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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.

Patients with relapsed/refractory multiple myeloma (RRMM) for whom the benefits of lenalidomide have been exhausted in early treatment lines need effective therapies. In cohort A of the phase 2 MM-014 trial, we examined the safety and efficacy of pomalidomide plus low-dose dexamethasone immediately after lenalidomide-based treatment failure in patients with RRMM and two prior lines of therapy. Pomalidomide 4mg was given on days 1 to 21 of 28-day cycles. Dexamethasone 40mg (20mg for patients aged>75years) was given on days 1, 8, 15 and 22 of 28-day cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. The intention-to-treat population comprised 56 patients; all received prior lenalidomide (87·5% lenalidomide refractory) and 39 (69·6%) received prior bortezomib. ORR was 32·1% (28·2% in the prior-bortezomib subgroup). Median PFS was 12·2months (7·9months in the prior-bortezomib subgroup). Median OS was 41·7months (38·6months in the prior-bortezomib subgroup). The most common grade 3/4 treatment-emergent adverse events were anaemia (25·0%), pneumonia (14·3%) and fatigue (14·3%). These findings support earlier sequencing of pomalidomide-based therapy in lenalidomide-pretreated patients with RRMM, including those who have become refractory to lenalidomide. Trial registration: www.ClinicalTrials.gov identifier NCT01946477.

Purpose Pomalidomide plus low-dose dexamethasone (POM-d), daratumumab monotherapy (DARA), and carfilzomib monotherapy (CAR) have been approved for use in the treatment of patients with heavily pretreated relapsed–refractory multiple myeloma (RRMM) in the US, based on findings from the MM-002, SIRIUS, and PX-171-003-A1 studies, respectively. The objective of this study was to assess the cost-effectiveness of POM-d, DARA, and CAR in this patient population from a US payer's perspective. Methods A cost-effectiveness model was developed to estimate the cost and health outcomes over a 3-year time horizon in 3 health states: progression-free, post-progression, and death. The main efficacy data source was a matching-adjusted indirect comparison using data from the aforementioned studies. Direct medical costs were considered, including: treatment acquisition and administration (initial line and subsequent line), pre- and post-medication, prophylaxis treatment, adverse event management, and health care resource utilization. Sensitivity analyses were conducted. A scenario analysis that assumed equal efficacy across all 3 treatments was conducted. Costs, life-years, and quality-adjusted life-years were estimated and discounted at 3% per annum. Findings Over 3 years, the use of POM-d was associated with similar life-years and quality-adjusted life-years gained compared with DARA and CAR (incremental: life-years, +0.02 and +0.07, respectively; quality-adjusted life-years, +0.01 and +0.05), and with a cost less than that of DARA (–$8,919) and similar to that of CAR (–$195). Sensitivity analyses illustrated that the results were sensitive to progression-free survival, treatment duration, and drug costs. An equal efficacy scenario resulted in cost-savings relative to those of both DARA and CAR (–$11,779 and –$12,595). Implications POM-d may be a cost-effective treatment option relative to DARA or CAR in heavily pretreated patients with RRMM in the US.

8027 Background: Recent trials of triple therapy in 2L and third-line (3L) Tx excluded pts refractory to LEN. This is not reflective of standard of care in first line and 2L where LEN is given until progressive disease (PD). MM-014 enrolled pts with RRMM and 2L LEN-based Tx failure. Here we report results only from cohort A of pts receiving POM + LoDEX. Cohort B will investigate POM + LoDEX + daratumumab. Methods: Adult pts with MM, 2 prior Tx lines, and PD after ≥ 2 cycles of 2L LEN-based Tx received POM + LoDEX. The primary endpoint was overall response rate (ORR). Other endpoints included time to response (TTR), PFS, second primary malignancies (SPMs), and biomarkers. Results: Of 51 pts in cohort A, 39 (76.5%) discontinued Tx. Most pts (88.2%) were refractory to their last LEN Tx, (median Tx duration 24.6 mos) and 72.5% had prior bortezomib. At a median follow-up of 13.6 mos, ORR was 29.4% (2.0% complete response, 9.8% very good partial response, and 17.6% partial response [PR]) and median TTR was 1.9 mos; 66% of pts had ongoing response at 1 yr. Minimal response [MR] was reached in 15.7%. Median PFS was 13.8 mos. Pts with ≥ MR had similar Tx durations as those achieving ≥ PR. Additional results in Table. Post-Tx T-cell populations were significantly higher vs baseline (CD3+, 72.6% vs 67.8%; CD3+/CD8+, 36.9% vs 32.1%). Relative changes from baseline were significantly greater in pts with response vs pts with no response (CD3+, 10.4 vs −0.8; CD3+/CD4+, 4.2 vs −3.5). Conclusions: This update confirms the safety and efficacy of POM + LoDEX following 2L LEN-based Tx failure in pts with RRMM. Hematologic adverse event (AE) rates improved and median PFS was longer with 3L use than previously reported with POM + LoDEX use in later Tx lines. In addition, achieving disease control of ≥ MR led to similar PFS rates as reaching ≥ PR. Clinical trial information: NCT01946477. [Table: see text]

INTRODUCTION: Several new agents and regimens are available for the treatment of relapsed refractory multiple myeloma (RRMM). Comparison of all these is not feasible, yet therapeutic selections need to be made for optimal patient care. Both the MM-002 (Richardson et al., 2014) and MM-003 (San Miguel et al., 2013) trials have demonstrated the clinical benefits of pomalidomide plus low-dose dexamethasone (POM+LoDEX) in improving survival outcomes for patients with RRMM who had received ≥2 prior lines of therapy. Daratumumab (DARA) monotherapy was approved in the US for the treatment of RRMM patients, based on the results of a single-arm trial (SIRIUS) (Lonial et al., 2016). To date, there are no head-to-head studies comparing POM+LoDEX with DARA. We performed an indirect comparison of the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) between POM+LoDEX and DARA in RRMM patients with ≥2 (median of 5) prior lines of therapy. METHODS: Matching-adjusted indirect comparison (MAIC) (Ishak et al., 2015; Signorovitch et al., 2012) is a method used to conduct indirect comparisons between relative efficacies of treatments after adjusting for imbalances across trials where the study populations were roughly similar. To perform a MAIC, it is necessary that the selected studies are compatible. Both MM-002 and SIRIUS were phase II trials and included mainly patients from North America, while other geographic regions were more widely represented in the phase III MM-003 trial. Thus, the MAIC was conducted using individual patient data from the intention-to-treat (ITT) population of POM+LoDEX from MM-002 and published aggregate data on patient characteristics and outcomes for the ITT population of DARA from SIRIUS. A propensity-score logistic regression equation was used to re-weight the POM+LoDEX patients such that their aggregate characteristics matched exactly those in SIRIUS for all prognostic factors (i.e., full set) which were available in both studies. These factors included age, gender, race, disease duration, immunoglobulin heavy chain type, Eastern Cooperative Oncology Group (ECOG) performance status, plasmacytoma, creatinine clearance, number of prior therapy lines, prior stem cell transplantation, and refractoriness to bortezomib, lenalidomide, or both. The relative treatment effects were estimated with a weighted logistic regression model for ORR and weighted Cox regression models for PFS and OS. Sensitivity analyses were also conducted by matching on only important prognostic factors (i.e., reduced set), identified from multivariate regression analyses for each endpoint. RESULTS: MM-002 and SIRIUS were generally similar in design and had sufficient overlap in baseline characteristics to allow adjustment for potential confounding. Most prognostic factors were similar between the two arms. However, patients on POM+LoDEX had worse ECOG status, while more patients on DARA had a plasmacytoma and creatinine clearance CONCLUSIONS: This analysis suggests that POM+LoDEX and DARA have similar clinical benefits with respect to ORR, PFS, and OS in RRMM patients with ≥2 prior lines of therapy. Treatment choice may be made between these two based on factors other than efficacy alone. MAIC analysis may be helpful in therapeutic decisions where direct comparative trials are not available, however as with any non-randomized study potential for residual confounding may still exist. Disclosures Parikh: Celgene Corporation: Employment, Equity Ownership, Research Funding. Proskorovsky:Evidera: Employment, Other: As a salaried Evidera employee, I am not allowed to accept any remuneration or honoraria. Evidera received funding from Celgene.. Abouzaid:Celgene Corporation: Employment, Equity Ownership, Research Funding. Krotneva:Evidera: Employment, Other: As a salaried Evidera employee, I am not allowed to accept any remuneration or honoraria. Evidera received funding from Celgene.. Page:Evidera: Other: As a salaried Evidera employee, I am not allowed to accept any remuneration or honoraria. Evidera received funding from Celgene.. Pelligra:Evidera: Employment, Other: As a salaried Evidera employee, I am not allowed to accept any remuneration or honoraria. Evidera received funding from Celgene.. Guo:Celgene: Consultancy. Mouro:Celgene: Employment, Equity Ownership. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.

Background: Pomalidomide (POM) in combination with low-dose dexamethasone (LoDEX) is approved for the treatment (Tx) of patients (pts) with multiple myeloma (MM) who have had ≥ 2 prior lines of therapy, including lenalidomide (LEN) and a proteasome inhibitor. Although LEN and POM are both IMiD® immunomodulatory agents, preclinical studies have shown that LEN is not cross-resistant with POM (Ocio et al, Leukemia, 2015) and that LEN-resistant myeloma cells remain sensitive to POM (Lopez-Girona et al, Leukemia, 2012). Furthermore, sub-analyses of the MM-002 and MM-003 trials demonstrated that POM + LoDEX had comparable efficacy in pts refractory to their last prior Tx with LEN as in the overall pt population (San Miguel et al, Lancet Oncol, 2013; Richardson et al, Blood, 2014). Here, we present an updated analysis of MM-014, a single-arm, phase 2 trial of POM + LoDEX in pts with MM relapsed or refractory to LEN-based second-line therapy. Methods: Pts were ≥ 18 years old with a documented diagnosis of MM, measurable disease, 2 prior lines of Tx, and progressive disease after ≥ 2 cycles of second-line Tx with a LEN-based therapy. The Tx regimen was POM 4 mg/day on days 1-21 and LoDEX 40 mg/day (20 mg/day for pts > 75 years old) on days 1, 8, 15, and 22 of a 28-day cycle; thromboprophylaxis was mandatory. Responses were assessed using modified International Myeloma Working Group criteria. The primary endpoint was overall response rate (ORR; ≥ partial response [PR]). Secondary endpoints included time to response (TTR), duration of response (DOR), time to progression (TTP), progression-free survival (PFS), and overall survival (OS). Secondary primary malignancies (SPMs) were monitored and recorded as serious AEs regardless of relationship to Tx. Exploratory endpoints included measures to identify potential molecular, immune, and cellular biomarkers for POM + LoDEX response, resistance, or mechanism of action. Results: Of 51 enrolled pts (N = 85 planned), 16 (31.4%) remain on Tx, and 35 (68.6%) discontinued from Tx (n = 20 due to PD, n = 7 due to withdrawal by pt, and n = 2 each due to adverse event [AE], death, lack of efficacy, and other reasons). The median age was 68.0 years, and most pts (92.2%) had an Eastern Cooperative Oncology Group performance status of ≤ 1; 34 pts (66.7%) were refractory to their last Tx with LEN, and 37 (72.5%), 2 (3.9%), and 1 (2.0%) pts had prior Tx with bortezomib, carfilzomib, or ixazomib, respectively. A total of 33 pts (64.7%) had prior stem cell transplant. The median duration of the most recent prior LEN-containing Tx was 24.6 months, and the median study follow-up time was 11.4 months. The ORR was 31.4%, including 3.9% (n = 2) with complete response, 5.9% (n = 3) with very good PR, and 21.6% (n = 11) with PR. The clinical benefit rate (≥ minimal response) was 41.2%. Of the 16 pts who achieved ≥ PR, 12 (75.0%) have an ongoing response; median TTR in these pts was 1.9 months. The median DOR based on Kaplan-Meier estimates was not reached. The 1-year PFS, OS, and TTP rates were 60.2%, 87.4%, and 64.6%, respectively. Common (≥ 5%) grade 3/4 AEs included anemia (23.5%), neutropenia (13.7%), thrombocytopenia (9.8%), fatigue (7.8%), and infections (19.6%; including pneumonia [7.8%]). AEs of special interest (any grade) included pulmonary embolism (3.9%), deep vein thrombosis (2.0%), and peripheral sensory neuropathy (3.9%); no SPMs were observed. The immune subset analysis showed a significantly elevated proportion of CD3+/CD8+ T cells after Tx (cycle 3, 5, day 1) compared with baseline (37.6% vs 30.5% of total lymphocytes; P < .01). A similar trend toward elevated proportions of CD3+ T cells (73.7% vs 66.6%) was observed; however, the difference was not significant. There was no significant change in CD3+/CD4+ T cells (35.9% vs 35.5%). Conclusions: This updated analysis of the MM-014 trial demonstrates the safety and efficacy of POM + LoDEX in pts who were relapsed or refractory to their last prior Tx with LEN. Results suggest that POM + LoDEX can be used immediately following LEN-based therapy to treat pts with relapsed/refractory MM. The study has been amended to include a cohort of pts treated with POM + LoDEX + daratumumab. Investigations of additional biomarkers, high-risk genetic aberrations, clonal evolution, and minimal residual disease in MM-014 are currently underway. Disclosures Siegel: Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Merck: Honoraria. Schiller:Incyte Corporation: Research Funding. Song:Otsuka: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria. Kaya:Celgene, Amgen, Takeda: Honoraria. Sebag:Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Reu:Celgene, Novartis and Takeda: Research Funding; Signal Genetics, Inc.: Consultancy. Mouro:Celgene: Employment, Equity Ownership. Chung:Celgene: Employment. Srinivasan:Celgene: Employment; Individual Patent: Patents & Royalties: US7,495,673B1 Used for MM-Connect Treatment Patterns Abstract.. Qian:Celgene: Employment. Rizvi:Celgene: Employment, Equity Ownership. Thakurta:Celgene: Employment, Equity Ownership. Bahlis:Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; BMS: Honoraria; Onyx: Consultancy, Honoraria.

Background: Preclinical studies indicate that lenalidomide (LEN) and POM are not cross-resistant (Ocio et al Leukemia, 2015) and that POM remains active in LEN-resistant myeloma cells (Lopez-Girona et al Leukemia, 2012). Likewise, POM + LoDEX showed comparable efficacy in patients (pts) refractory to LEN administered as last prior Tx vs the full population in subanalyses of the clinical trials MM-002 and MM-003 (San Miguel et al Lancet Oncol, 2013; Richardson et al Blood, 2014). To confirm these observations, we initiated a single-arm, phase 2 trial evaluating POM + LoDEX immediately following second-line LEN-based Tx in advanced RRMM (MM-014; NCT01946477). Methods: Eligible pts (aged ≥ 18 yrs) had received 2 prior lines of Tx, with ≥ 2 cycles of LEN-based Tx in the second line. Pts must have had documented progressive disease (PD) during or after their last antimyeloma Tx and Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. POM was administered 4 mg/day on days 1-21 of a 28-day cycle with LoDEX 40 mg/day (20 mg/day for pts aged > 75 yrs) on days 1, 8, 15, and 22 until PD or discontinuation for any reason. Pts received mandatory thromboprophylaxis. The primary end point was overall response rate by modified International Myeloma Working Group criteria (including minor response). Secondary end points included progression-free survival, overall survival, time to progression, safety, and duration of response. Exploratory end points were included to identify molecular, immune, and cellular biomarkers that might inform POM + LoDEX response, resistance, or mechanism of action. Results: As of March 20, 2015, 27 of the 85 planned pts were enrolled and received POM + LoDEX. Twelve pts remain on Tx, whereas 15 have discontinued, due to PD (n = 7) and withdrawal (n = 5), but not adverse events (n = 0). Males comprised 59% of pts; 85% were white and the median age was 69 yrs (range, 44-85 yrs), with 67% of pts aged ≥ 65 yrs. The median time since diagnosis was 3.9 yrs (range, 1.3-13.3 yrs), and 59% of pts received prior stem cell transplant. Most pts (81%) were refractory to the most recent prior LEN-containing Tx, and the median duration of the most recent prior LEN Tx was 8.3 mos (range, 0.3-56.3 mos). The 19% of pts who were not refractory to the most recent prior LEN-containing Tx remain on Tx. Pts predominantly had ECOG performance status 0 or 1 (30% and 63%, respectively) vs 2 (7%). Of the 19 pts with International Staging System assessment reported, most were stage I (n = 7) or II (n = 11) vs III (n = 1). Efficacy and safety data will be presented. Conclusions: The MM-014 study is assessing the efficacy and safety of POM + LoDEX in pts with RRMM who have received second-line LEN-based Tx. MM-014 is designed to confirm and expand the results from MM-002 and MM-003 with translational data. Clonality and biomarkers, including Aiolos, Ikaros, IRF-4, and c-Myc, will be evaluated to determine association with POM + LoDEX synergy, high-risk MM-associated genetic aberrations, clonal evolution, and minimal residual disease. Disclosures Siegel: Celgene Corporation: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Merck: Speakers Bureau; Novartis: Speakers Bureau. Schiller:Celgene Corporation: Research Funding. Song:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stockerl-Goldstein:Celgene Corporation: Speakers Bureau; Onyx: Speakers Bureau. Kaya:Novartis: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Sebag:Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria. Reu:Takeda/Millennium: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Mouro:Celgene Corporation: Employment, Equity Ownership. Sturniolo:Celgene Corporation: Employment. Srinivasan:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene Corporation: Employment, Equity Ownership. Nagarwala:Celgene Corporation: Employment, Equity Ownership. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Johnson & Johnson: Research Funding.

TPS8606 Background: Combination of the immunomodulatory agent lenalidomide (Revlimid) with rituximab (R2) is a promising therapeutic option for patients with R/R NHL. As frontline therapy, R2 provi...

TPS8617 Background: Immunomodulation with lenalidomide (L) + rituximab (R) is a promising treatment approach for patients (pts) with indolent NHL. In indolent NHL, frontline L+R provided a 90% over...