Prior Bortezomib Therapy Research Articles

Overall Survival of Patients with Relapsed Multiple Myeloma Treated with Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone According to Prior Line of Therapy and Previous Exposure to Bortezomib: Secondary Analysis of the Phase 3 Endeavor Study

Overall Survival of Patients with Relapsed Multiple Myeloma Treated with Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone According to Prior Line of Therapy and Previous Exposure to Bortezomib: Secondary Analysis of the Phase 3 Endeavor Study

Impact of prior bortezomib therapy on the incidence of lenalidomide-induced skin rash in multiple myeloma: a propensity score-matched multi-institutional cohort study

This retrospective cohort study was conducted to investigate the association between prior bortezomib (BOR) therapy and lenalidomide (LEN)-induced rash in multiple myeloma (MM) patients. Eligible MM patients initially treated with LEN were divided into two propensity score-matched cohorts according to the presence or absence of prior BOR therapy. The primary endpoint of the study was rash incidence. We evaluated 144 patients and each cohort contained 43 patients after matching propensity-score. Rash incidence significantly decreased in patients with prior BOR therapy than in those without (30% vs. 53%, p < .05). Moreover, patients with rash showed a significantly higher incidence of eosinophilia within 1 month after LEN initiation than those without rash. Our findings indicate that prior BOR therapy may reduce the incidence of LEN-induced rash, which may be characterized by eosinophilia. Accordingly, in patients who discontinued LEN therapy due to rash, LEN re-treatment may be successful after BOR therapy.

1026P - Impact of prior bortezomib therapy on the incidence of lenalidomide-induced skin rash in multiple myeloma: A propensity score-matched multi-institutional cohort study

AbstractThis retrospective cohort study was conducted to investigate the association between prior bortezomib (BOR) therapy and lenalidomide (LEN)-induced rash in multiple myeloma (MM) patients. El...

Phase I/II Trial of Plerixafor and Bortezomib As a Chemosensitization Strategy in Relapsed or Relapsed/Refractory Multiple Myeloma

Phase I/II Trial of Plerixafor and Bortezomib As a Chemosensitization Strategy in Relapsed or Relapsed/Refractory Multiple Myeloma

Phase I/II Trial of Plerixafor and Bortezomib As a Chemosensitization Strategy In Relapsed Or Relapsed/Refractory Multiple Myeloma

IntroductionThis study aimed to determine the safety and activity of plerixafor (CXCR4 inhibitor) in combination with bortezomib as a chemosensitization strategy in multiple myeloma (MM). The phase I portion of this study was to determine the maximum tolerated dose (MTD). The phase II portion was designed to assess the toxicity profile and the proportion of overall confirmed response (CR + PR). This was based on preclinical studies demonstrating that plerixafor (Mozobil, Sanofi Corporation, MA) induces de-adhesion of MM cells and sensitization to bortezomib in preclinical animal models. MethodsEligibility criteria included: 1) patients with relapsed or relapsed/refractory MM with 1–5 prior lines of therapy including bortezomib (unless patients were refractory to bortezomib), 2) measurable disease, 3) not receiving chemotherapy > 3 weeks, or biological therapy for MM > 2 weeks prior to study treatment. Phase I included eight cohorts with different doses and two treatment schedules. In cohorts 1–5, patients received plerixafor at the recommended dose subcutaneously (sq) on days 1–6 of each cycle and bortezomib at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. Cohort 5b–7 plerixafor was given at the recommended dose sq on days 1, 3, 6, 10, and 13 and bortezomib was given at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. For the phase II portion patients received plerixafor at the MTD, 320 mcg/kg sq on days 1, 2, 3, 6, 10, and 13. Bortezomib was given 1.3 mg/m2 sq twice a week on days 3, 6, 10, 13, every 21 days. Dexamethasone was given at 40mg on days of Bortezomib. Patients in both cohorts were assessed after every cycle by IMWG criteria. Patients who had a response or stable disease went on to receive a total of 8 cycles with maintenance therapy for patients with at least a minimal response (MR). Peripheral blood samples were obtained from the patients in the phase I portion of trial at 0, 1, 2, 3, 4 and 24 hours post-dose on days 1 and 3, and time points 0, 2, and 4 hours post-dose on days 6, 10 and 13 of cycle 1. ResultsTwenty-five patients were enrolled in the phase I portion of trial from June 2009 to May 2011. Median age was 60 years (range, 44–85) and median lines of prior therapy were 2 (range, 1–4) with all but 3 patients receiving prior bortezomib. The median number of cycles on therapy was 3 (1–11). Dose limiting toxicities including insomnia, restlessness, and psychosis were observed in two patients at dose level 6 (plerixafor 0.40 mg/kg and bortezomib 1.3 mg/m2). To further explore the safety of maximum tolerated dose, three additional patients were enrolled at dose level 5b (plerixafor 0.32 mg/kg and bortezomib 1.3 mg/m2). There were no grade 4 toxicities. Grade 3 toxicities included lymphopenia (40%), hypophosphatemia (20%), anemia (10%), hyponatremia (10%), hypercalcemia (10%), and bone fracture due to myeloma bone disease (10%). In the phase II portion, eleven patients have been treated to date. The median age is 65 (56-80), the median lines of prior therapy were 2 (1-4). The median number of cycles on therapy was 4 (1-8). Grade 4 toxicities include lymphopenia (10%) and thrombocytopenia (20%). Grade 3 toxicities include anemia (10%), thrombocytopenia (10%), lymphopenia (20%), hyperglycemia (10%), and hypophosphatemia (10%). Ten patients are evaluable for response, including 1(10%) very good partial response (VGPR) and 3 (30%) partial response (PR), with an overall response rate (VGPR + PR) of 4 (40%) in this relapsed/refractory population. In addition, 4 (40%) patients had stable disease (SD), and 2 (20%) had progressive disease (PD). We also examined in vivo mobilization of plasma cells, CD34+ hematopoietic stem cells and other accessory bone marrow cells. Analysis of these samples showed rapid mobilization of plasma cells at 2 hours post-plerixafor with a rapid return to normal levels at 4 and 24 hours post plerixafor. Similar results were observed on days 1 and 3. ConclusionsThe combination of plerixafor and bortezomib was generally well tolerated in this study, with minimal neuropathy or other toxicities seen to date. The responses observed are encouraging with 40% PR or better in this relapsed and refractory population including prior bortezomib therapy. This study was supported by R01CA133799-01, and by Sanofi and Millennium/Takeda Corporations. Disclosures:Ghobrial:Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Sanofi: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Munshi:Celgene: Consultancy; Novartis: Consultancy; Millennium: Consultancy. Anderson:celgene: Consultancy; onyx: Consultancy; gilead: Consultancy; sanofi aventis: Consultancy; oncopep: Equity Ownership; acetylon: Equity Ownership. Richardson:Millenium: Consultancy; Celgene: Consultancy; Johnson & Johnson: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy.

Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma

BackgroundBruton's tyrosine kinase (BTK) is a mediator of the B-cell–receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma.MethodsIn this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety.ResultsThe median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.ConclusionsIbrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)

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]

A Phase 2 Study of Prolonged Carfilzomib Therapy in Patients with Multiple Myeloma Previously Enrolled in Carfilzomib Clinical Trials.

AbstractAbstract 2962 Background:Carfilzomib (CFZ) is a next-generation selective proteasome inhibitor for the treatment of patients with relapsed and refractory multiple myeloma. PX-171-010 (NCT00884312) is a phase 2 extension study for patients who had previously received CFZ treatment in any phase 1 or 2 study, typically for 12–18 months. Herein we report updated safety and efficacy results for patients enrolled in this ongoing study. Methods:The primary endpoint was safety, and patients were also followed for efficacy. All serious adverse events (SAEs), peripheral neuropathy (PN) AEs, and AEs ≥Grade 3 were to be reported, as were any AEs resulting in dose modifications. Patients were evaluated for response every 2 cycles, although more frequent assessments were permitted per local standards of care. Investigator-assessed responses are reported here. Regimen changes consisted of the following: i) changes in CFZ dosing (increases to achieve or maintain disease control or decreases for toxicity); ii) the addition of other approved anti-MM agents at the time of confirmed or suspected progression; and iii) a combination of i) and ii). CFZ dosing could range from 11 mg/m2 to 56 mg/m2with a dose frequency of Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle or alternatively Days 1, 2, 15, and 16. Results:A total of 98 patients were enrolled, including 9 patients with solid tumors and 89 patients with MM. At the time of 010 enrollment, the median time since diagnosis for MM patients was 4 years (range, 1–24), and 46.1% had received prior bortezomib therapy. Overall in the safety population (N=98), patients during the 010 study started a median of 10.5 cycles (range, 1–33) of CFZ. When considering treatment during a prior CFZ study as well, total exposure to CFZ was a median of 22 cycles or 89 weeks. The CFZ regimen was changed in 60% of patients during 010; reasons included confirmed or suspected PD (43.9%), AEs (9.2%), and/or other reasons (eg, patient preference, investigator discretion; 20.2%). The median number of regimen changes was 1 (range, 0–7). The CFZ dose was increased in 25.5% of patients, and in 42%, CFZ was used in combination with other anti-MM agents, including dexamethasone (34.7%), lenalidomide (22.4%), and cyclophosphamide (17.3%). Overall, AEs were reported in 82.7% of patients, the most common being upper respiratory tract infection (17.3%), fatigue (17.3%), and anemia (16.3%). Of note, 6.1% reported PN with just 1 patient experiencing a Grade 3 event. SAEs were reported in 50% of patients, most commonly pneumonia (8.2%), influenza (6.1%), dyspnea (6.1%), pyrexia (5.1%), and acute renal failure (5.1%). Discontinuation due to an AE occurred in 11.2%, the most common reason being myocardial infarction (2%). There have been 5 deaths on study with 3 due to AEs (1 related to CFZ), events being myocardial infarction, pneumonia, and 1 pt with both myocardial infarction and pneumonia as cause of death, and 2 due to PD (1 with associated Grade 5 hypercalcemia). The table summarizes response data by CFZ regimen for patients with MM during 010 through the third regimen (at the time of abstract submission, limited response data were available for patients who received ≥4 regimens).Response Status at Baseline for MM PatientsRegimen* During 010 Study for MM Patients(n = 76)1 (n = 39)2 (n = 30)3 (n = 14)ORR, %48.743.630.021.4CBR, %59.251.336.735.7DOR, median (range), monthsNA20.0 (11.3–23.4)18.0 (2.6–NE)NECBR, clinical benefit rate (≥minimal response); DOR, duration of response; NA, not applicable; NE, not estimable; ORR, overall response rate (≥partial response)*Regimen 1 is defined as the first treatment patients received on the 010 study, with every subsequent change indicated by a serial increase in regimen numbers. Conclusions:Extended treatment with CFZ as single agent or in combination with other anti-MM therapy was well tolerated with a safety profile that was consistent with previous CFZ studies. Notably, there was no evidence of unique or late-onset cumulative toxicity. When compared to previous phase 1 and 2 CFZ trials, PN incidence continued to be low and was generally mild to moderate in severity. Similarly, and importantly, patients continued to obtain clinically meaningful responses with multiple regimen and dose changes. Taken together, the safety profile, long-term tolerability, and responses associated with extended treatment with CFZ are promising. Disclosures:Siegel:Millennium: Advisory Boards, Advisory Boards Other, Honoraria, Speakers Bureau; Merck: Advisory Boards, Advisory Boards Other, Honoraria, Speakers Bureau; Celgene: Advisory Boards, Advisory Boards Other, Honoraria, Speakers Bureau; Onyx Pharmaceuticals: Advisory Boards Other, Honoraria, Speakers Bureau. Off Label Use: Carfilzomib (CFZ) is a next-generation selective proteasome inhibitor that was recently approved for the treatment of patients with relapsed and refractory multiple myeloma. Wang:Onyx Pharmaceuticals: Honoraria, Research Funding. Martin:Onyx Pharmaceuticals: Consultancy; Celgene: Honoraria. Kaufman:Onyx Pharmaceuticals: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millenium: Consultancy. Ranjangam:Onyx Pharmaceuticals: Employment. Huang:Onyx Pharmaceuticals: Employment. Bilotti:Celgene: Consultancy, Speakers Bureau; Onyx Therapeutics: Consultancy. Vij:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium: Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Research Funding.

Phase I trial of obatoclax mesylate in combination with bortezomib for treatment of relapsed multiple myeloma.

8013 Background: Obatoclax mesylate (GX15-070MS) is a BH3 mimetic that inhibits Bcl-2 protein family members including MCL-1, a dominant target in myeloma (MM). Obatoclax (OBX) inhibited viability of 14 MM cell lines (mean IC50 215 nM) and primary MM samples while exhibiting pre clinical synergy with bortezomib (BTZ). Sensitivity correlated with basal levels of Mcl-1 and Bcl-XL, but not Bcl2, Bim, Bax or Bak expression. Methods: We report a phase I trial of OBX in combination with BTZ. Eligibility required measureable disease, &gt; 1 prior MM therapy, ≤10 cycles of prior BTZ and did not progress on prior BTZ therapy, creatinine ≤2 ULN. Starting dose level 1 was OBX 14 mg/m2 24-hour continuous iv. infusion days 1, 8, 15 of a 21-day cycle. BTZ given at 1.3mg/m2 iv. days 1, 4, 8 and 11. After protocol amendment OBX level 1 dosing was 30 mg/m2, level 2 was 40 mg/m2 IV both by continuous 3 hour infusion days 1, 8 and 15 on a 21 day schedule. Pre med. with famotidine was required. Results: Eleven patients were accrued, median age 62 (range: 46-77), median time from diagnosis was 4.7 years. Median of 2.5 cycles (range: 1-10). Median follow-up for patients still alive is 11.6 months (range: 0.9-35.5). At dose level 1, there were 2 DLTs. After amendment 8 patients were accrued (3 hour infusion): 4 at amended dose level 1 and 4 at dose level 2. All patients are now off treatment. 10 patients are evaluable for response: 2 patients at original dose level 1 (2 PR), 3 patients at dose level 1 (2 PR, 1 MR), no patients at dose level 2 responded: overall PR of 40%, clinical benefit response in 50% (95% CI: 19-81%). 6 patients had disease progression and 2 patients died. 4 DLTs were seen: at original dose level 1 grade 4 thrombocytopenia and delay of therapy &gt; 15 days. At dose level 2, 1 patient had grade 3 somnolence, a 2nd patient grade 3 euphoria and grade 4 thrombocytopenia. No DLTs were seen at amended dose level 1. Common adverse events of any grade included GI, hematologic and neurologic e.g. euphoria, decreased level of consciousness, psychosis, speech. Conclusions: In summary MTD is OBX 30mg/m2 by 3 hour iv infusion once weekly, BTZ 1.3 mg/m2 days 1,4,8, and 11. Major toxicities were central neurologic and hematologic. This P2C consortium study was supported by NCI N01-CM62205.

Efficacy and safety of lenalidomide oral monotherapy in patients with relapsed or refractory mantle-cell lymphoma: Results from an international study (NHL-003)

8569 Introduction: Relapsed or refractory MCL patients demonstrated a promising overall response rate (ORR) of 53% with a median duration of response (DR) of 13.7 months to single-agent lenalidomide when analyzed as a subset in a recent a phase II study (NHL-002). A supporting international phase II trial (NHL-003) of single-agent lenalidomide was initiated for patients with relapsed or refractory aggressive NHL. In this report, we analyze the current results from the MCL patients enrolled in this trial. Methods: Patients with relapsed or refractory MCL and measurable disease 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg of lenalidomide orally once daily on days 1–21 of every 28-day cycle. Patients continued therapy until disease progression or toxicity. The 1999 IWLRC methodology was used to assess response and progression. Results: Fifty-four MCL patients were enrolled and were evaluable for response assessment. Median age was 69 years (33–82) and 40 patients (74%) were male. Median time from diagnosis was 3.2 years (0.4–10.4), patients had received a median of 3 prior treatments (1–8), 17 of the patients (32%) had received prior bortezomib therapy (MCL-bortezomib), and 14 (26%) had received a prior stem cell transplant (MCL-stem cell). Response rates are shown in the Table. The most common grade 3 or 4 adverse events were neutropenia (43%), thrombocytopenia (22%) and anemia (11%). Conclusions: This is the second study to demonstrate that lenalidomide oral monotherapy is effective in the treatment of patients with relapsed or refractory MCL, with manageable side effects. [Table: see text] [Table: see text]

Phase I Trial of CCI-779 (Temsirolimus) and Weekly Bortezomib in Relapsed and/or Refractory Multiple Myeloma

BACKGROUND: Preclinical studies have demonstrated activity of the combination of mTOR inhibitors and bortezomib in Multiple Myeloma (MM). Single agent mTOR inhibitors (including CCI-779) have shown modest activity in MM. The objective of this phase I dose-escalation study was aimed to determine the maximum tolerated dose (MTD) as well as the activity of the combination of CCI-779 (Wyeth Pharmaceutical, PA) and bortezomib (Millennium Pharmaceutical, MA) in patients with relapsed and/or relapsed, refractory MM.METHODS: Four cohorts (3 patients each) were planned, with dosing of bortezomib 1.3 or 1.6mg/m2 (days 1, 8, 15 and 22) every 35 days (1 cycle) and CCI-779 15 or 25 mg IV (days 1, 8, 15, 22 and 29) every cycle. Dexamethasone was not permitted during therapy. NCI CTCAE v3.0 was used for toxicity assessment; Dose limiting toxicity (DLT) was defined as any grade (G) 3 or greater non-hematologic toxicity related to therapy, G4 neutropenia for 7 d and/or neutropenic fever, or platelets <10,000/mm3 on >1 occasion despite transfusion, inability to receive day 1 dose for cycle 2 due to toxicity. Response was assessed by modified EBMT criteria. Prior therapy with bortezomib or CCI-779 was allowed. Patients remained on therapy until progression of disease or intolerance.RESULTS: Twenty patients (13 men and 7 women) have been treated to date, of these 5 were on cohort 3 and 9 on cohort 4. The median age was 58 yrs (range: 48–81), and median number of prior therapies was 5 (range: 1–10), including prior stem cell transplant with autologous, or allogeneic transplant, bortezomib, lenalidomide, thalidomide, and combination chemotherapy. All of the patients had received prior bortezomib therapy except for one patient. One DLT was observed in cohort 4 (death due to sepsis and septic shock grade 5, possibly related to therapy and underlying myeloma). Cohort 4 was expanded and no further DLTs were observed. MTD was therefore declared at CCI-779 of 25 mg and bortezomib of 1.6mg/m2. Grade (G) 3 and 4 related toxicities included thrombocytopenia (G3 in 35%, G4 in 25%) leucopenia and neutropenia G3 in 25% with no G4 toxicity, G3 anemia in 15%, and nausea, vomiting, viral infection, hyponatremia, pneumonia, hyperglycemia, mucositis, fatigue, and renal insufficiency in 2% of patients. No significant (G2 to G4) peripheral neuropathy has been seen thus far. No anticoagulant prophylaxis has been required, and no DVTs have occurred. The median time of follow up is 6 months (1–13 months). Response was assessed after completion of 2 cycles of therapy. In 15 evaluable patients, the overall response rate (CR+PR+MR) was 33% (5 patients), including 1nCR and 4 MR. The median time of therapy of patients who achieved response was 8 months (2–12 months). All responses occurred in patients who have received prior bortezomib. Six patients had stable disease for a median of 7 months (6–11 months), and 4 patients showed progression of disease (at 3–5 months post initiation of therapy). Responses occurred in the early cohorts indicating activity of these agents even at lower doses.Conclusions: The combination of CCI-779 25 mg and weekly bortezomib 1.6mg/m2 weekly is active and well tolerated, and minimal peripheral neuropathy to date. The ORR of 33% in heavily pretreated patients with MM, including prior bortezomib therapy, is encouraging. The phase II trial using the MTD of this combination is currently being initiated and enrollment is ongoing.

Combination of Vorinostat Plus Bortezomib for the Treatment of Patients with Multiple Myeloma Who Have Previously Received Bortezomib

The proteasome inhibitor bortezomib represents an important advance for the treatment of both previously untreated and treated patients with multiple myeloma (MM). However, nearly all patients eventually relapse or become refractory to bortezomib therapy, so there is a continued need for new therapies. Vorinostat is a potent oral inhibitor of Class I and II histone deacetylases (HDACs) and has demonstrated antiproliferative and proapoptotic activity alone and in combination with bortezomib in preclinical models of MM. Preliminary results from an open-label, multicenter Phase I trial of oral vorinostat in combination with bortezomib have shown that the combination is generally well tolerated and effective in heavily pretreated patients with advanced MM (Weber et al. Haematologica 2008; 93(S1):0640). Patients (aged ≥18 years with an ECOG performance status 0–2) were sequentially enrolled on escalating doses of vorinostat combination therapy using a standard 3+3 design for ≤8 cycles. Cycles were repeated every 21 days and consisted of vorinostat 200 mg bid or 400 mg daily (Days 1–14) in combination with bortezomib 0.7 or 0.9 mg/m2 i.v. on Days 4, 8, 11, and 15 or escalated to 0.9, 1.1, or 1.3 mg/m2 i.v. on Days 1, 4, 8, and 11. The addition of oral dexamethasone 20 mg on Days 1–4 and 9–12 was allowed for disease progression. We now report the safety and efficacy results for a cohort of patients with relapsed/refactory MM who were previously treated with bortezomib but not within 3 months prior to study enrollment. To date, 13 patients who received prior bortezomib therapy have been enrolled in the trial. Drug-related adverse events (AEs) occurred in 11/13 patients; 90% of these AEs were mild to moderate in severity and 5 patients had serious AEs (7 events). One patient experienced Grade 4 thrombocytopenia, and 8 patients experienced Grade 3 drug-related AEs. The most common drug-related toxicities of any grade were fatigue, nausea and diarrhea. Eleven patients have now discontinued treatment: 6 due to progressive disease and 5 due to AEs. For the 13 patients previously treated with bortezomib, the best response was partial response in 5 patients (duration 99 to 203 days), minimal response in 1 patient (duration 122 days) and stable disease in 7 patients (duration 25 to 320 days). These preliminary data indicate that in this important subset of patients with MM who have relapsed while on, or were refractory to, previous bortezomib therapy, this combination of bortezomib and vorinostat (+/− dexamethasone) administered in a 21-day cycle shows activity, with acceptable tolerability. Further to these promising early findings, data will be presented according to whether patients had relapsed or refractory MM after prior bortezomib. The effect of adding dexamethasone to the combination of vorinostat and bortezomib will also be presented. Supplementary studies in patients clearly resistant to bortezomib are warranted to determine the additional effect of vorinostat in this combination.

A Phase I/II Trial Evaluating the Combination of Arsenic Trioxide, Bortezomib and Ascorbic Acid for Patients with Relapsed or Refractory Multiple Myeloma.

Background: Both arsenic trioxide and bortezomib as single agents have shown efficacy for patients with relapsed/refractory multiple myeloma (MM). Recently, we have demonstrated synergistic anti-MM effects when these two agents are combined to treat human MM in SCID mice and evaluated in in vitro studies. In addition, we and others have also shown that the addition of ascorbic acid (AA) sensitizes MM cells to the cytotoxic effects of arsenic trioxide both through in vitro and in vivo studies. Thus, the objective of the current Phase I clinical trial was to assess the safety and tolerability of bortezomib + arsenic trioxide + AA treatment for patients with refractory/relapsed MM.Methods: A treatment cycle comprised of intravenous injections of arsenic trioxide, bortezomib and AA on days 1, 4, 8, and 11 followed by a 10-day rest period every three weeks. Bortezomib was given at one of three dose levels (0.7, 1.0, or 1.3 mg/m2), followed by arsenic trioxide at one of two doses (0.125 or 0.25 mg/kg) intravenously followed by AA (1000 mg). Patients were treated for a maximum of eight cycles and were eligible for maintenance therapy with the same treatments given once every other week.Results: Eighteen patients have been enrolled to date, with three patients enrolled in each of the six cohorts. Patients had received a median of three prior therapies (range, 1–6), and five patients had received prior bortezomib therapy. Fifteen patients are evaluable for efficacy to date, and response data are summarized in Table 1. Overall, among the 15 evaluable patients, seven patients responded (2 PR, 5 MR), three patients showed stable disease, and five patients progressed. Among the six patients (in cohorts 1 and 4) enrolled at the lowest (0.7 mg/m2) bortezomib dose level, only one achieved a MR whereas among the nine evaluable patients enrolled at the higher (1.0 and 1.3 mg/m2) bortezomib dose levels six patients responded (2 PR, 4 MR). In general, the regimen was well tolerated. One patient in cohort 3 was removed from study during the first cycle because of the development of an asymptomatic arrhythmia which resolved spontaneously. Other serious adverse events included pneumonia in two patients, chest pain, and abdominal pain (one patient each).Conclusion: These early results from this Phase I/II study indicate that the combination of bortezomib, arsenic trioxide and ascorbic acid has efficacy and is well tolerated in a heavily pretreated population of patients with relapsed or refractory MM. Because of these encouraging clinical results, we plan to further evaluate this combination in a larger group of patients with relapsed/refractory myeloma.Table 1Dose escalation schemeCohortsArsenic trioxideBortezomibNo. of evaluable ptsResponseCohort 10.125 mg/kg0.7 mg/m231 MR, 2 PDCohort 20.125 mg/kg1.0 mg/m231 PR, 1 SD, 1 PDCohort 30.125 mg/kg1.3 mg/m21*1 PRCohort 40.25 mg/kg0.7 mg/m231 SD, 2 PDCohort 50.25 mg/kg1.0 mg/m233 MRCohort 60.25 mg/kg1.3 mg/m22*1 SD, 1 MR*one patient in cohort 3 went off study during cycle 1 (see above), and the other two patients (one each in cohorts 3 and 6) are too early for response evaluation