BTZ-containing Regimen Research Articles

Carfilzomib, Dexamethasone, and Daratumumab Versus Carfilzomib and Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Primary Analysis Results from the Randomized, Open-Label, Phase 3 Study Candor (NCT03158688)

Carfilzomib, Dexamethasone, and Daratumumab Versus Carfilzomib and Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Primary Analysis Results from the Randomized, Open-Label, Phase 3 Study Candor (NCT03158688)

Safety of BTZ retreatment for patients with low-grade peripheral neuropathy during the initial treatment

Neuropathy is an important complication that may limit treatment options for patients with multiple myeloma. Previous studies have focused on treatment efficacy and have shown that retreatment with bortezomib (BTZ) is an effective treatment option. The goal of this study was to focus on the clinical manifestations of peripheral neuropathy (PN) and to retrospectively compare the incidence and severity of PN between the initial BTZ regimen and upon retreatment. Furthermore, this study evaluated how certain factors affect BIPN, which will help determine what conditions should be considered prior to retreatment. Charts were reviewed from 93 patients who were retreated with a BTZ-containing regimen after previously being treated with this drug. Among the patients who developed PN, most patients in the study had low-grade neuropathy during the initial BTZ treatment (n=52, 68%). The results showed no evidence of cumulative toxicity, and there was no significant difference in the incidence and severity of PN upon retreatment. Factors such as the presence of baseline PN, number of prior treatments, dose of BTZ, and comorbidities did not increase the severity of PN upon retreatment. The lapse of time between the two regimens also did not affect the severity of PN. The results suggest that retreatment with BTZ may be a feasible option, without additional risks of PN, for MM patients even with peripheral neuropathy during their initial treatment with this drug.

Neuropathy and efficacy of once weekly subcutaneous bortezomib in multiple myeloma and light chain (AL) amyloidosis.

IntroductionRandomized studies have shown that bortezomib (BTZ) can be given weekly via intravenous (IV) route or twice weekly via subcutaneous (SC) route with lower neuropathy risk and no loss of anti-myeloma efficacy compared to original standard IV twice weekly schedule. Weekly SC should therefore yield the best therapeutic index and is widely used but has not been compared to established administration schedules in the context of a clinical trial.MethodsComprehensive electronic medical record review was done for disease control and neuropathy symptoms of 344 consecutive patients who received their first BTZ-containing regimen for myeloma or AL amyloidosis before or after we changed to SC weekly in December 2010. Univariate and multivariable analyses were carried out that adjusted for age, underlying disease, concurrently used anticancer agents, underlying conditions predisposing to neuropathy, and number of prior regimens compared SC weekly to other schedules.ResultsFifty-three patients received BTZ SC weekly, 17 SC twice weekly, 127 IV weekly and 147 IV twice weekly. Risk for neuropathy of any grade was higher with other schedules compared to SC weekly (44.3% vs. 26.9%, p = 0.001) while response rate was similar (72.1% vs. 76.6%, respectively, p = 0.15). Multivariable analyses upheld higher neuropathy risk (Odds ratio 2.45, 95% CI 1.26–4.76, p = 0.008) while the likelihood of not achieving a response (= partial response or better) was comparable (Odds ratio 1.25, 95% CI 0.58–2.71, p = 0.56) for other schedules compared to SC weekly, respectively. Lower neuropathy risk translated into longer treatment duration when BTZ was started SC weekly (p = 0.001).ConclusionsWeekly SC BTZ has activity comparable to other schedules and causes low rates of neuropathy.

Cost-effectiveness of bortezomib for multiple myeloma: a systematic review.

ObjectivesTo review published cost-effectiveness analyses (CEA) assessing bortezomib (BTZ) for multiple myeloma (MM) and explore possible bias affecting the cost-effectiveness of BTZ.MethodsLiterature was searched for published CEAs assessing BTZ or BTZ-containing regimens for MM from 2003 to 2015. The reported incremental cost-effectiveness ratios (ICER) were adjusted by 2014 country-specific gross domestic product per capita (GDPPC) to compare the cost-effectiveness threshold of the World Health Organization (3 GDPPC per gained quality-adjusted life year [QALY]).ResultsA total of 17 published CEAs were included in this review. When compared to non-BTZ treatments, BTZ-containing regimens were cost-effective for induction treatment prior to stem cell transplantation (SCT) in Canada, Poland, and Germany (ICER per QALY: 0.9299–2.254 GDPPC). BTZ/melphalan/prednisolone (VMP) was cost-effective for previously untreated and SCT-ineligible MM patients when compared to melphalan plus prednisolone (MP), melphalan/prednisone/lenalidomide with lenalidomide maintenance, and cyclophosphamide/thalidomide/dexamethasone (CTD) (ICER per QALY: dominant to 2.374 GDPPC) in Canada, UK, and USA. BTZ was cost-effective for relapsed/refractory MM when compared to best supportive care (ICER per life year: 0.9317–1.8210 GDPPC) in the UK and the USA, thalidomide in USA (0.5178 GDPPC/LY), and dexamethasone (DEX) in four Nordic countries (€54,451–€81,560/QALY). However, the cost-effectiveness for VMP versus MP plus thalidomide (MPT) and continuous lenalidomide (LEN) plus low-dose DEX (RD) for previously untreated and SCT-ineligible MM patients and BTZ versus LEN/DEX for relapsed/refractory MM patients could be unreliable because of the bias associated with model design and the indirect comparisons of treatment effects.ConclusionPublished CEAs suggested that BTZ or BTZ-containing regimens were cost-effective when compared to most non-BTZ treatments for MM. However, the conflicting cost-effectiveness for VMP versus MPT for previously untreated and SCT-ineligible MM and BTZ versus LEN/DEX for relapsed/refractory MM needs more robust evidence for further clarification.

A Retrospective Study to Evaluate the Incidence and Severity of Peripheral Neuropathy for Relapsed/Refractory Multiple Myeloma Patients upon Retreatment with Bortezomib

Background: Peripheral neuropathy (PN) is associated with multiple myeloma (MM) and often worsened with thalidomide (THAL) and vincristine (VCR) therapy. Bortezomib (BTZ) is a proteasome inhibitor approved for the treatment of MM that has been also shown to cause PN. An increased risk of BTZ-induced PN has been associated with the presence of both PN and diabetes mellitus (DM) before treatment. However, the incidence and characteristics of BTZ-induced PN among MM patients (pts) retreated with another BTZ-containing regimen is unknown. We analyzed the incidence, severity and risk factors for PN after treatment of MM pts with a second BTZ-containing regimen.Methods: Retrospective chart analysis. MM pts that had progressed from at least one prior BTZ-containing regimen and had received treatment with another BTZ-containing regimen were eligible. Pts had to have experienced PN during the course of the first BTZ regimen and could not have received therapy with THAL or VCR. The protocol was later amended to allow inclusion of pts without PN during their first BTZ treatment and those who had received THAL or VCR. Statistical significance was assessed using Fisher’s or McNemar’s tests as appropriate. The relationship between comorbidities, prior THAL or VCR treatment and PN grade after BTZ treatment and re-treatment was analyzed using a multivariate logistics regression model. All statistical analyses were two-sided and were performed at the 0.05 level of significance.Results: As of July 3, 2014, 83 pts have been accrued to the retrospective analysis, and 58 chart reviews have been completed. The median age of pts included in the analysis was 64 years (range: 31-84 years); 57% of the pts were male and 69% were Caucasian. Pts had received a median of 2 prior regimens (range: 2-10); 43% of the pts had received prior regimens containing THAL and 15% of those had also received therapy with VCR. Prior to the protocol amendment, the eligibility criteria required pts to have experienced PN after the first BTZ treatment; therefore, most pts included in this analysis (88%) had PN.During their first BTZ treatment, the most severe grade of PN experienced by the majority of the pts was grade 1 (N=34), followed by grade 2 (N=13) and grade 3 (N=4). A comparison of the symptoms assessed when pts had their most severe grade of PN during this treatment and the severity reported at its onset showed that PN worsened in only 16% of pts. Nearly half (48%) of pts showed no change in PN whereas symptoms improved or resolved in 15% and 9% of the pts, respectively. During treatment with the second BTZ-containing regimen, a comparable proportion of pts (N=44; 76%) reported having experienced PN. Among those experiencing PN upon re-treatment, the most severe grade of PN experienced by the majority of the pts (N=29) was also grade 1, followed by grade 2 (N=12) and grade 3 (N=3). During the second BTZ treatment, a comparison of the symptoms that pts had when PN was at its worst and those recorded at its onset demonstrated that PN worsened in only 7% of the pts. PN showed no change in 47%, improved in 15%, or resolved in 7% of the pts.Interestingly, 17% of the pts (N=10) who had reported PN while receiving their first BTZ-containing regimen did not report this complication during their second BTZ treatment, while 7% of the pts (N=4) experienced PN only upon re-exposure. There was no association between the incidence of PN during the first BTZ treatment and its incidence during re-treatment (p=0.1213) or between the severity of PN (defined as worsening vs. not worsening) after first BTZ treatment and its severity after BTZ re-exposure (p=0.1306).Fifty-four percent of the pts presented with comorbidities, including DM (26%), hypertension (HTN, 22%) and peripheral vascular disease (PVD, 13%). There were no associations between PN grade after BTZ treatment and prior THAL or VCR exposure (p=0.5569) or between PN grade and comorbidities (DM, p=0.6657; HTN, p=0.9966; PVD, p=0.9966). Similar results were found for BTZ re-exposure (THAL or VCR, p=0.8672; DM, p=0.4137; HTN, p=0.2033; PVD, p=0.9954).Conclusions: Results from this retrospective study show that the severity and incidence of PN did not change with a second BTZ-containing regimen. Comorbidities or prior therapy with other PN-inducing agents such as THAL or VCR did not significantly increase the risk of PN after BTZ re-treatment. Enrollment into the study continues and updated results will be presented at the meeting. DisclosuresBerenson:Millennium: Consultancy, Honoraria, Research Funding, Speakers Bureau. Tabbara:Millennium: Speakers Bureau. Lutzky:Millennium: Speakers Bureau. Ailawadhi:Millennium: Consultancy. Moezi:Millennium: Speakers Bureau.

Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Induction Therapy For Newly Diagnosed Light Chain Amyloidosis

Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Induction Therapy For Newly Diagnosed Light Chain Amyloidosis

Clinical Profile Of Single-Agent Modified-Release Oprozomib Tablets In Patients (Pts) With Hematologic Malignancies: Updated Results From a Multicenter, Open-Label, Dose Escalation Phase 1b/2 Study

Clinical Profile Of Single-Agent Modified-Release Oprozomib Tablets In Patients (Pts) With Hematologic Malignancies: Updated Results From a Multicenter, Open-Label, Dose Escalation Phase 1b/2 Study

Time To Event Analyses in PANORAMA 2: A Phase 2 Study Of Panobinostat, Bortezomib, and Dexamethasone In Patients With Relapsed and Bortezomib-Refractory Multiple Myeloma

Time To Event Analyses in PANORAMA 2: A Phase 2 Study Of Panobinostat, Bortezomib, and Dexamethasone In Patients With Relapsed and Bortezomib-Refractory Multiple Myeloma

Results of a phase I/II study (NCT01365559) of carfilzomib (CFZ) replacing bortezomib (BTZ) in BTZ-containing regimens for BTZ-treated patients (pts) with relapsed and refractory multiple myeloma (MM).

8599 Background: Recent data has shown that single-agent CFZ can produce responses among MM pts refractory to previous treatment regimens including those containing BTZ. We conducted an intrapatient phase I/II trial investigating the safety and efficacy of CFZ as a replacement for BTZ in BTZEcontaining regimens to which pts have progressed. Methods: Eligible pts progressed while receiving their most recent BTZEcontaining regimen after at least 4 doses of BTZ at ≥1.0 mg/m² in ≤4 weeks per cycle. CFZ replaced BTZ in each regimen via intravenous administration over 30 min on days 1, 2, 8, 9, 15, and 16 of each cycle. Treatment continued using the same dose(s) and schedule(s) of each drug administered in the BTZEcontaining regimen. CFZ doses were escalated on each of the first 4 cycles from 20 to 27, 36, and 45 mg/m² or until a maximum tolerated dose (MTD) was reached for that regimen. Results: Of 37 enrolled pts, 33 were evaluable for efficacy and 37 for safety. Pts received a median of 4 prior treatments (range, 1-23) and 2 different BTZ-containing regimens (range, 1-13). Pts were treated with CFZ and a variety of different combinations of agents, including: bendamustine, clarithromycin, cyclophosphamide, dexamethasone, melphalan, methylprednisolone, pegylated liposomal doxorubicin, thalidomide, lenalidomide, and ascorbic acid. Pts have completed a median of 3 cycles with 12 pts going on to maintenance. One of 14 combinations, CFZ + ascorbic acid + cyclophosphamide, has reached a MTD at 45 mg/m2. Clinical benefit was seen in 23 (70%) evaluable pts (complete response = 6%; very good partial response = 18%; partial response = 21%; minor response = 24%) with another 18% showing stable disease. The median time to progression is 8.8 mo. (95% CI: 6.4-11.1 mo.) with 21 pts progressing overall and 9 progressing on study treatment. The most common ≥ G3 adverse events were lymphopenia (35% of pts), thrombocytopenia (19%), neutropenia (11%), and anemia (8%). Conclusions: These results suggest that replacement of BTZ with CFZ in a BTZ-containing combination regimen to which a MM patient is failing often leads to responses and is well-tolerated. Clinical trial information: NCT01365559.

Clinical response by baseline characteristics in patients (pts) with relapsed and bortezomib (BTZ)-refractory multiple myeloma treated with panobinostat (PAN), BTZ, and dexamethasone (DEX; PANORAMA 2).

8531 Background: In PANORAMA 2, PAN + BTZ + DEX recaptured responses in heavily pretreated pts with BTZ-refractory MM; overall response rate (ORR), clinical benefit rate (CBR), and progression-free survival (PFS) were 34.5%, 52.7%, and 5.4 months, respectively. Here, we evaluate clinical response per baseline characteristics. Methods: Response was based on European Group of Blood and Marrow Transplantation 1998 criteria. High-risk cytogenetics was defined as del(17p), t(4;14), or t(14;16). Quality of life (QoL) was measured with Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) v4.0 scale. Results: Response rate trended higher in pts whose prior BTZ therapy was not their last line of therapy (Table). Although no trend in response rate was noted, PFS appeared longer in pts progressing within 60 days of their last BTZ-containing regimen than in those progressing on their last BTZ-containing regimen. In the 14 pts with high-risk cytogenetics, ORR was 42.9% and CBR was 71.4%. The mean FACT/GOG-Ntx subscale did not exhibit a clinically meaningful change from baseline (mean ± standard deviation [SD], 114.2 ± 21.1; n = 41) to cycle 9 day 1 (day 169; 104.2 ± 15.4; n = 16) as determined by 50% SD threshold for minimally important difference. Other QoL parameters were similarly unchanged. Conclusions: PAN + BTZ + DEX demonstrated activity regardless of baseline demographics in heavily pretreated pts with BTZ-refractory MM. Clinical trial information: NCT01083602. [Table: see text]

PANORAMA 2: Panobinostat Combined with Bortezomib and Dexamethasone in Patients with Relapsed and Bortezomib-Refractory Multiple Myeloma

Abstract Abstract 1852 Background: There are limited treatment options for patients (pts) with multiple myeloma (MM) whose disease is refractory to bortezomib (BTZ) and are relapsed and/or refractory, intolerant or ineligible to receive an immunomodulatory (IMiD) drug. These pts have a poor prognosis with a response rate for subsequent BTZ-containing regimens of 20% and median event-free survival of 5 months (Kumar S, et al. Leukemia. 2011). Panobinostat (PAN) is an oral pan-deacetylase inhibitor (pan-DACi) that has low nanomolar activity against all class I, II, and IV histone deacetylase enzymes, including those implicated as potential targets in MM. PAN synergizes with BTZ to inhibit both the aggresome and proteasome pathways in preclinical studies. Phase 1 results with PAN + BTZ demonstrated clinical responses in pts with BTZ-refractory disease. PANORAMA 2 expands upon these results and evaluates whether PAN can recapture responses in BTZ-refractory MM pts. Methods: Pts with relapsed and BTZ-refractory MM (≥2 prior lines of therapy including an IMiD and who had progressed on or within 60 days of the last BTZ-based therapy) were treated in this single-arm, phase 2 study with PAN + BTZ + dexamethasone (Dex) in 2 phases. Treatment phase 1 (TP1) consisted of 8 three-week cycles of oral PAN (20 mg) + intravenous BTZ (1.3 mg/m2) + oral Dex (20 mg). Pts demonstrating clinical benefit (≥stable disease [SD]) could proceed to treatment phase 2 (TP2), which consisted of 6-week cycles until disease progression. The primary endpoint was overall response rate (≥partial response [PR]), as defined by the European Group of Blood and Marrow Transplantation (EBMT) 1998 criteria, in TP1. Secondary efficacy endpoints included minimal response (MR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), time to progression (TTP), and overall survival (OS). Secondary safety endpoints included safety and tolerability. Results: Fifty-five pts with BTZ-refractory MM were enrolled (median age, 61 years [range, 41–88 years]). Pts were heavily pretreated with a median of 4 prior regimens (range, 2–11), and a median of 2 prior BTZ-containing regimens (range, 1–6). All pts (100%) were previously treated with BTZ, Dex, and at least 1 IMiD (lenalidomide [98%], thalidomide [69%]). The majority of pts received prior autologous stem cell transplant (64%). Forty-five pts (82%) received Dex with their last BTZ-containing regimen. In the most recent prior line of therapy, 27 pts (49%) had BTZ. As of the February 20, 2012, cutoff, all pts had completed TP1 or stopped treatment, and 7 of the 18 pts who entered TP2 were ongoing. The overall response rate was 35% (1 near complete response [nCR] and 18 PR or better, with 3 pts [5%] achieving a very good partial response [VGPR; Table]). An additional 10 pts achieved MR, for a clinical benefit rate of 53%. The median duration of exposure was 4.6 months (range, < 1–14.8 months). The median PFS and TTP were 4.9 months. The PFS rates for pts whose disease progressed on BTZ (n = 39) and within 60 days of BTZ (n = 16) were 4.2 and 7.6 months, respectively. In pts who achieved a response, the mean TTR was 1.7 months (range, 0.1–3.9), and the median DOR was 6.0 months. With a median follow-up time of 8.1 months, the median OS has not been reached. Common adverse events (AEs) of any grade regardless of study drug relationship included diarrhea (71%), fatigue (69%), thrombocytopenia (65%), nausea (60%), anemia (47%), dyspnea (44%), decreased appetite (42%), and peripheral edema (40%). Common grade 3/4 AEs regardless of study drug relationship included thrombocytopenia (64%), fatigue (20%), diarrhea (20%), anemia (15%), pneumonia (15%), and neutropenia (15%). Only 1 pt (2%) experienced grade 3 peripheral neuropathy. Conclusions: PAN, when combined with BTZ and Dex can recapture responses in heavily pretreated, BTZ- and Dex-refractory MM pts. The regimen was tolerable with manageable toxicities, with 33% of pts on therapy for > 8 cycles. The combination of PAN, BTZ and Dex is therefore an important potential therapeutic option for relapsed and refractory MM pts, including those with BTZ, Dex, and IMiD resistance. Disclosures: Richardson: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Alsina:Millenium: Consultancy, Research Funding. Weber:Novartis: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy. Gasparetto: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. Mukhopadhyay:Novartis: Employment. Ondovik:Novartis: Employment, Equity Ownership. Khan:Novartis: Employment. Paley:Novartis: Employment, Equity Ownership. Schlossman:Celgene: Membership on an entity's Board of Directors or advisory committees.

A phase I/II study of carfilzomib (CFZ) as a replacement for bortezomib (BTZ) for multiple myeloma (MM) patients (Pts) progressing while receiving a BTZ-containing combination regimen.

8098 Background: Recent data has shown that single-agent CFZ can produce responses among MM pts refractory to previous treatment regimens including those containing BTZ. We conducted an intrapatient Phase 1/2 trial investigating the safety and efficacy of CFZ as a replacement for BTZ in BTZ‑containing regimens to which pts have progressed. Methods: Eligible pts had to have progressed while receiving their most recent BTZ‑containing regimen after at least 4 doses of BTZ at > 1.0 mg/m² in < 4 weeks per cycle. Combination regimens containing an alkylating agent, anthracycline, or a glucocorticosteroid were eligible. CFZ replaced BTZ in each regimen via intravenous administration over 30 min on days 1, 2, 8, 9, 15, and 16 of each cycle. Treatment continued using the same dose(s) and schedule(s) of each drug administered in the BTZ‑containing regimen. CFZ doses were escalated on each of the first 4 cycles from 20 to 27, 36, and 45 mg/m² or until a maximum tolerated dose (MTD) was reached for that regimen. Results: Of 19 enrolled pts 13 are evaluable to date and 6 have recently started treatment. Pts received a median of 7 (range, 1-18) prior treatments and 5 (range, 1-5) different BTZ-containing regimens. Pts were treated with CFZ and the following different combinations: bendamustine (BEND) alone, BEND + methylprednisolone, dexamethasone (DEX) alone, DEX + pegylated liposomal doxorubicin, ascorbic acid + cyclophosphamide, and melphalan alone. Pts have completed a median of 3 cycles. Clinical benefit was seen in 10 (77%) pts (complete response = 8%; very good partial response = 8%; partial response = 31%; minor response = 31%) with another 23% showing stable disease. The median time to progression (range: 2-8 months) has not been reached and only 2 pts have progressed. The most common grade 3/4 adverse events were thrombocytopenia occurring in 5 pts (all = grade 3 except 1 event) and fever occurring in two pts (grade 3). Four pts experienced a serious adverse event but no regimen has reached a MTD. Conclusions: These early results suggest that CFZ is an effective and tolerable replacement for BTZ for pts who are refractory to BTZ-containing combination regimens.

The effect of carfilzomib (CFZ) in patients (Pts) with bortezomib (BTZ)-naive relapsed or refractory multiple myeloma (MM): Updated results from the PX-171-004 study.

8026 Background: CFZ, a selective epoxyketone proteasome inhibitor, has potent, sustained action and lacks many BTZ-associated off-target activities. Durable activity has been observed in pts with advanced relapsed/refractory (R/R) MM, including those whose disease progressed on a BTZ-containing regimen. PX-171-004 is an ongoing phase (ph) II study of single-agent CFZ in pts with relapsed MM following 1–3 prior regimens. Here we present updated response, toxicity, and duration of response (DOR) data on BTZ-naive pts treated on this study. Methods: Pts in 2 sequential cohorts (Cohort 1 and Cohort 2) received IV CFZ on Days 1, 2, 8, 9, 15, 16 of every 28-day cycle (C), for up to 12 C. Both cohorts received 20 mg/m2 in C1; Cohort 2 dose escalated to 27 mg/m2 for C2–12. Primary endpoint was overall response rate (ORR) per IMWG criteria. Secondary endpoints were clinical benefit response (CBR), progression-free survival (PFS), DOR, overall survival (OS), time to progression (TTP), and safety. Results: 123 BTZ-naive pts were response-evaluable. Prior therapies included thalidomide (58%), lenalidomide (59%), alkylating agents (82%), and stem cell transplant (73%). 44 patients had disease refractory to the last prior therapy. Median TTP of 8.3 mo and median DOR of 13.1 mo were observed for Cohort 1; median TTP and DOR for Cohort 2 have not been reached. The most common grade (G) 3/4 AEs (all cause) were anemia (13%), lymphopenia (13%), pneumonia (13%), neutropenia (12%), and thrombocytopenia (11%). Treatment-emergent peripheral neuropathy (PN) was infrequent (18%) and mild. Only 1 case of G3 PN was observed. Overall, 49 pts (~40%) completed 12 C (~1 yr) and 27 pts continued CFZ therapy on an extension protocol. Conclusions: At the recommended phase III dose of CFZ, the 53% ORR is noteworthy for a single-agent regimen. Moreover, prolonged CFZ treatment is well-tolerated, with ~ 40% of pts completing 12 C and ~22% continuing treatment beyond 1 yr. Best response Cohort 1 N=59 20 mg/m2 n (%) Cohort 2 N=64 20/27 mg/m2 n (%) CR 2 (3) 1 (2) VGPR 8 (14) 17 (27) PR 15 (25) 16 (25) MR 10 (17) 6 (9) SD 13 (22) 12 (19) ORR (CR + VGPR + PR) 25 (42) 34 (53) CBR (ORR + MR) 35 (59) 40 (63)