies, ORR ranged between 21% and 54% [4].

The pomalidomide+carfilzomib+dexamethasone combination was assessed in RRMM patients in a phase I dose-escalation study. The observed MTD was pomalidomide 4 mg daily 21/28, carfilzomib 20/27 mg/m² on days 1, 2, 8, 9, 15, 16 and dexamethasone 40 mg/week. Hematologic adverse events (AEs) occurred in >60% of patients. The ORR was 50% [5].

The phase I trial MM-005 showed that the pomalidomide+bortezomib+low-dose dexamethasone combination in MM patients RR to lenalidomide is safe and effective. Indeed, no DLTs were reported at the maximum planned dose (pomalidomide 4 mg on days 1–14, bortezomib 1.3 mg/m² on days 1, 4, 8, 11 and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12). There were no reports of grade 3–4 peripheral neuropathy. The ORR of the 34 patients enrolled was 65% [6].

A phase Ib study evaluated the safety and the efficacy of the combination of oprozomib, an oral, irreversible proteasome inhibitor, with pomalidomide+dexamethasone in 31 RRMM patients. Preliminary results showed that this triplet has encouraging antimyeloma activity and is generally well tolerated; the most common grade 3–4 AEs were anemia and diarrhea [7].

Finally, a phase Ib study evaluated the addition of the anti-CD38 daratumumab to pomalidomide+dexamethasone in 98 RRMM patients. The combination was well tolerated with no additional toxicities with the exception of daratumumab-related infusion reactions. The ORR was 71% [8].

4. Phase I and II clinical studies

A phase I and II study evaluated the safety and efficacy of the pomalidomide+cyclophosphamide+prednisone combination in lenalidomide RRMM. The MTD of pomalidomide combined with cyclophosphamide and prednisone (50 mg each every other day) was 2.5 mg daily 21/28. Toxicity, including 42% severe neutropenia, was comparable with that observed with pomalidomide+dexamethasone alone. In the phase II study, the ORR was 51% with a median PFS of 10.4 months [9].

A phase I/II trial evaluated safety and efficacy of the pomalidomide+bortezomib+dexamethasone (PVD) combination in patients RR to lenalidomide MM. The MTD consisted of pomalidomide 4 mg on days 1–21, bortezomib 1.3 mg/m² on days 1, 8, 15, and 22 intravenously or subcutaneously, and dexamethasone 40 mg on days 1, 8, 15, and 22 given every 28 days. Phase II of the trial showed that PVD was highly effective for RRMM patients with an ORR>80%. Toxicities were manageable, consisting of mild cytopenias with no significant neuropathy or DVT [10].

Another phase I and II study explored the safety and efficacy of the pomalidomide-dexamethasone and ixazomib combination in MM patients RR to lenalidomide and proteasome inhibitor. Preliminary results in the 17 evaluable patients showed that this combination has an acceptable toxicity profile associated with encouraging efficacy [11].

5. Phase II clinical studies

A large randomized phase II study showed that pomalidomide (4 mg 21/28) + low-dose dexamethasone significantly improved ORR and PFS over pomalidomide alone in RRMM patients. The most common severe AEs were neutropenia, anemia, thrombocytopenia, and fatigue [12].

A comparison of two sequential phase II trials showed pomalidomide given continuously at the dosage of 4 mg was not superior to pomalidomide given at the dosage of 2 mg in MM patients refractory to bortezomib and lenalidomide [13].

The Intergroupe Francophone du Myélome (IFM) conducted a phase II randomized study comparing discontinuous or continuous pomalidomide+dexamethasone schedules (pomalidomide 4 mg on days 1–21 every 28 days versus pomalidomide 4 mg on days 1–28) in 84 refractory to bortezomib and lenalidomide MM patients. The ORR was 35% with a median PFS of 5.4 months. No significant differences in efficacy were observed. The discontinuous schedule was selected as the standard regimen for pomalidomide administration [14].

A randomized, multicenter phase II study evaluated the pomalidomide+dexamethasone+cyclophosphamide combination versus pomalidomide+dexamethasone in RR to lenalidomide MM patients. The triple combination resulted in a superior ORR and PFS compared with pomalidomide+dexamethasone, with comparable toxicity [15].

Finally, in an ongoing single arm, phase II study 24 RRMM patients received pomalidomide+dexamethasone associated with the anti-PD-1 monoclonal antibody pembrolizumab. Preliminary data showed that this triple combination has promising therapeutic activity and an acceptable safety profile [16].

6. Phase III studies

The MM-003 trial evaluated the clinical benefit of pomalidomide (4 mg on days 1–21 of 28-day cycles) and low-dose dexamethasone versus high-dose dexamethasone in 455 RRMM patients failing both bortezomib and lenalidomide therapy [17]. Patients treated with pomalidomide+dexamethasone showed a higher ORR (31% versus 10%), and longer median PFS (4 versus 1.9 months) and OS (12.7 versus 8.1 months) than patients treated with high-dose dexamethasone. The OS benefit of pomalidomide+dexamethasone was probably underestimated given the protocol allowed the crossover of progressive patients from the high-dose dexamethasone arm to pomalidomide+dexamethasone arm. Furthermore, the PFS benefit remained consistent regardless of prior therapies or refractory status. A recent landmark analysis of this study showed pomalidomide+dexamethasone is an effective treatment option also for patients who achieved a stable disease (SD) as the best response. Indeed, patients with SD at the start of cycles 3, 5 and 7 showed no significant difference in OS than responding patients at the same time points [19].

The STRATUS study assessed safety and efficacy of pomalidomide (4 mg daily 21/28) + low-dose dexamethasone in the largest cohort to date of RRMM patients (N = 682) failing treatment with bortezomib and lenalidomide. The ORR was 32.6%; the median PFS and OS were 4.6 months and 11.9 months, respectively [18].

7. Patients with renal or hepatic impairment

A pooled analysis of three clinical trials (MM-002, MM-003, MM-010) showed that a combination of pomalidomide+low-dose dexamethasone is safe and well tolerated in MM patients with moderate renal failure. Indeed, discontinuations, dose modifications, and AEs were comparable in patients with moderate renal impairment and in those with normal renal function. Moreover, ORR and PFS were analogous in both subgroups. Nevertheless, patients with moderate renal impairment showed a significantly lower OS than patients without renal impairment [20]. Preliminary data from the MM013 trial showed that pomalidomide+low-dose dexamethasone is safe and effective in patients with severe renal failure, including those on dialysis [21].

Since hepatic impairment has a modest effect on the pharmacokinetics of pomalidomide, no adjustment of the starting dose is required for patients with hepatic impairment, although these patients should be carefully monitored.

8. Patients with extramedullary disease (EMD)

A 31% ORR has been observed in relapsed MM patients with EMD treated with pomalidomide+low-dose dexamethasone [22]. Since animal studies showed that pomalidomide crosses the blood–brain barrier, this drug should be considered for the treatment of patients with CNS involvement.

9. Patients with high-risk cytogenetics

A phase II study, conducted by the IFM group on 50 MM patients with adverse cytogenetics [del(17p) and/or t(4;14)], showed that the combination pomalidomide+dexamethasone is safe and effective for cases with del(17p). However, it seems that this combination is less effective in patients with t(4;14) [23]. A subanalysis of the MM-003 trial confirmed the favorable impact of pomalidomide+dexamethasone in patients with del(17p) [17].

10. Safety

Major toxicity due to pomalidomide therapy in MM patients is hematological [17,18]. Severe neutropenia has been observed in roughly 50% of patients. Anemia and thrombocytopenia were reported in 50% and 33%, respectively. Pneumonia was recorded in 11–13%. Nonhematological toxicity is less frequent with fatigue being the most commonly reported AE, but is generally mild to moderate. Systematic thromboprophylaxis is mandatory for all patients treated with pomalidomide. Although low-dose aspirin is generally recommended, patients at high-risk of DVT should receive low-molecular-weight heparin or vitamin K antagonists. Using thromboprophylaxis DVT is a rare event (<5% of cases) [17,18].

11. Expert opinion

Pomalidomide is a third-generation IMiD shown to be a safe and effective drug for RRMM patients previously treated with bortezomib and lenalidomide. In this setting pomalidomide in combination with dexamethasone achieves a response in roughly 30% of cases with a median PFS of nearly 5 months. Furthermore, the combination of pomalidomide and dexamethasone is also effective in high-risk myeloma, including patients with del(17p). For renally impaired patients, accumulating data confirm that pomalidomide dose adjustments are not necessary. To improve the response rate and the duration of response, pomalidomide+dexamethasone is currently being evaluated in triple combinations with an alkylating agent (cyclophosphamide) and a proteasome inhibitor (carfilzomib) showing promising efficacy results and manageable toxicity. Further studies and longer follow-up are needed to determine the best combination strategies in relapsed MM patients.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded