Abstract It is important to have an effective therapy for patients with multiple myeloma (MM) at first relapse, particularly if an autologous stem cell transplant (ASCT) is considered at this stage. This multicenter, phase 2 trial evaluated the efficacy and safety of weekly oral pomalidomide-cyclophosphamide-dexamethasone (PCD) in patients with MM in first relapse after treatment with lenalidomide-bortezomib-dexamethasone (RVD). All patients had received RVD as induction and consolidation therapy, plus lenalidomide maintenance for 1 year (arm A). Half had also received an ASCT after induction (arm B). At MM relapse, all patients received 4 oral cycles of pomalidomide 4 mg (days 1-21), cyclophosphamide 300 mg (days 1, 8, 15, and 22), and dexamethasone 40 mg (days 1-4 and days 15-18 of a 28-day cycle; PCD). Responding patients in arm A underwent ASCT and received 2 additional cycles of PCD, whereas those in arm B received 5 cycles of PCD. All patients received pomalidomide-dexamethasone maintenance until disease progression. Primary end point was partial remission or better after the initial 4 cycles of PCD. Responses were obtained in 82/97 (85%) patients evaluated: complete remission (n = 1; 1%), very good partial remission (n = 32; 33%), and partial remission (n = 49; 51%). Three patients (3%) had stable disease, and 6 (6%) had disease progression (6 response failures). Forty-five (94%) of the 48 patients in arm A underwent planned ASCT. PCD was effective therapy after first relapse with RVD. After 4 cycles, the rate of partial remission or better was 85%, and 94% of planned ASCTs were performed. Toxicity was mostly hematologic and manageable. This trial was registered at www.clinicaltrials.gov as #NCT02244125.

The study was originally presented as a poster at the ASH 2021 annual meeting.

Background: The role of maintenance lenalidomide in myeloma, following autologous stem cell transplantation (ASCT) or not, is well established. However, 29% of patients discontinue the treatment with a median duration of less than 2 years with an increased rate of secondary primary malignancies (SPM). Pomalidomide could provide alternative maintenance therapy. Methods: This was a single arm phase II study of pomalidomide/dex (PD) maintenance therapy for MM patients (pts) in first relapse after treatment in the IFM 2009 trial. At first relapse, 100 pts received pomalidomide/cyclophosphamide/dex (PCD) for 4 cycles, after which half underwent ASCT (if no first line transplant) followed by 2 cycles of PCD consolidation (Arm A), or 5 cycles of PCD (if previously transplanted) (Arm B). All pts then received maintenance therapy consisting of 28-day cycles of pomalidomide 4 mg daily on days 1-21 and dex 20 mg once a week until progression (Blood 2018). The primary objective was to establish the safety and efficacy of PD as maintenance therapy. Results: A total of 75 pts were enrolled in the maintenance phase from January 2015 to November 2017 (Table 1) and the database was locked on 07/07/2021. The median age was 60 (range 39-70); 67% (50/75) were male. 53 pts had ISS stage I, 10 stage II and 3 stage III disease (9 missing). Infectious prophylaxis was antiviral in 94%, sulfamethoxazole/trimethoprim in 76%, penicillin in 69% and fluoroquinolone in 38%. A granulocyte colony stimulating factor was administered in 15 (20%) pts and immunoglobulins in 13 (17%). One quarter had thromboprophylaxis. The median follow-up was 73 months (95% CI: 68-75). Among the 75 pts, 63 (84%) left the study, 34 (54%) due to progressive disease, 19 (30%) due to AE/SAE, 7 (11%) on investigator (PI) discretion and 3 (5%) after consent withdrawal. 12 (16%) remained on therapy in July 2021.The median duration of maintenance was 23.7 months (IQR: 14.5-44). Pts received a median of 26 cycles (range 1-80) and 17 (23%) had 50 or more cycles. The reasons for pomalidomide discontinuation were progression or death in 54%, AE/SAE in 30%, PI decisions in 11% and patient decisions in 5%. 56 (75%) pts required a reduction in the dose of pomalidomide due to AE/SAE in 50%, omission in 19%, resumption of treatment in 11%, PI decisions in 16% and patient decisions in 2.7%. The reasons for dex discontinuation were progression or death in 30%, AE/SAE in 43%, PI decisions in 22% and patient decisions in 3%. 57 (76%) pts required a reduction in the dose of dex due to AE/SAE in 54%, omission in 3.4%, resumption of treatment in 0.3%, PI decisions in 38.7% and patient decisions in 3.1%. 31 SAE were reported in 22 pts: 13 (42%) infections, 5 tumors, 1 case of thrombosis, 1 diabetic ketoacidosis and 12 others. Grade 3/4 hematologic AE included neutropenia (51%), lymphopenia (35%), anemia and thrombocytopenia (0%). G3/4 drug-related non-hematologic AE (>5%) comprised 13% infections (5% pneumonia). G1/2 AE included 69% infections (49% bronchitis), 49.3% gastrointestinal disorders (20% diarrhea, 20% constipation), 48% fatigue, 31% skin disorders, 25% muscle spasms, 24% insomnia and 14.7% eye disorders (6.7% cataracts, 4% dry eyes). Concerning peripheral neuropathy, one patient had G3/4 and 45% G1/2. Eight pts developed SPM: 4 basocellular carcinoma, 1 epidermoid carcinoma, 1 melanoma, 1 colon carcinoma and 1 non small cell bronchial carcinoma. We observed an improvement in the response from the initiation of treatment: PR: 32.4 to 17.4%, VGPR: 56.8 to 49.3%, CR: 9.5 to 28%, sCR: 0 to 5.3% (at initiation to best response, respectively). A total of 33.4% of pts improved their response. The median PFS was 33.2 months (95% CI: 25.6-53.3). 41 pts died and the median OS was not reached (95% CI: 70.7-NR). All deaths were related to myeloma progression except 2 due to pulmonary infection, 1 lung carcinoma and 1 colorectal cancer. Conclusions: In the first relapse PCD trial, 75% initiated maintenance therapy. Long term administration of pomalidomide/dexamethasone as maintenance therapy is feasible. Thirty percent stopped pomalidomide because of SAE/AE, mostly related to hematologic AE, but this could be managed with dose reductions. There was generally G1/2 neuropathy, rare SPM and no other unexpected toxicity. One third of the pts improved their depth of response. The combination is safe, feasible and well tolerated and experience to date supports its further exploration with monoclonal antibodies. Figure 1 Figure 1. Disclosures Garderet: Amgen: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Roussel: Amgen: Consultancy; BMS: Honoraria; GSK: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Leleu: Novartis: Honoraria; Mundipharma: Honoraria; Merck: Honoraria; Karyopharm Therapeutics: Honoraria; Janssen-Cilag: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support. Karlin: Takeda: Honoraria, Other: member of advisory board; Amgen: Honoraria, Other: travel support and advisory board ; Sanofi: Honoraria; Abbvie: Honoraria; oncopeptide: Honoraria; GSK: Honoraria, Other: member of advisory board; Janssen: Honoraria, Other: member of advisory board, travel support; Celgene-BMS: Honoraria, Other: member of advisory board. Perrot: Abbvie: Honoraria; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau: Abbvie: Honoraria; Oncopeptides: Honoraria; Celgene BMS: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Janssen: Honoraria. Macro: abbvie: Honoraria; sanofi: Honoraria; celgene bms: Honoraria; takeda: Honoraria; janssen: Honoraria. Jourdan: Novartis: Consultancy; Abbvie: Consultancy; bms/celgene: Consultancy. Jaccard: Pfizer: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria. Mohty: Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Sanofi: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Adaptive Biotechnologies: Honoraria. Hulin: Celgene/BMS: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; abbvie: Honoraria. OffLabel Disclosure: pomalidomide as maintenance treatment