Kumar, Shaji

8033 Background: MLN9708 is an oral, reversible 20S proteasome inhibitor. The feasibility of combining a proteasome inhibitor with an immunomodulatory drug and a steroid in previously untreated MM has been demonstrated with the RVD regimen. This is the first study of MLN9708 in combination with lenalidomide and dexamethasone (NCT01217957). Here we report the phase (Ph) 1 MTD and preliminary Ph 2 results. Methods: Pts with previously untreated MM, aged ≥18 yrs with measurable disease received oral MLN9708 (phase 1: 1.68–3.95 mg/m2) days 1, 8, and 15, lenalidomide 25 mg days 1–21, and dexamethasone 40 mg days 1, 8, 15, and 22, for up to twelve 28-day cycles. Primary objectives were determination of safety, MTD, and recommended phase 2 dose (RP2D) (Ph 1), and CR+VGPR rate (Ph 2). Results: At data cut-off (Dec 1, 2011), 29 pts had been enrolled (15 Ph 1, 14 Ph 2). Median age was 64 yrs (range 40–82); 69% ISS stage II/III. In Ph 1, the MLN9708 MTD was determined as 2.97 mg/m2 and the RP2D as 2.23 mg/m2; for Ph 2, the RP2D was converted to a 4.0 mg fixed dose based on population PK results. Ph 1 pts have received a median of 6 treatment cycles (range 1–11), 8 received ≥6 cycles; 6 stopped to receive ASCT, 7 are ongoing. Ph 2 pts received a median of 1 (range 1–2), all are ongoing. Grade ≥3 hematologic toxicity was reversible and included anemia (n=2) and thrombocytopenia (n=1). Grade ≥3 nonhematologic toxicity included erythematous rash, syncope, and vomiting (2 pts each). All-grade drug-related peripheral neuropathy was seen in 6 pts (21%), including grade 2 with pain in 2 (both Ph 1 at doses above the MTD). Two pts discontinued due to AE; there were 5 pts who had serious drug-related AE (all Ph 1). Of 19 response-evaluable pts (Ph 1 + Ph 2), all achieved ≥PR, including 5 CR (1 sCR), 4 VGPR, and 10 PR; all remain in response with duration of confirmed response of up to 9.5 months. Of 4 response-evaluable Ph 2 pts, 1 has achieved VGPR and 3 PR to date. Conclusions: Oral MLN9708 plus lenalidomide and dexamethasone appears well tolerated with manageable toxicity. These data show antitumor activity at the RP2D in pts with previously untreated MM, with ≥PR in all pts to date.

8096 Background: The combination of lenalidomide and dexamethasone (Len-Dex) is a commonly used initial therapy for newly diagnosed multiple myeloma. While the short-term outcomes with respect to response and toxicity is well-known, long-term outcome with this combination as initial therapy is not well described. Methods: We studied 286 consecutive patients with newly diagnosed MM seen at our institution, who received initial therapy with Len-Dex, and who had complete follow up records. Data regarding the clinical course was obtained from medical records. Results: The median (range) age at diagnosis was 63 (28-92) yrs; 166 (58% were ≤ 65 yrs and175 (61%) were male. The median estimated follow-up was 3.9 yrs (95% CI, 3.4, 4.2) and 203 (71%) pts were alive at the time of last follow up. The median estimated duration on Len-Dex was 5.3 mos (95% CI, 4.6, 6.4). The best overall response (≥PR) was 72%, including 26% with VGPR or better and 14 (5%) not being evaluable for a response. At last follow up, 41 (14%) patients were continuing on therapy. There were 93 pts (32%) who stayed on therapy for 12 months or more. Among these patients, the ORR was 86%, including 45% with VGPR or better. The median overall survival (OS) for the entire cohort from diagnosis was 7.4 yrs (95% CI; 5.8, NR) and the estimated 5-yr survival was 67%. There were 16 (5.5%) pts who died within a year of diagnosis. The median time to first disease progression, irrespective of transplant status, was 30.2 mos (95% CI, 25, 42). Overall, 143 (50%) of the patients have gone to stem cell transplant. Censoring those patients who proceeded to SCT prior to relapse at the time of BMT, the median TTP was 25.5 mos (95% CI, 22, 29). The median OS was 7.4 yrs for those ≤65 yrs, compared with 6.2 yrs for the older patients (P=0.01). The 5-yr OS estimate for patients in ISS stage 1, 2 and 3 were 82, 65, and 44 months respectively. Conclusions: The current study provides long-term estimates of responses and survival in a series of patients treated initially with lenalidomide and dexamethasone. The median survival of nearly 8 years reflects the efficacy of the novel agents both at diagnosis and at relapse and confirms the survival improvements seen in MM in the last decade.

8095 Background: Multiple myeloma (MM) remains incurable and invariably relapses after initial therapy. There is no uniform approach to management of relapsed MM and is dictated by type of initial therapy and the response seen, and availability of new drugs. The outcomes associated with current approaches have not been systematically examined. Methods: We enrolled 383 patients (pts) with myeloma who had a documented relapse between Jan 2007 and June 2010, including 220 from Europe, 106 from Asia, and 31 from South America and 26 from North America. Time Zero (T0) was defined as date of treatment after first relapse. Results: Across the study, 61% were male and 49% were over 65 years at T0. ISS stage distribution at diagnosis included 26, 40 and 33% of patients in stages 1, 2 and 3, respectively. Among regimens used at first relapse; bortezomib (Btz) containing regimens were most common (54%), followed by lenalidomide (Len, 25%) and cyclophosphamide (21%). The overall response rate (>=PR) to first therapy after relapse was 58% including 14% with a CR. There was a progressive decrease in the response rates with successive regimen; 45%, 30% and 15% for regimens 2, 3 and 4 respectively. Len use was considerably lower in the Asian cohort, while Btz use was comparable across the regions. The median PFS from T0 was 13 mos and OS was 35 mos, for the entire cohort. The PFS to first salvage regimen was similar across the regions, while OS was shorter for the Asian and South American cohorts. In a univariate analysis, ISS stage 3, presence of cytogenetic abnormalities, history of plasma cell leukemia or extramedullary disease (EMD), bone marrow PC% > 33% and presence of renal insufficiency were all associated with a shorter PFS as well as shorter OS (P<=0.01). In a multivariate model, ISS stage 3 and presence of EMD were most associated with short OS. Conclusions: Median PFS for current second line regimens, typically containing Btz or Len appear to be 1 yr with an OS from first relapse of about 3 yrs. The OS from first relapse is nearly double that seen in a cohort of patients in first relapse prior to introduction of new drugs. Clear-cut regional differences can be seen in terms of patterns of drug use and likely reflect drug availability and healthcare costs.

8034 Background: Phase 1 studies are evaluating IV and oral dosing of the reversible proteasome inhibitor MLN9708 in multiple tumor types. We report the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary responses with weekly oral MLN9708 in pts with relapsed/refractory MM (NCT00963820). Methods: Pts aged ≥18 yrs received MLN9708 on d 1, 8, and 15 of 28-d cycles. In the dose-escalation phase, pts required ≥2 prior therapies (including bortezomib, thalidomide/lenalidomide, and corticosteroids). At the MTD, pts were to be enrolled to relapsed and refractory (RR), bortezomib-relapsed (VR), proteasome inhibitor (PI) naïve, and carfilzomib (CZ) expansion cohorts. Results: 36 pts have been enrolled to date (data cut-off: Dec 1, 2011), 32 in the dose-escalation phase (0.24–3.95 mg/m2) and 8 to expansion cohorts (2 RR, 5 VR, 1 PI naïve; RR and VR cohorts each include 2 pts from MTD dose-escalation cohort). Median age was 64.5 yrs (range 40–79), 53% were male, and median number of prior lines of therapy was 3.5 (range 1-13), including 92%, 92%, 56%, and 8% who had prior bortezomib, lenalidomide, thalidomide, and carfilzomib, respectively. Pts have received a median of 2 cycles (range 1–11); 5 pts remain on treatment. Among 24 DLT-evaluable pts, 3 DLTs were seen: 2 at 3.95 mg/m2 (1 grade 3 rash, 1 grade 3 GI AEs) and 1 at 2.97 mg/m2 (grade 3 GI AEs). The MTD was determined as 2.97 mg/m2. Overall, 69% of pts had drug-related AEs, and 28% had related grade ≥3 AEs, including thrombocytopenia (17%), diarrhea (11%), nausea, neutropenia, and fatigue (each 8%). Only 3 (8%) pts had drug-related peripheral neuropathy (PN; no grade ≥3). 2 pts discontinued due to AEs. In 18 response-evaluable pts, 1 had a VGPR at 3.95 mg/m2, 1 had a PR at 2.97 mg/m2, and 8 have achieved SD durable for up to 9.5 mos. PK analyses showed linear plasma PK (0.8–3.95 mg/m2), Tmax of 0.5-2 hr, and terminal half-life of 7 d for MLN2238 (biologically active hydrolysis product). There was a trend for a dose-dependent increase in whole blood 20S proteasome inhibition. Conclusions: Current data suggest weekly oral MLN9708 is generally well tolerated with infrequent PN, and shows early signs of antitumor activity.

7621 Background: Thalidomide (Thal) in combination with dexamethasone (Dex) is an effective therapy for myeloma (MM). Though initially evaluated in MM because of its anti-angiogenic properties, it is not clear how much this contribute to its anti-MM effects. We examined whether the degree of angiogenesis influences response to Thal + Dex, as well as effect of therapy on marrow angiogenesis. We also examined whether expression of angiogenic cytokines by MM cells affect response to therapy. Methods: A total of 207 pts with newly diagnosed MM were randomized on the ECOG phase III trial (E1A00) to either Thal-Dex or Dex alone. Bone marrow microvessel density (MVD) was determined on 88 pts at diagnosis and at 4 mos after therapy in 25 pts. Expression of fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) by MM cells was determined by RTPCR on 60 pts at diagnosis and on 22 pts at 4 mos. In addition, the percentage of marrow PCs in apoptosis was determined at diagnosis and 4 mos in 43 pts. A decrease in the serum M protein by 50% or in its absence, a decrease in urine M protein by 50% was considered a response. Results: The median BM MVD at diagnosis was 33 (3–118), and was similar in the pts responding to therapy (36.4) and in the non responders (45.4). We also separately looked at those receiving the combination vs. Dex alone, and did not find any correlation. The expression of FGF and VEGF in the PCs did not predict response to therapy with either the combination or Dex. Among the 17 responding pts, MVD decreased by a mean of 12 compared to an increase in the mean MVD of 3 among the non responders (P = NS). There was no significant correlation between the level of FGF or VEGF expression and the marrow MVD. There was no correlation between the percentage of myeloma cells in apoptosis at baseline and response to therapy. Conclusion: While the anti-angiogenic activity of Thal may play a role in its anti-myeloma effect, baseline MVD or tumor cell expression of angiogenic cytokines do not predict resistance or response to Thal-Dex or Dex alone. The findings here confirm previous observations that marrow angiogenesis is not related to the degree of secretion of angiogenic cytokines by individual cells, but rather the cumulative effect of the tumor mass. No significant financial relationships to disclose.

7605 Background: In the setting of autologous stem cell transplantation (ASCT) in multiple myeloma (MM), it has been shown that peripheral blood absolute lymphocyte count (ALC) on day 15 is an independent prognostic factor for clinical outcomes. Recently the International Staging System (ISS) for MM has been developed as a simple staging system to assess survival in newly diagnosed MM patients. The role of ALC on survival in newly diagnosed MM patients is unknown. Methods: Between 1994 and 2002, 1,835 consecutive MM patients were evaluated at the Mayo Clinic, Rochester. Of these patients, we retrospectively analyzed 584 MM patients that were originally diagnosed and followed at the Mayo Clinic. The primary end point was to assess the role of ALC at the time of MM diagnosis on overall survival (OS). OS was measured from the date of diagnosis to time of death or last follow-up. ALC was analyzed as a continuous variable and dichotomized based on finding the optimal cut point based on the log-rank statistic. ALC was then compared to the ISS. Results: The median age of the cohort was 67 years (range: 29–94 years), including 234 females and 350 males. The median follow-up was 32 months (range: 1–136 months). The median ALC at diagnosis was 1.2 x 109/L (range: 0.12–5.44 x 109/L). ALC, as a continuos variables was identified as a prognostic factor for OS (HR= 0.466, 95%CI= 0.396–0.547, p < 0.0001). MM patients with an ALC ≥ 1.3 x 109/L experienced a superior OS compared with MM patients with an ALC < 1.3 x 109/L (55.5 months versus 22.6 months, p< 0.0001). In the multivariate analysis, ALC was independent prognostic factor when compared to the ISS (HR = 0.580, 95%CI=0.518–0.647, p< 0.0001). Conclusions: Our study shows that ALC at diagnosis for MM is an independent prognostic factor for OS, suggesting how the host immune status plays a critical role in the survival of patients with MM. No significant financial relationships to disclose.

AbstractObjectivesIn the TOURMALINE‐MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib‐lenalidomide‐dexamethasone (IRd) showed different magnitudes of progression‐free survival (PFS) benefit vs placebo‐Rd according to number and type of prior therapies, with greater benefit seen in patients with >1 prior line of therapy or 1 prior line of therapy without stem cell transplantation (SCT).MethodsRNA sequencing data were used to investigate the basis of these differences.ResultsThe PFS benefit of IRd vs placebo‐Rd was greater in patients with tumors expressing high c‐MYC levels (median not reached vs 11.3 months; hazard ratio [HR] 0.42; 95% CI, 0.26, 0.66; P < .001) compared with in those expressing low c‐MYC levels (median 20.6 vs 16.6 months; HR 0.75; 95% CI, 0.42, 1.2). Expression of c‐MYC in tumors varied based on the number and type of prior therapy received, with the lowest levels observed in tumors of patients who had received 1 prior line of therapy including SCT. These tumors also had higher expression levels of CD19 and CD81.ConclusionsPFS analyses suggest that lenalidomide and ixazomib target tumors with different levels of c‐MYC, CD19, and CD81 expression, thus providing a potential rationale for the differential benefits observed in the TOURMALINE‐MM1 study. This trial was registered at www.clinicaltrials.gov as: NCT01564537

8118 Background: Autologous stem cell transplantation (ASCT) improves survival and remains the standard of care for patients with newly diagnosed myeloma considered eligible for transplant. However, ASCT is not curative and patients relapse after a median interval of 24–30 months. While new therapeutic options have become available for relapsed MM, repeat ASCT remains an option especially when previously collected stem cells are available. The outcome of pts going to a second SCT in the relapsed setting has not been studied extensively. Methods: We identified pts with myeloma who received a second SCT from a prospectively maintained database. Planned tandem ASCTs were excluded. 56 pts received a second SCT for relapsed MM, including 11 allogeneic SCTs. Among the 45 second ASCTs, 5 were followed by reduced intensity allogeneic SCT and were analyzed with the allogeneic group. Results: The median age at second ASCT was 60.2 yrs (range, 41.3–74.4) and 27 (68%) were males. The median time to second ASCT from diagnosis, first ASCT and relapse were 47.4 mos (22.8–158.6), 36.3 mos (13.5–129.8) and 7.2 mos (1–32) respectively. Among patients receiving second APBSC, 14 (35%) patients were alive with a median follow up of 10.5 mos (1–45 mos). All patients received melphalan conditioning. The median time to neutrophil engraftment was 15 days and platelet engraftment was 16 days. The median hospitalization was 4 days (range 0–33) and there was one transplant related death in the group. The best response included 13 pts with CR (33%), 4 with VGPR (10%), and 19 with PR (48%). MM has relapsed in 22 (55%) pts with a median PFS of 12.5 mos from second ASCT. The median estimated OS from diagnosis, first ASCT and second ASCT were 100.5 mos, 65.9 mos, and 30.6 mos respectively. Among the 16 pts receiving allogeneic SCT, 8 pts (50%) were alive at analysis with a median PFS and OS from transplant of 17.9 mos and 33.5 mos respectively. Conclusions: Second ASCT as salvage therapy for relapsed MM is a viable approach and has a favorable outcome in this selected group of patients. The toxicity, engraftment kinetics, hospitalization and the response rates are comparable to patients undergoing initial ASCT. Allogeneic SCT with or with out a preceding ASCT results in comparable survival in selected patients with high risk disease. No significant financial relationships to disclose.

8105 Background: IL-6 is the central myeloma growth factor and we have shown that abnormal production of IL-1beta in the myeloma microenvironment stimulates the generation of paracrine IL-6. A Phase II trial was completed using IL-1ra, which inhibits paracrine IL-6 production, and low dose Dexamethasone (Dex), which decreases IL-1 levels through myeloma cell apoptosis, in patients with smoldering/indolent MM (SMM/IMM). These patients are at the greatest risk for progression to active MM and most likely to benefit from anti- cytokine therapy. Methods: Patients that had ≥ 10% bone marrow plasma cells and/or an IgG or IgA M-spike ≥ 3 g/dL and did not require immediate chemotherapy were eligible. A total of 47 patients received 100 mg of IL-1ra SQ qd for 6 months unless clinical progression occurred. Responding patients were allowed to continue on therapy with IL-1ra alone. Low dose Dex (20 mg qweek) was added after 6 months of IL-1ra in non-responding patients. The primary endpoint was progression-free survival (PFS). Results: The 47 patients were at high risk for progression to active MM with 98% having ≥ 10% plasma cells, 89% generating IL-1 levels consistent with myeloma (≥ 1.0), and 32% having bone lesions. All 47 patients received IL-1ra initially and 25/47 subsequently received IL-1Ra/Dex. For the group of 47 patients, the median overall progression-free survival was 37.5 months. Three patients achieved a minor response (MR) to Anakinra alone; 5 pts achieved a PR and 4 patients an MR after addition of Dex. Seven patients had a decrease in the plasma cell labeling index (PCLI; a marker of myeloma cell growth) on Anakinra alone which paralleled a decrease in the high sensitivity CRP (a marker of serum IL-6 levels). The median PFS for patients without (n=12) and with (n=35) a ≥ 15% decrease in their baseline hsCRP was 6 months and > 3 yrs, respectively (p=0.002). Conclusions: In SMM/IMM patients at high risk for progression to active myeloma, treatment with IL-1 inhibitors (IL-1ra ± Dex) results in an increased PFS in patients that demonstrate a ≥15% reduction in the baseline CRP compared to those that do not respond. No significant financial relationships to disclose.