ALBERT

Description: MGUS occurs in 5% of individuals over 70 yrs of age and these pts have been found to have increased rates of bone resorption. Osteoporosis associated with MGUS have higher bone resorption compared to sex and aged-matched pts with osteoporosis but without evidence of MGUS. Not only do pts with MGUS have a higher prevalence of osteopenia/osteoporosis than the normal population but they also have an increased risk of fractures (fx). ZOL has been shown to increase BMD in the treatment of gonadotropin agonist-induced osteoporosis in men with prostate cancer without metastatic bone disease when administered every 3 mos at 4 mg. The rationale for the use of ZOL for pts with osteopenia/osteoporosis in the setting of MGUS is based on these studies coupled with the knowledge that pts with this disorder have a higher prevalence of bone loss and fx risk. To date, no agents have been formally studied in the treatment of osteopenia/osteoporosis associated with MGUS. A schedule of 4 mg every 6 mos has been shown to be safe and effective in increasing BMD for other cancer pts without metastatic bone disease but with significant bone loss. This open-label study was designed to evaluate the efficacy and safety of this dose and schedule of ZOL for MGUS pts with significant loss of bone. Pts had to have osteopenia/osteoporosis (T-score worse than -1) as verified by a DEXA scan and a diagnosis of MGUS. Pts with prior use of oral bisphosphonates (BIS) or fluorides for more than three mos within the last two yrs or prior use of intravenous (IV) BIS within the last two yrs were excluded. ZOL at 4 mg was administered IV at 0, 6, and 12 mos. To assess the efficacy of ZOL therapy, DEXA scans and skeletal surveys were conducted at screening and one mo after the final ZOL infusion (13 mos). Fifty-four pts were enrolled on this trial with an average age of 68 (range, 50 to 91 yrs). The starting L-spine T-scores ranged from −3.97 to −1.10 (mean = −2.16). After one year of ZOL therapy, T-scores improved by a mean of +0.55 (range, −0.40 to +3.90; P = 0.0042). This corresponded to a mean increase in BMD of +25.5% (range, −19.0% to +134%). Similar evaluation in the hip showed baseline T-scores of −3.50 to −1.00 (mean = −1.88). The mean change in T-score was +0.27 (range, −0.60 to +2.00; P = 0.0046) corresponding to a mean increase of +14.4% (range, −54.5% to +163%). One pt developed chronic lymphocytic leukemia while on study whereas no other pt showed progression to myeloma or a related B-cell disorder. No pt developed osteonecrosis of the jaw or a significant adverse renal event. During the study, no pt developed a new fx. This trial suggests that ZOL administered at 4 mg every 6 mos significantly improves BMD in MGUS pts with bone loss (osteopenia/osteoporosis); and, thus, suggests that this is a safe and effective treatment to prevent the development of new fxs in this high risk population.

Description: Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who previously received POM treatment were ineligible. POM was administered orally on days 1-21 of a 28-day cycle, while DEX (40 mg) and PLD (5mg/m2) were both infused on days 1, 4, 8, and 11. During phase 1 enrollment, three cohorts were enrolled at 2, 3 and 4 mg doses of POM, and DEX and PLD were both administered at fixed doses. Phase 2 enrollment commenced once the MTD was established from the phase 1 portion of the study. Results As of August 1, 2015, 70 pts were screened, 68 were enrolled in the trial (with the pre-planned enrollment goal reached) and had received study drug, and a total of 50 pts were evaluable for safety and efficacy. Among all enrolled pts, 60pts discontinued treatment and 8 remain active. Pts had received a median of 4 prior treatments (range 1-18). Median number of cycles for all pts was 4 (range 1-8), with a median follow-up time of 5.5 months (range 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 57 pts enrolled in phase 2, 53% percent were refractory to LEN and steroids with or without other agents and 31% had previously received PLD. A median of 4 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Fifty-five pts were evaluable for response as 2 pts are active but have not yet had any post-baseline disease assessment. Among all evaluable pts (n=55) enrolled in phase 2, the overall response rate (ORR) was 33% (CR= 5%, VGPR= 5% and PR=23%) and clinical benefit rate (CBR) was 47% with 11 pts (26%) showing stable disease and 5 pts (12%) demonstrating progressive disease. For all evaluable pts enrolled in phase 2, the median follow-up time was 3.6 months (range 0-12 months) and the median PFS was 4.2 months (range 0.3- 29.0+). ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (36% and 51%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (49 pts; 72.0%), lymphopenia (36 pts; 52.9%), leukopenia (33 pts; 48.5%), hyponatremia (27 pts; 39.7%), and hypokalemia (26pts; 38.2%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures No relevant conflicts of interest to declare.

Description: Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/ progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who have previously received POM treatment were ineligible. In the phase 1 portion, POM was administered at 2, 3 or 4 mg daily in three cohorts on days 1-21 of a 28-day cycle and DEX (40 mg) and PLD (5 mg/m2) were fixed and given intravenously on days 1, 4, 8, and 11. Results As of June 20th, 2014, 48 pts were enrolled in the trial and a total of 47 pts had received study drug. Pts had received a median of 4 prior treatments (range 1-18), with a median of 2 prior IMiD-containing regimens (range, 0-8). Fifty-three percent of the pts had received a prior PLD-containing regimen and 21% had received a prior IMiD and PLD combination treatment. Among all enrolled pts, 40 pts discontinued treatment and seven remain active. Pts completed a median of 3 cycles (range: 1-8), with a median follow-up time of 5.4 months (range: 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 36 pts enrolled in phase 2, 78% percent were refractory to LEN and steroids with or without other agents and 47% had previously received PLD. A median of 2 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Thirty-five pts were evaluable for response as one pt was active but had not yet had any post-baseline disease assessments. Among all pts enrolled in phase 2, the overall response rate (ORR) and clinical benefit rate (CBR) were 29% and 49%, respectively, with 6 pts (17%) showing stable disease and 12 pts (34%) demonstrating progressive disease. For all pts enrolled in phase 2, the median follow-up time was 4.7 months (range 0-12) and the median PFS was 5.3 months. ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (32% and 58%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (21 pts; 44.7%), lymphopenia (10 pts; 21.3%), and hyponatremia (4 pts; 8.5%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Consultancy, Honoraria. Vescio:Celgene: Honoraria.

Description: Abstract 3044 Background: Despite the availability of many new therapeutic options showing efficacy for R/R MM patients, many of these treatments produce significant side effects and the disease remains incurable. The combination of PLD and bortezomib has shown significant anti-MM efficacy leading to FDA approval of that combination for patients who have received one prior therapy and are naïve to bortezomib. Moreover, the combination of lenalidomide and dexamethasone has also been approved for patients who have received one prior regimen. However, both regimens are associated with significant toxicity and produce response rates in only 40–60% of patients. Previous studies in our laboratory show the increased efficacy and improved tolerability of PLD given daily compared to weekly administration in severe combined immunodeficient mice bearing human MM. Based on these results and the frequent occurrence of peripheral neuropathy with bortezomib when given at 1.3 mg/m2 dose on days 1, 4, 8, and 11 of a 3-week schedule, we modified the doses and schedules of both drugs and added intravenous (i.v) dexamethasone for MM patients. Using a modified lower dose (1.0 mg/m2) and longer cycle (4 weeks) of bortezomib administered on days 1, 4, 8, and 11 with lower dose PLD and intravenous (i.v.) dexamethasone administered on the same days for MM patients in both the frontline and R/R setting, we have shown the efficacy and marked reduction in AEs including neuropathy, hematologic, and hand-foot syndrome. A recent phase I/II trial investigating the combination of higher doses of lenalidomide, bortezomib, oral dexamethasone, and PLD on a 3-week schedule for newly diagnosed MM patients showed a high response rate but was associated with frequent AEs. Methods: Thus, we conducted a single-arm multi-center phase II study for R/R MM patients to evaluate the combination of i.v. dexamethasone, bortezomib, PLD, and lenalidomide. The treatment consisted of 40 mg dexamethasone followed by 1.0 mg/m2 bortezomib and then 4.0 mg/m2 PLD on days 1, 4, 8, and 11 of a 28-day cycle. Lenalidomide was administered orally at a dose of 10 mg daily on days 1–14 of each cycle. Patients were treated to a maximum response plus two additional cycles or completed a maximum of eight cycles of therapy without disease progression. Results: Eighteen (of 40 planned) patients have been enrolled to date with a median age of 72 years (range, 34–82 years). Patients were heavily pretreated with a median of 4 (1-17) prior regimens. Sixteen (89%) patients received prior bortezomib and 11 (61%) were previously treated with either doxorubicin or PLD. Seven (39%) of these patients were exposed to both drugs. Fifteen (83%) had received prior glucocorticoids. Nine (50%) individuals had received immunomodulatory agents with 6 (33%) having been exposed to lenalidomide and all 9 to thalidomide. The majority of patients (72 %) showed International Staging System II or III disease. To date, 16 patients (89%) have shown objective responses to the DVD-R regimen, including 1 complete response (6%), 5 very good partial responses (28%), 4 partial responses (22%) and 6 minimal responses (33%). One of the nonresponding patients showed stable disease and the other progressed after one cycle of therapy. Thus, disease control was achieved in all but one patient (94%). To date, 6 patients have shown progressive disease after a median follow-up time of 6 months (1+ - 9+ months). The DVD-R regimen was well tolerated and only one patient discontinued treatment because of toxicity (peripheral neuropathy). Ten patients experienced grade 3 or 4 adverse events. The most common grade 3 adverse events were reversible neutropenia (n=3), pneumonia (n=3), reversible anemia (n=2), and thrombocytopenia (n=2). There were two patients with grade 4 thrombocytopenia that was reversible. To date, 5 patients (28%) have developed treatment-emergent peripheral neuropathy (four grade 1 and one grade 3). Notably, there have been no cases of stomatitis or hand-foot syndrome. Conclusions: Thus, these results suggest that the DVD-R regimen using a modified schedule and doses of the combination of intravenous dexamethasone, bortezomib, PLD and lenalidomide is a well tolerated treatment that produces high response rates for heavily previously treated MM patients with R/R disease. Disclosures: Berenson: Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Centocor OrthoBiotech: Consultancy. Vescio:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Swift:Millennium: Consultancy.

Description: Previously, we and others have shown that bortezomib overcomes chemotherapy resistance in multiple myeloma cells. We recently published a Phase I trial that established the maximum tolerated dose (1.0 mg/m2 of bortezomib on days 1, 4, 8, and 11 with melphalan 0.1. mg/kg PO daily on days 1–4 of a 28-day cycle) for this combination and suggested its clinical activity in relapsed or refractory MM. The anti-MM activity of melphalan is dependent upon reactive oxygen species (ROS) and free glutathione (GSH) reduces intracellular ROS. Ascorbic acid (AA) reduces free GSH levels; and thus, should enhance the anti-MM activity of melphalan as our laboratory has recently demonstrated both in vitro and in vivo (Campbell et al. Brit J Haematol 2007). Therefore, we conducted a single-arm multi-center phase II study that evaluated the combination of bortezomib, ascorbic acid and melphalan (BAM) regimen in newly diagnosed pts with symptomatic myeloma. Treatment consisted of a 28-day cycle of bortezomib administered at a dose of 1.0 mg/m2 on days 1, 4, 8, and 11, and on days 1, 2, 3, and 4 oral AA at a dose of 1 g and oral melphalan 0.1 mg/kg were given. Based on preclinical studies suggesting potential inhibitory effects of AA on bortezomib’s anti-MM activity, bortezomib was administered in the morning and AA with melphalan in the evening. Pts were treated to maximum response plus two additional cycles or completed eight cycles of therapy without disease progression. These pts were eligible to be subsequently treated with bortezomib at a dose of 1.3 mg/m2 every other week until progressive disease occurred. Thirty-five pts, at a median age of 70 years (range, 50–90 years); have been enrolled in this study. To date, 27 pts are evaluable with a median survival of 12 months (range, 2 to 19+ months). Responses occurred in 17 of 27 pts (63%), including four complete responses (15%), two very good responses (7%), four partial responses (15%), and seven minimal responses (26%). Eight pts (30%) had stable disease. Thus, disease control was achieved in 25 (93%) pts. Six of the 27 pts have shown progressive disease after 2–13 months of treatment. Eleven pts experienced ≥ grade III adverse events with only one patient demonstrating a grade IV toxicity (shortness of breath). Six of these adverse events were judged not to be related to the study medications including the only grade IV event. The most common grade III adverse events included reversible neutropenia (4 events), neuropathy (2 events) and reversible thrombocytopenia (2 events). Only 11 pts had some form of increased neuropathy from baseline (Grade I (n=7), Grade II (n=2), and Grade III (n=2) with one of those pts starting with a Grade I). The peripheral neuropathy was reversible. BAM represents a steroid and IMID-free regimen with a high response rate (63%) as frontline therapy for MM pts. Importantly, this regimen was well tolerated with few significant adverse events. Treatment-related neuropathy was reported but reversible in all but one case. Thus, BAM has proven to be a promising new regimen for the first-line treatment of pts with MM.