Pomalidomide | Oga Signal

Pomalidomide, Cyclophosphamide, and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma: Real-World Analysis of the Pethema-GEM Experience

Paula Rodriguez-Otero,1 Maialen Sirvent,2 Ana Pilar González-Rodríguez,3 Esperanza Lavilla,4 Alfonso García de Coca,5 José María Arguiñano,6 Josep M. Martí,7 Valentin Cabañas,8 Cristina Motlló,9 Erik de Cabo,10 Cristina Encinas,11 Ilda Murillo,12 Jose Ángel Hernández-Rivas,13 Ernesto Pérez-Persona,14 Felipe Casado,15 Antonia Sampol,16 Ricarda García,17 María Jesús Blanchard,18 Magdalena Anguita,19 Ana Paz Lafuente,20 Belén Iñigo,21 Aurelio López,22 Paz Ribas,23 Mario Arnao,24 Roberto Maldonado,25 Joan Bladé,26 María Victoria Mateos,27 Juan José Lahuerta,28 Jesús F. San Miguel1

Abstract

Treatment of relapsed/refractory multiple myeloma (RRMM) is highly challenging. We analyzed the efficacy and safety of pomalidomide, cyclophosphamide, and dexamethasone (PomCiDex) in a real-world RRMM population. Median progression-free and overall survival were 7.6 and 12.6 months, respectively, which compares favorably with other triplets in the same setting. PomCiDex remains a manageable, cost-effective, and all-oral triplet combination for RRMM.
Introduction: Treatment of relapsed/refractory multiple myeloma (RRMM) is highly challenging, especially for patients with disease refractory to initial therapy, and in particular for disease developing refractoriness to lenalidomide. Indeed, with currently approved treatments, median progression-free survival (PFS) in the lenalidomiderefractory setting is less than 10 months, reflecting the difficulty in treating this patient population. Pomalidomide is a second-generation immunomodulatory drug that has shown activity in lenalidomide-refractory disease in the setting of different combinations.
Patients and Methods: A real-world study was conducted by the Spanish Myeloma group in a cohort of patients with RRMM treated with pomalidomide, cyclophosphamide, and dexamethasone (PomCiDex). One hundred patientswere treated with amedian of 3 prior linesof therapy.
Results: Overall response rate was 39%, with a clinical benefit rate of 93%. Median PFS was 7.6 months; median overall survival (OS) was 12.6 months. Median PFS and OS survival were consistent across the different subgroups analyzed. Prolonged PFS and OS were found in patients with responsive disease.
Conclusion: Our results compared favorably with those obtained with different pomalidomide-based combinations in a similar patient population. PomCiDex remains a manageable, cost-effective, and all-oral triplet combination for RRMM patients.

Keyword: Lenalidomide-refractoriness, Pomalidomide, Real-world study, Refractory multiple myeloma, Triplet therapy

Introduction

Treatment of relapsed/refractory multiple myeloma (RRMM) is highly challenging, in particular for patients with disease that becomes refractory to initial treatments that include proteasome inhibitors (PIs) and immunomodulatory drugs (IMIDs). Indeed, outcomes for patients with disease refractory to a PI and an IMID agent remain very poor, with overall response rate (ORR) of less than 30%, progression-free survival (PFS) between 4 and 6 months, and overall survival (OS) ranging from 7 to 11 months.1 Moreover, as treatment patterns evolve and lenalidomide is incorporated in frontline therapy, the proportion of patients with disease becoming refractory to lenalidomide in earlier lines of treatment is increasing, and it has been shown that this difficult-to-treat population has a median PFS of less than 10 months, even upon treatment with recently approved combinations such as daratumumab/bortezomib/ dexamethasone, carfilzomib/dexamethasone (Kd), or pomalidomide/bortezomib/dexamethasone.2,3
Pomalidomide is a second-generation IMID compound pharmacologically distinct from lenalidomide in several ways.3 It has a higher potency against cereblon, different substrate degradation kinetics, and a distinct gene-activation profile leading to differentiated antitumor and immunostimulating properties.3-7 Indeed, pomalidomide has greater direct antiproliferative effects on myeloma tumor cells compared to lenalidomide and is active in the context of lenalidomide-resistant cell lines and animal models.4,6 In addition, it has demonstrated clinical efficacy in combination with low-dose dexamethasone in a population of patients with doublerefractory RRMM.8 In the randomized phase 3 MM-003 trial, RRMM patients who had received at least 2 prior lines of therapy and had disease refractory or intolerant to both PIs and IMIDs were included. Pomalidomide in combination with low-dose dexamethasone was compared to high-dose dexamethasone and showed significantly better ORR (31% vs 10%, P< .0001) and longer PFS (3.8 vs 1.9 months; hazard ratio [HR] 0.41, P< .0001) and OS (11.9 vs 7.8 months; HR 0.53, P¼ .0002). These results led to the worldwide approval of pomalidomide in combination with lowdose dexamethasone (Pd) for the treatment of RRMM in patients who had received at least 2 prior therapies including lenalidomide and a PI and whose disease exhibited refractoriness to the last treatment.
In parallel, and in order to improve the efficacy of this regimen, Pd has been combined with several agents including bortezomib (PVd),3 elotuzumab (EPd),9 and anti-CD38 monoclonal antibodies (daratumumab10 [DPd] and isatuximab11 [IsaPd]), resulting in improved ORR and PFS. However, some of these schemes are prohibitively expensive, particularly in countries with limited resources, and therefore other combinations are needed.
Alkylating agents (including melphalan and cyclophosphamide) continue to represent standard-of-care options for patients with multiple myeloma and are widely used in different countries.12 In a recent phase 1/2 study that evaluated retreatment with lenalidomide in combination with continuous oral low-dose cyclophosphamide and prednisone in a population of patients with lenalidomiderefractory disease, the ORR was 67% with a median PFS of 12.1 months and median OS of 29 months, thus indicating that cyclophosphamide might be able to overcome resistance to lenalidomide in the clinical setting.13 Likewise, in another phase 2 study that included 60 patients with RRMM and treated with pomalidomide and dexamethasone, the addition of cyclophosphamide at the moment of disease progression or suboptimal response was able to rescue a substantial proportion of patients.14
On the basis of these data, in January 2015 in the context of the Spanish Myeloma Group, we proposed a clinical care guideline for the treatment of RRMM, with patients considered candidates for pomalidomide therapy. Pomalidomide was provided in combination with continuous low-dose cyclophosphamide and dexamethasone (PomCiDex). The aims of the guideline were to provide uniformity in the management of patients with relapsed disease who were candidates to receive pomalidomide; and to improve the ORR, quality of the response, and PFS using a convenient and cheap oral delivery scheme.
Here we report the first analysis of 100 patients included in a multicenter, real-world PETHEMA study (GEM-POMCIDEX) based on the PomCiDex regimen for RRMM (funded by Celgene; ClinicalTrials.gov NCT03477643).

Patients and Methods

The current analysis was designed for RRMM patients treated in Spain according the GEM-POMCIDEX clinical care guideline. A total of 162 centers were contacted, and 27 decided to participate in the present study and reported patients with PomCiDex. Between April 27, 2018, and December 20, 2019, a total of 108 patients were included. Eight patients were excluded because of screening failures, so an analysis of the remaining 100 patients is provided here. The eligible population included adult patients with histologically confirmed multiple myeloma who had received at least 2 prior lines of therapy including a PI and an immunomodulatory drug, and had experienced disease progression while receiving the last regimen.
All patients received pomalidomide at a dose of 4 mg on days 1 through 21 of 28-day cycles, cyclophosphamide 50 mg per day on days 1 through 21 of 28-day cycles, and dexamethasone 40 mg weekly (or 20 mg in patients aged 75 years or with severe comorbidities). Treatment was continued until disease progression, unacceptable toxicity, or patient or physician decision. All patients received antithrombotic prophylaxis on the basis of their risk stratification with low-dose aspirin or low-molecular-weight heparin. Other prophylaxis was provided according to investigator discretion.
In all patients, data regarding disease features at diagnosis (cytogenetic abnormalities, International Staging System score, and Revised International Staging System score), prior therapies, doses and duration of prior regimen, best response to every line of therapy, date of relapse, and refractoriness to prior drugs were collected. Data on dose, duration of treatment, dose modifications and interruptions, treatment-related adverse events (AEs), response, and progression were collected for every 28-day cycle during the PomCiDex regimen. We used the International Myeloma Working
Group criteria for the definition of refractoriness, response, and time to event. The study was performed following the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. The study was classified as an observational retrospective study by the Spanish Medical Agency and was approved by the ethical committee of 12 de Octubre Hospital.
Data were collected retrospectively 3 months after center activation. All analyses were performed on an intent-to-treat basis. Comparisons for categorical variables among different groups were made by the chi-square test, with the Fisher exact test used when appropriate. Time to event (progression, death) was calculated from the date of the first dose of pomalidomide. PFS and OS curves were plotted with the Kaplan-Meier method, and comparisons among groups were made using the Cox proportional hazard model. Multivariate analysis was performed by Cox proportional hazard models. All statistical analyses were performed by Stata 15 software (StataCorp, College Station, TX). Data cutoff was January 13, 2020. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Results

Between April 26, 2018, and December 20, 2019, a total of 108 patients were included. The median age of the patients included in this analysis was 71 years (range, 40-89 years). Baseline patient characteristics are presented in Table 1. Median number of prior lines of therapy was 3 (range, 1-9); 39.4% had received prior autologous stem-cell transplantation, 64% had disease refractory to PIs, 89% had disease refractory to lenalidomide, and 60% had double-refractory disease—that is, refractory to both a PI and IMIDs. Eighty-two percent of the patients had disease refractory to the last line of therapy, and 58% received lenalidomide as the immediate line before initiating PomCiDex therapy. Extramedullary disease (EMD) was detected in 24 patients at inclusion. Fluorescence in-situ hybridization analysis results were available for 56 patients at the moment of study entry. Only 5 patients had highrisk cytogenetic abnormalities, which we defined as the presence of del(17p), t(4;14), or t(14;16).
The median time from diagnosis to start of PomCiDex regimen was 48.6 months (95% confidence interval [CI] 40.2-60). The median number of PomCiDex cycles was 6.5 (range, 1-39). Overall, 95 patients discontinued therapy. The main reason for discontinuation of PomCiDex was disease progression (56%). Only 2 patients discontinued treatment because of treatment-related AEs. Reasons for treatment discontinuation were initiation of new therapy and physician decision in 20 and 17 patients, respectively.
Thirty-nine patients (39%) experienced at least a partial response (PR) after PomCiDex therapy, including 7% of complete response/ stringent complete response, 12% very good PR, and 20% PR.
Clinical benefit rate (defined as stable disease or better) was observed in 93% of the patients. ORR was consistent across the different subgroups analyzed in the univariate analysis (Figure 1). Indeed, ORR in patients with lenalidomide-refractory disease after any prior line of therapy was comparable (38.2%) with that of the overall population (P ¼ .642), and the same was found in patients with double-refractory disease (ORR 21%, P¼ .390). Similarly, ORR was maintained regardless of the duration of previous lenalidomide therapy (< 12 vs 12 months). Only 2 groups showed significantly lower ORR: patients with EMD (12.5% vs 48%, P¼ .006) and patients who received lenalidomide in the last line of therapy (ORR 29% vs 50%; odds ratio 2.35, P¼ .043).

Lenalidomide

The median PFS in the entire series was 7.58 months (95% CI 5.78-10.12) (Figure 2A). Median PFS was significantly longer in those patients who experienced at least a PR (10.41 months [95% CI 7.39-19.08] vs 5.38 months [95% CI 3.94-8.14], HR 2.01, P¼ Abbreviations: EMD ¼ extramedullary disease; PI ¼ proteasome inhibitor.
Median OS for the whole cohort of patients was 12.6 months (95% CI 9.3-18.2) (Figure 4A). Median OS was significantly longer in the group of patients who experienced an objective response (PR or better) (median OS 18.2 months [95% CI 11.2-41.3]) compared to those who experienced less than a PR (median OS 9.8 months [95% CI 7.1-14.0], HR 0.52, P¼ .009) (Figure 4B). The OS was consistent across the different groups analyzed (Figure 3B). No differences in OS were found between patients with lenalidomiderefractory disease (14.0 months [95% CI 6.37-26.4]) and lenalidomide non-refractory disease (12.6 months [95% CI 9.2-18.2]) (HR 1.00 [95% CI 0.5-2.02]) or in patients with double-refractory disease (HR 1.14 months [95% CI 0.72-1.8], P ¼ .567). The median OS was also comparable between patients who had received prolonged prior lenalidomide treatment ( 12 months) (14 months [95% CI 9.3-22.7]) and those with less than 12 months of prior lenalidomide treatment (11.9 months [95% CI 8.5-18.9]) (HR 1.1 [95% CI 0.7-1.7]). Likewise, no differences in OS were observed for patients with disease refractory to the last therapy (HR 1.23 [95% CI 0.76-2.5]) and those receiving lenalidomide in the last line (HR 1.09 [95% CI 0.68-1.74]). Similarly, no differences in OS were found between patients with fewer than 3 (median OS 14.0 months [95% CI 6.4-24.7]) and 3 or more prior lines of therapy (median OS 11.9 months [95% CI 9.2-17.4]) (HR 1.16 [95% CI 0.72-1.87]).
In the multivariate analysis, the only variable independently associated with both PFS (HR 0.52 [95% CI 0.3-0.8], P¼ .006) and OS (HR 0.52 [95% CI 0.3-0.9], P¼ .016) was experiencing at least a PR. Regarding safety, hematologic and nonhematologic AEs were registered in 43% and 79% of the patients, respectively. The most common all-grade AEs reported were infections (63.1%), neutropenia (45.8%), thrombocytopenia (15.8%), and gastrointestinal toxicity (15.5%). Among these, the most common nonhematologic grade 3/4 AEs were infections (62.2%) and gastrointestinal toxicity (46%), and the most common hematologic grade 3/4 AEs were neutropenia (97.4%) and thrombocytopenia (61.5%). A total of 57% of patients experienced modifications (reduction or interruptions) in pomalidomide dose, 31% in cyclophosphamide dose, and 21% in the dexamethasone dose. The main reason for discontinuation of PomCiDex treatment was disease progression (56%); only 2 patients discontinued the treatment because of AEs. A total of 76% of the patients died (57% disease progression, 6% AEs). Overall, the safety profile was consistent with that previously reported for this combination.

Discussion

In this retrospective real-world study, the all-oral triplet combination of pomalidomide/cyclophosphamide and dexamethasone resulted in an ORR of 39% with a PFS of 7.6 months and median OS of 12.6 months in a population of patients with lenalidomiderefractory disease and refractoriness to the last line of therapy. These results compare favorably with other triplet combinations that have been tested in similar populations of RRMM. Indeed, in patients with responsive disease, both PFS and OS are significantly prolonged, with a median of 10.4 and 18.2 months, respectively. ORR, PFS, and OS were consistent in the different subgroups analyzed; interestingly, response and survival were comparable in the group of patients with disease refractory to lenalidomide.
Currently patients with lenalidomide-refractory disease have emerged as a difficult-to-treat population and represent an unmet medical need, particularly now that lenalidomide is frequently used in the up-front setting both in transplant-eligible and nonetransplant-eligible patients as part of induction, maintenance, and continuous therapy. All these situations are associated with poor outcome if the patient has treatment-refractory disease. In vitro and animal studies from our group have demonstrated that pomalidomide can overcome lenalidomide refractoriness and has been approved in this setting in combination with dexamethasone.6,8 However, the PFS is relatively short (4 months), and for this reason, other pomalidomide-based combinations are needed.
An obvious alternative would be to use drugs with a different mechanism of action; indeed, both carfilzomib and daratumumab have shown the possibility of rescuing patients with lenalidomiderefractory disease. However, once again, their efficacy as single agents is limited. For this reason, several combinations have been tested, with the most promising ones being anti-CD38 combined with either carfilzomib or pomalidomide, or carfilzomib plus pomalidomide. Nevertheless, some of these combinations have not yet been tested in large randomized phase 3 trials. Interestingly, data recently reported in a less heavily pretreated RRMM population evaluating the triplet combination of carfilzomib, cyclophosphamide, and dexamethasone in a phase 2 randomized study showed that in the IMID-refractory population, the addition of cyclophosphamide to carfilzomib/dexamethasone resulted in a significant benefit in terms of PFS (median 26.2 vs 7.7 months in the Kd arm; P¼ .01).15 Currently some of the most robust data in this setting comes from the OPTIMISMM study, which included 70% of patients with lenalidomide-refractory disease and showed an ORR of 82.2% and a median PFS of 11.2 months; however, patients included in this study had received a median of 2 prior therapy lines, reflecting a population with less advanced RRMM.3 The same is also true for the combination of daratumumab, bortezomib, and dexamethasone (DVd) evaluated in the phase 3 CASTOR study, in which only 30% of the patients included and treated with DVd had disease refractory to lenalidomide, with the median PFS in this subgroup not exceeding 8 months (7.8 months).16 Similar results were reported in the ENDEAVOUR study comparing Kd with bortezomib/dexamethasone, with a similar proportion of patients having disease refractory to lenalidomide included (24.4%); the median PFS in patients with lenalidomide-refractory disease treated with Kd was 8.6 months, which compares favorably with the PFS reported in this study.17
Recently 2 randomized studies evaluated 2 combinations of pomalidomide/dexamethasone in combination with 2 different monoclonal antibodies: elotuzumab (ELOQUENT-3 study) and isatuximab (ICARIA). In both studies, more than 90% and 94% of the patients, respectively, had disease refractory to lenalidomide, and the median number of prior therapy lines was comparable with the population here presented.9,11 Among patientstreated withelotuzumab/pomalidomide/ dexamethasoneinthephase2randomizedELOQUENT-3study,ORR was 53% and median PFS 10.3 months.9 Likewise, with the combination of IsaPd, ORR was 60% and median PFS was 11.53 months.11
In addition, patients with EMD have also been identified as a difficult-to-treat population, and current therapies are of limited efficacy. Indeed, the median PFS reported in the ICARIA study for patients with soft tissue plasmacytoma treated with IsaPd was 4.57 months, which is comparable to the PFS reported here for patients with EMD of 5.4 months.18
Nevertheless, some of the abovementioned regimens are associated with high cost and limited access in many countries. Moreover, some of themhavetheinconvenienceofrequiringintravenousinfusionorregular visitstothehospitalforsubcutaneousadministration.Thepresenttriplet combinationofPomCiDexcomparesfavorablywiththoseobtainedwith pomalidomideanddexamethasonealoneinasimilarpatientpopulation. Moreover, it has several advantages over other triplets: it is based on oral drugs, ithasa lowdosecyclophosphamide,itmay beuseddaily,itiseasy to adjust the dose, and hospital visits may be avoided. The median PFS herereportedof7.58monthsiscomparabletothatofPVdorDVd,andis also comparable to the combination of pomalidomide, cyclophosphamide,anddexamethasonereportedinaphase2randomizedstudy.12The lowerresponserateobtainedwithPomCiDexcomparedtoPVdorIsaPd may reflect the mechanism of action of cyclophosphamide, which prolongs the duration of response rather than increasing the response rate. Finally,thetoxicityprofilewasmanageable.ThemostfrequentAEswere infections and neutropenia; these were grade 3 or higher in a significant proportion of patients and were managed with dose modification. Very few patients (6%) had to discontinue treatment because of toxicity.
The main limitations of the current study are its retrospective nature and the small number of patients; nevertheless, we consider our real-world PomCiDex experience to represent a valuable alternative, particularly for patients who prefer to avoid frequent hospital visits and for countries with limited resources.

Clinical Practice Points

References

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