Abstract: Carfilzomib (Cfz) synergizes with lenalidomide and dexamethasone (Len-dex) to provide impressive response rates as upfront treatment of multiple myeloma (MM) (Jakubowiak et al 2012). The addition of clarithromycin to Len-dex has shown superior time to progression compared to Len-dex alone (Gay et al 2010). We hypothesized that sequential treatment with Cfz-dex and BiRD would lead to enhanced efficacy, response duration, and tolerability. We thus tested a sequential approach of upfront carfilzomib / dexamethasone, consolidation with BiRd, and lenalidomide maintenance to evaluate overall response and safety as first line therapy for MM. Methods Twenty-four patients (pts) with symptomatic untreated MM were enrolled in a single institution study to evaluate the efficacy and tolerability of Car-BiRd. Car-BiRd therapy is: Cfz IV over 30 minutes on Days 1, 2, 8, 9, 15, 16 of a 28-day cycle at a dose of 20mg/m2 on days 1, 2 of the 1st cycle only and 45mg/m2 for each successive dose thereafter and dex 40mg on D1, 8, 15, 22. Cfz-dex was continued until plateau in disease response defined as unchanged M-protein for 2 cycles. Elective autologous stem cell collection was then performed per physician and patient discretion and consolidation with BiRd initiated. Transplant ineligible pts proceeded directly to BiRd. BiRd is: Clarithromycin 500mg BID, lenalidomide 25mg daily on D1-21, and dex 40mg daily D1, 8, 15, 22 of 28-day cycle. Therapy was continued until a 2nd plateau in disease response after which lenalidomide maintenance at a dose of 10mg daily D1-21 of 28 day cycle was continued until disease progression or intolerability. Results 24 pts have currently been enrolled; 23 have completed at least 1 cycle of therapy and were evaluable for response. Sixteen pts (67%) harbored high-risk cytogenetics, as defined by the presence of one or more of the following on iFISH: del 17p, gain 1q, del 1p, t(4;14), t(14;16), or complex karyotypic abnormalities. Median study follow-up was 30.8 weeks (range 4.5-62.2). Response to the Car-BiRD regimen was: overall response rate (ORR) 87%, stringent complete response (sCR) 13%, very good partial response (VGPR) 48%, partial response (PR) 26%, stable disease (SD) 13%. Maximum response to the Cfz-dex induction was: ORR 87%, sCR 9%, VGPR 39%, PR 35%, SD 13%. Median time to PR and maximum response with Cfz-dex was 2 cycles (range 1-2) and 4 cycles (range 1-5) respectively. Median M-spike percentage decrease with Cfz-dex was 92% (range 13-100%). Twelve pts thereafter received BiRD consolidation with 5 pts (41%) further decreasing the M-spike by a median of 8% (range 1-45%). A median of 3 cycles (range 2-7) of BiRD was given until a 2nd response plateau was achieved. Seven pts subsequently received lenalidomide and all have maintained their response after a median of 5 cycles (range 1-8) of follow-up. Seven pts (30%) have come off study, 2 (8%) secondary to disease progression (1 during Car-Dex and 1 during BiRD) and 5 pts (22%) due to toxicity (2 pts due to Grade III renal failure, both attributable to Cfz, and 2 pts due to Grade III CHF during Cfz-Dex, 1 attributable to Cfz; 1 pt with Grade III Thromboembolic event during BiRD, attributable to Len-dex). Discussion This is the first prospective study evaluating the response to induction Cfz/Dex in treatment-naïve MM. Cfz/Dex therapy appears safe and effective in newly diagnosed myeloma patients. Responses deepen with subsequent IMiD(R)-based consolidation and maintenance. Toxicities due to each component of the regimen were manageable. The ORR of 87% and rate of VGPR or better of 61% in group with a high percentage of unfavorable cytogenetics compares favorably to similar studies using 1st generation proteasome inhibitor combinations, and may continue to improve with longer study follow-up. Disclosures: Mark: Onyx: Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Carfilzomib is not approved for front line use in myeloma. Rossi:Celgene: Speakers Bureau. Zafar:Onyx: Speakers Bureau; Millennium: Speakers Bureau; Celgene: Speakers Bureau. Pekle:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Niesvizky:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract: Combination treatment regimens including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD) and a corticosteroid are standards of care for initial treatment of multiple myeloma (MM). We aimed to evaluate if a sequential treatment program using PI induction followed by IMiD based consolidation and maintenance could achieve similar outcomes with reduced toxicities. This phase 2 study was designed to assess the safety and efficacy of the Car‐BiRd regimen: carfilzomib and dexamethasone (Kd) induction until maximum response, followed by lenalidomide, clarithromycin and dexamethasone (BiRd) consolidation until next maximum response, then lenalidomide maintenance in patients with newly diagnosed MM. Seventy‐two patients, including both transplant eligible and ineligible patients, were enrolled and evaluated for response. The overall response rate to the Car‐BiRd regimen was 94% with 83% of patients achieving a ≥ VGPR and 35% achieving a CR/sCR. The rate of CR/sCR increased from 7% with Kd induction to 21% with BiRd consolidation and 35% with lenalidomide maintenance. These results did not meet the study's target endpoint of a CR rate of 55%. The median PFS using this deferred transplant approach was 37.3 months (95% CI 27.9, 52.7) and median OS was not reached with a median follow‐up of 60 months. Toxicities were primarily low grade and manageable. Hematologic toxicities were lower than those expected with a combination PI/IMiD protocol. The sequential Car‐BiRd regimen is an effective and safe approach for the upfront treatment of MM including patients unfit for transplant.

Abstract: Pomalidomide and Carfilzomib (Cfz) are two recently approved agents for the treatment of multiple myeloma (MM) that has relapsed after prior therapy including an IMiD and bortezomib. The sequencing of these agents to achieve maximum tumor reduction is thus far not known. We have previously reported response data from the combination clarithromycin, pomalidomide, dexamethasone (ClaPD) for relapsed or refractory MM. (Mark et al, ASH 2012). We examined the subset of these patients that had received a Cfz-based regimen prior to ClaPD as well as the subset of patients that received a Cfz-based regimen after ClaPD to determine whether the sequence of agents had any impact on response. Methods One hundred nineteen patients with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPD. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included lenalidomide. ClaPD is clarithromycin 500mg twice daily; pomalidomide 4mg for days 1-21, and dexamethasone 40mg on days 1,8,15,22 of a 28-day cycle. Two subsets of patients were compared: 1) Subjects that had received treatment with a Cfz-based prior to ClaPD (CP) and 2) Subjects that had received a Cfz-based therapy after progression on ClaPD (PC). Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Results Fourteen patients comprised CP and 20 in PC. Patients in the CP group were more heavily pre-treated with a median of 6 (range 3-15) lines of therapy, as compared to 5 lines (range 3-10) for PC. Responses are shown in Table 1. Median cycles of ClaPD and Cfz received in PC was 6.5 (range 2-16) and 5 (1-14), respectively. Median cycles of Cfz and ClaPD in the CP group was 8 (1-19) and 5 (1-23), respectively. CR complete response; VGPR: very good partial response; PR: partial response; SD: stable disease; PD: progressive disease; ORR: overall response rate Conclusions ClaPD and a Cfz-based regimen appear to have equally effective response regardless of sequence in salvage chemotherapy. Somewhat deeper responses are seen with ClaPD after Cfz as compared to Cfz after ClaPD, which is intriguing given that the CP group had more prior lines of treatment than PC. Longer follow-up to analyze duration of the response is needed prior to concluding which sequence (PC vs CP) is more effective. This data supports the use of pomalidomide after carfilzomib failure and vice-versa as potent salvage therapeutic options. Disclosures: Mark: Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Zafar:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Onyx: Speakers Bureau. Pekle:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Niesvizky:Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract: Background- Currently combination regimens for induction therapy based around a proteasome inhibitor (PI), an immunomodulatory agent (IMiD) or both are standard for the treatment of newly diagnosed multiple myeloma (NDMM). In phase II studies the combination of Carfilzomib, Lenalidomide and Dexamethasone (Dex) has led to very high rates of overall and deep responses as induction therapy (Jakubowiak Blood 2012). According to the Norton-Simon hypothesis, the sequential, dose-dense use of agents that are not cross-resistant and have minimal overlapping toxicity may eliminate the emergence of residual inherently resistant sub-clones which are responsible for relapse. A sequential approach may also allow for medications to be administered at higher doses and the incorporation of more active agents into an initial therapeutic platform than can be tolerated in a single combinatorial induction approach. To date limited research has been done which evaluates a planned sequential therapeutic protocol built around the successive administration of a highly active PI and IMiD for NDMM. We conducted a phase II study evaluating high dose Carfilzomib and Dex induction (Kd) followed by Lenalidomide, clarithromycin and Dex (BiRD) consolidation and Lenalidomide maintenance in NDMM to evaluate safety and efficacy of this approach Methods Between 2012 and 2015, 72 patients were enrolled in a phase II trial of the CarBiRD regimen for initial treatment of symptomatic NDMM. Patients received Carfilzomib intravenously over 30 minutes on days 1, 2, 8, 9, 15, 16 of a 28 day cycle with Dex 20mg orally on days of Carfilzomib therapy. Carfilzomib was administered at a dose of 20mg/m2 on days 1 and 2 of cycle one of therapy before escalation to target dosing on all subsequent treatment days. The initial protocol was designed with a target Carfilzomib dosing of 45mg/m2, following the enrollment of the first 26 patients on protocol the dosing was increased to 56mg/m2. After maximum response was achieved with Kd, defined as complete response or stable m-protein for 2 consecutive cycles, patients who were eligible for autologous stem cell transplant underwent stem cell collection. Patients then initiated consolidation with Lenalidomide, clarithromycin and Dex (BiRD). BiRD consisted of Lenalidomide 25mg daily on days 1-21 of 28 day cycles, with clarithromycin 500mg twice daily and Dex 40mg on days 1, 8, 15 and 22. BiRD was also continued until achievement of maximum response and patients subsequently initiated maintenance Lenalidomide (Len) at a dose of 10mg on 21 of 28 day cycles. Results 70 out off 72 patients completed at least one cycle of Kd and were evaluated for response. 15 patients came off trial during Carfilzomib therapy: 7 for toxicity, 2 for progression of disease and 6 for either withdrawal of consent, insurance issues or non-compliance. 3 patients came off trial during BiRD consolidation: 1 each for toxicity, progression of disease and withdrawal of consent. The remaining 57 patients initiated BiRD and 54 Len maintenance respectively. Responses are summarized in table 1. The overall response rate was 94% with 84% of patient's achieving a VGPR or better and 37% achieving CR or stringent CR. The rate of CR/sCR increased from 13% (9 of 70 patients) with Kd induction to 28% (16 of 57) with BiRD consolidation and 48% (26 of 54) with Len maintenance. 30% of patients (17 of 57) experience an increased depth of response by at least 1 IMWG response category during BiRD consolidation from their maximum response to Kd. 19% (10 of 54) had an increased depth of response category during Len maintenance. The large majority of adverse events were grade 1 or 2. The most common toxicities across protocol were low-grade gastrointestinal events. The most common grade 3 or higher toxicities were infectious with 17% of patients (12 of 72) experiencing at least one grade 3 or higher infection. Peripheral neuropathy developed in 31% of patients with no grade 3 or higher neuropathy emerging during treatment. The rate of emergent hematologic toxicities was very low across protocol. Discussion CarBiRD is an effective and well-tolerated treatment regimen for patients with NDMM. Using a sequential treatment approach with a highly effective PI and IMiD as the back bones of successive therapies led to high rates of overall response, VGPR or better and complete response in a deferred transplant and transplant ineligible setting. Disclosures Rossi: Takeda: Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Perry:Celgene: Speakers Bureau. Pekle:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Coleman:Immunomedies: Equity Ownership, Other: Leadership; AbbVie: Equity Ownership; Gilead: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Research Funding, Speakers Bureau; Pfizer: Research Funding; GSK: Research Funding; Karyoharm: Research Funding. Allan:Pharmacyclics: Speakers Bureau; Genentech: Speakers Bureau; Abbvie: Speakers Bureau. Niesvizky:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mark:Onyx: Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract: Carfilzomib and dexamethasone (Kd) has significant activity in relapsed and refractory multiple myeloma. Kd has not previously been evaluated in newly diagnosed multiple myeloma (NDMM). We report a single‐arm phase 2 study of 72 patients with NDMM to evaluate the efficacy and tolerability of Kd induction. Carfilzomib was administered in two dosing cohorts with dosing of 20/45 mg/m 2 in the first 25 patients and 20/56 mg/m 2 in the subsequent 47 patients. Carfilzomib was administered on days 1, 2, 8, 9, 15 and 16 of a 28‐day cycle, dexamethasone 20 mg was administered orally on days 1, 2, 8, 9, 15, 16, 22 and 23. Treatment was continued to maximum response, progression of disease, or regimen intolerability. Endpoints included overall response rate (ORR), regimen toxicity and impact of carfilzomib on CD34+ stem cell collection yield. Sixty‐five pts achieved at least a partial response (PR) for an ORR of 90%. The maximum response achieved was complete response or better in 5 (7%), very good partial response (VGPR) in 42 (58%), PR in 18 (25%) and stable disease in 7 pts (10%). Toxicities were predominantly low grade with 547 grade 1/2 adverse events and 44 grade ≥3 events. The rate of grade ≥3 cardiovascular adverse events was 11.1% with eight observed events. The activity of Kd described represents the highest rate of overall response and ≥VGPR for any 2‐agent combination in NDMM reported to date. Kd demonstrated a safety profile consistent with previously reported carfilzomib studies.

Abstract: The First Cambridge Conference on Advances in Treating Metastatic Bone Cancer, a symposium held in Cambridge, Massachusetts, October 28 to 29, 2005, was convened to discuss recent advances and research related to the natural history of bone metastases and skeletal complications, bone cancer biology, treatment of myeloma and other solid tumors, and treatment-induced bone loss. The conference format combined brief presentations with extended periods of discussion. The conclusions reached during the 2-day meeting are summarized in this article and presented in more detail in the individual articles and accompanying discussion sessions that comprise the conference proceedings.

Abstract: Crystal-storing histiocytosis (CSH) is rare in plasma cell dyscrasias, with only 3 cases reported in the setting of amyloid. No cases of crystal-negative histiocytosis coincident with multiple myeloma and amyloidosis have been reported previously. Methods A 58-year-old woman presented with pain due to destructive bone lesions and was found to have plasma cell myeloma (PCM) and marrow amyloid deposition associated with crystal-negative histiocytosis. Differential diagnoses included Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai Dorfman disease. BRAF mutations were negative, and there was no evidence of paraprotein crystals, arguing against typical CSH. Results The patient was treated with bortezomib, cyclophosphamide, and dexamethasone, and she subsequently underwent autologous stem cell transplant and ixazomib maintenance. She achieved complete remission with improvement of her symptoms and preserved remission after following up at 60 months. Conclusions We describe a case of crystal-negative histiocytosis associated with PCM. CSH is a rare disorder associated with paraprotein-producing conditions in which immunoglobulins aggregate as intracellular crystals in the lysosomes of organ-specific phagocytic macrophages. Light chain tropism in PCM can also lead to the development of amyloid deposition in organs and, in rare cases, is associated with light chain aggregation as intracellular crystals in macrophages.

Abstract: Introduction: Thalidomide and the IMiDs are rapidly becoming mainstays in the treatment of multiple myeloma. To improve the efficacy of thalidomide (T) or Revlimid (lenalidomide) (R), we have developed the BLT-D (Biaxin® (clarithromycin) (B), low dose T, and dexamethasone (D)), and the BiRD (B, R, D) regimens. These regimens have produced remarkably high responses, including complete and near complete remissions, with almost every patient not previously exposed to thalidomide. When the BLT-D regimen was initiated, an excessive number of thrombotic episodes were noted. Subsequent to this initial observation, others have also reported an inordinate number of thrombotic events, usually when T was combined with other biological or chemotherapy agents. Given the putative antiangiogenic properties of T or R, we postulated that endothelial damage may be responsible for the enhanced thrombosis and thus, subsequently initiated low dose aspirin (ASA), 81mgs, as prophylaxis in patients (pts) undergoing treatment. We report the effect of low dose ASA as a prophylactic treatment when given to pts receiving L/T containing regimens as follows: A retrospective analysis of pts receiving BLT-D before ASA prophylaxis compared to a similar group after ASA was instituted; An examination of the incidence of thromboembolic phenomena in pts receiving either D alone, not receiving ASA, compared to combined D and low dose T, receiving ASA, as part of a prospective sequential randomized study also studying the impact of subsequent B and 3) An evaluation of thrombosis in pts receiving the BiRD regimen with mandated low dose ASA. Results: Low dose ASA significantly reduced the incidence of thrombosis in pts receiving BLT-D. Of the 60 pts studied, 5 (8%) developed grade 1–2 thrombosis, primarily thrombophlebitis (DVT), and 9 pts (15%) developed grade ≥3 thrombosis, primarily pulmonary embolism (PE) and coronary thrombosis. All episodes of thrombosis occurred prior to the institution of ASA. Slightly less thrombotic events were recorded in pts receiving low dose ASA and the T-D combination with or without B (1/12) when compared to pts not receiving ASA and D with or without B (3/11). 3) Three of 22 pts treated with the BiRD regimen have developed thromboembolic complications, all while off the prescribed ASA. Patient 1, a 44 yo male discontinued (d/c’ed) ASA due to epistaxis. Exactly 7 days after d/c’ing ASA, and while remaining on BiRD, he developed a DVT and PE. Patient 2 underwent exploratory laparotomy to investigate a renal mass. ASA and BiRD were discontinued 7 days prior to surgery. Ten days after surgery, the patient developed DVT. Patient 3 underwent closure of a colostomy; ASA and BiRD were d/c’ed 7 days prior surgery. Two days after the surgery, despite low dose heparin, he suffered a fatal massive PE. No thrombotic episodes with BiRD have not occurred with pts remaining on ASA. Conclusions: Low dose ASA appears to reduce the incidence of thrombosis in pts receiving combination T or R therapy. Endothelial damage may persist beyond the residual salutary effects of discontinued ASA.