scholarly journals A phase 1b study of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma

Blood ◽  
2019 ◽  
Vol 134 (2) ◽  
pp. 123-133 ◽  
Author(s):  
Joseph Mikhael ◽  
Paul Richardson ◽  
Saad Z. Usmani ◽  
Noopur Raje ◽  
William Bensinger ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Clinical Activity ◽  
Upper Respiratory Tract ◽  
Dose Escalation Study ◽  
Refractory Multiple Myeloma ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Phase 1B

Abstract This phase 1b dose-escalation study evaluated isatuximab plus pomalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior MM therapies, including lenalidomide and a proteasome inhibitor (PI), were enrolled and received isatuximab at 5, 10, or 20 mg/kg (weekly for 4 weeks, followed by every 2 weeks), pomalidomide 4 mg (days 1-21), and dexamethasone 40 mg (weekly) in 28-day cycles until progression/intolerable toxicity. The primary objective was to determine the safety and recommended dose of isatuximab with this combination. Secondary objectives included evaluation of pharmacokinetics, immunogenicity, and efficacy. Forty-five patients received isatuximab (5 [n = 8], 10 [n = 31], or 20 [n = 6] mg/kg). Patients received a median of 3 (range, 1-10) prior lines; most were refractory to their last regimen (91%), with 82% lenalidomide-refractory and 84% PI-refractory. Median treatment duration was 9.6 months; 19 patients (42%) remain on treatment. Most common adverse events included fatigue (62%), and upper respiratory tract infection (42%), infusion reactions (42%), and dyspnea (40%). The most common grade ≥3 treatment-emergent adverse event was pneumonia, which occurred in 8 patients (17.8%). Hematologic laboratory abnormalities were common (lymphopenia, leukopenia, anemia, 98% each; neutropenia, 93%; and thrombocytopenia, 84%). Overall response rate was 62%; median duration of response was 18.7 months; median progression-free survival was 17.6 months. These results demonstrate potential meaningful clinical activity and a manageable safety profile of isatuximab plus pomalidomide/dexamethasone in heavily pretreated patients with RRMM. The 10 mg/kg weekly/every 2 weeks isatuximab dose was selected for future studies. This trial was registered at www.clinicaltrials.gov as #NCT02283775.

scholarly journals Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma

2021 ◽  
Vol 11 (2) ◽  
Author(s):  
Jacob P. Laubach ◽  
Sascha A. Tuchman ◽  
Jacalyn M. Rosenblatt ◽  
Constantine S. Mitsiades ◽  
Kathleen Colson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Dose Escalation Study ◽  
Refractory Multiple Myeloma ◽  
Duration Of Response ◽  
Label Dose ◽  
Grade 3

AbstractAdditional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50–77]) and a median of four prior regimens (range: 2–14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1–74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.

scholarly journals Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma

2020 ◽  
pp. JCO.20.02259
Author(s):  
Paul G. Richardson ◽  
Albert Oriol ◽  
Alessandra Larocca ◽  
Joan Bladé ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Free Survival ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

scholarly journals Carfilzomib Based Treatment Strategies in the Management of Relapsed/Refractory Multiple Myeloma with Extramedullary Disease

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1035 ◽  
Author(s):  
Xiang Zhou ◽  
Patricia Flüchter ◽  
Katharina Nickel ◽  
Katharina Meckel ◽  
Janin Messerschmidt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Serological Response ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Extramedullary Disease ◽  
Heavily Pretreated ◽  
Pretreated Patients

Published experience with carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) and extramedullary disease (EMD) is still limited. The current study aimed to assess the efficacy and safety of carfilzomib containing therapy regimens in EMD. We retrospectively analyzed 45 patients with extramedullary RRMM treated with carfilzomib from June 2013 to September 2019. The median age at the start of carfilzomib was 64 (range 40–80) years. Twenty (44%) and 25 (56%) patients had paraosseous manifestation and EMD without adjacency to bone, respectively. The serological overall response rate (ORR) was 59%. Extramedullary response was evaluable in 33 patients, nine (27%) of them achieved partial remission (PR) (ORR = 27%). In 15 (33%) patients, we observed no extramedullary response despite serological response. The median progression-free survival (PFS) and overall survival (OS) were five (95% CI, 3.5–6.5) and ten (95% CI, 7.5–12.5) months, respectively. EMD without adjacency to bone was associated with a significantly inferior PFS (p = 0.004) and OS (p = 0.04) compared to paraosseous lesions. Carfilzomib based treatment strategies showed some efficacy in heavily pretreated patients with extramedullary RRMM but could not overcome the negative prognostic value of EMD. Due to the discrepancy between serological and extramedullary response, evaluation of extramedullary response using imaging is mandatory in these patients.

scholarly journals Single-agent belantamab mafodotin for relapsed/refractory multiple myeloma: analysis of the lyophilised presentation cohort from the pivotal DREAMM-2 study

2020 ◽  
Vol 10 (10) ◽  
Author(s):  
Paul G. Richardson ◽  
Hans C. Lee ◽  
Al-Ola Abdallah ◽  
Adam D. Cohen ◽  
Prashant Kapoor ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Agent ◽  
Pathological Finding ◽  
Progression Free Survival ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Blurred Vision ◽  
Refractory Multiple Myeloma ◽  
Open Label Phase ◽  
Duration Of Response

Abstract DREAMM-2 (NCT03525678) is an ongoing global, open-label, phase 2 study of single-agent belantamab mafodotin (belamaf; GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, in a frozen-liquid presentation in patients with relapsed/refractory multiple myeloma (RRMM). Alongside the main study, following identical inclusion/exclusion criteria, a separate patient cohort was enrolled to receive belamaf in a lyophilised presentation (3.4 mg/kg, every 3 weeks) until disease progression/unacceptable toxicity. Primary outcome was independent review committee-assessed overall response rate (ORR). Twenty-five patients were enrolled; 24 received ≥1 dose of belamaf. As of 31 January 2020, ORR was 52% (95% CI: 31.3–72.2); 24% of patients achieved very good partial response. Median duration of response was 9.0 months (2.8–not reached [NR]); median progression-free survival was 5.7 months (2.2–9.7); median overall survival was not reached (8.7 months–NR). Most common grade 3/4 adverse events were keratopathy (microcyst-like corneal epithelial changes, a pathological finding seen on eye examination [75%]), thrombocytopenia (21%), anaemia (17%), hypercalcaemia and hypophosphatemia (both 13%), neutropenia and blurred vision (both 8%). Pharmacokinetics supported comparability of frozen-liquid and lyophilised presentations. Single-agent belamaf in a lyophilised presentation (intended for future use) showed a deep and durable clinical response and acceptable safety profile in patients with heavily pre-treated RRMM.

scholarly journals Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study

Blood ◽  
2012 ◽  
Vol 119 (20) ◽  
pp. 4608-4613 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Amy O'Sullivan ◽  
Ryan C. Kennedy ◽  
Mohammad Abbas ◽  
Lijun Dai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Response Rate ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Dose Escalation Study ◽  
Refractory Multiple Myeloma ◽  
One Year

Abstract This multicenter phase 1/2 trial investigated the combination of bendamustine, lenalidomide, and dexamethasone in repeating 4-week cycles as treatment for relapsed refractory multiple myeloma (MM). Phase 1 established maximum tolerated dose (MTD). Phase 2 assessed overall response rate at the MTD. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A total of 29 evaluable patients were enrolled. Median age was 63 years (range, 38-80 years). Median number of prior therapies was 3 (range, 1-6). MTD was bendamustine 75 mg/m2 (days 1 and 2), lenalidomide 10 mg (days 1-21), and dexamethasone 40 mg (weekly) of a 28-day cycle. Partial response rate was 52%, with very good partial response achieved in 24%, and minimal response in an additional 24% of patients. Median follow-up was 13 months; median OS has not been reached. One-year OS is 93% (95% confidence interval [CI], 59%-99%). Median PFS is 6.1 months (95% CI, 3.7-9.4 months) with one-year PFS of 20% (95% CI, 6%-41%). Grade 3/4 adverse events included neutropenia, thrombocytopenia, anemia, hyperglycemia, and fatigue. This first phase 1/2 trial testing bendamustine, lenalidomide, and dexamethasone as treatment of relapsed refractory MM was feasible and highly active. This study is registered at www.clinicaltrials.gov as #NCT01042704.

scholarly journals Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma

Blood ◽  
2019 ◽  
Vol 134 (5) ◽  
pp. 421-431 ◽  
Author(s):  
Ajai Chari ◽  
Joaquín Martinez-Lopez ◽  
María-Victoria Mateos ◽  
Joan Bladé ◽  
Lotfi Benboubker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Common Grade ◽  
Frontline Treatment ◽  
Phase 1B ◽  
Immunomodulatory Drug ◽  
Grade 3

Abstract Patients with relapsed or refractory multiple myeloma (RRMM) have limited treatment options and poor survival outcomes. The increasing adoption of lenalidomide-based therapy for frontline treatment of multiple myeloma has resulted in a need for effective regimens for lenalidomide-refractory patients. This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with RRMM after 1 to 3 prior lines of therapy, including bortezomib and an immunomodulatory drug; lenalidomide-refractory patients were eligible. Carfilzomib- and daratumumab-naïve patients (n = 85) received carfilzomib weekly on days 1, 8, and 15 of each 28-day cycle (20 mg/m2 initial dose, escalated to 70 mg/m2 thereafter) and dexamethasone (40 mg/wk). Of these, 10 patients received the first daratumumab dose as a single infusion (16 mg/kg, day 1 cycle 1), and 75 patients received a split first dose (8 mg/kg, days 1-2 cycle 1). Subsequent dosing was per the approved schedule for daratumumab. Patients received a median of 2 (range, 1-4) prior lines of therapy; 60% were lenalidomide refractory. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (31%), lymphopenia (24%), anemia (21%), and neutropenia (21%). Infusion-related reactions were observed in 60% and 43% of single and split first-dose patients, respectively. Overall response rate was 84% (79% in lenalidomide-refractory patients). Median progression-free survival (PFS) was not reached; 12-month PFS rates were 74% for all treated patients and 65% for lenalidomide-refractory patients. D-Kd was well tolerated with low neutropenia rates, and it demonstrated deep responses and encouraging PFS, including in patients refractory to lenalidomide. The trial was registered at www.clinicaltrials.gov as #NCT01998971.

Preliminary data from a phase II study of cetuximab with irinotecan in heavily pretreated patients with epidermal growth factor (EGFR)-expressing metastatic colorectal cancer (mCRC): LABEL

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14521-14521 ◽  
Author(s):  
A. Buzaid ◽  
C. de Cerqueira Mathias ◽  
F. Perazzo ◽  
S. Simon ◽  
L. Fein ◽  
...  
Keyword(s):  
Latin American ◽  
Phase Ii ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Treatment Regimens ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

14521 Background: Cetuximab (Erbitux) is a monoclonal antibody directed against EGFR that is active in combination with irinotecan in patients (pts) with mCRC, who have progressed during or after a prior irinotecan therapy. Methods: This open, single-arm phase II Latin American study investigated this combination in pts with EGFR-expressing mCRC progressing on or within 3 months of chemotherapy containing at least 6 weeks (w) of irinotecan-based therapy. The primary objective was to assess the best overall confirmed response rate (RR). Sample size calculations were based on an expected rate of 20% (±8%). Planned enrollment was 100 pts. Secondary objectives were to explore the duration of response (DOR), progression-free survival (PFS) time, the 12-week PFS rate, and overall survival time. Pts were treated with cetuximab (initial dose 400 mg/m2 then 250 mg/m2 weekly), plus irinotecan at the same dose and schedule (including dose reductions) as pre-study. Preliminary Results: Of 151 pts from 14 centers screened and in the database, 106 (70%, 3 pts missing) were EGFR-expressing and, of these, 79/106 (75%) were treated on-study. Forty (51%) were male; median age was 59 years [27–82]; 70 (89%) pts had a Karnofsky performance status = 90 and 9 (11%) pts = 80. Nineteen (24%) pts had received = 3 prior treatment regimens, 42 (53%) were previously treated with an oxaliplatin-based regimen for metastatic disease. The confirmed overall RR was 26.6% [17.3–37.7]. Median DOR was 23.9 w [17.1–30], median PFS time was 17.7 w [11.7–18.9], and the 12-week PFS rate was 58% [47–69]. Thirty-three (42%) pts were alive at data cut-off. Median survival was 9.7 months [7.9–13.1]. Treatment was well tolerated with the most common grade 3/4 adverse events including: diarrhea, 20%; neutropenia,10%; acne-like rash, 9%. No grade 3/4 infusion-related reactions were reported. Conclusions: The overall confirmed RRs observed in this heavily pretreated population fully met the expectations for the primary endpoint of this study. LABEL confirmed in a Latin American setting the activity and safety of cetuximab plus irinotecan seen in previous studies. No significant financial relationships to disclose.

Lenalidomide Plus Bortezomib (Rev-Vel) in Relapsed and/or Refractory Multiple Myeloma (MM): Final Results of a Multicenter Phase 1 Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 405-405 ◽  
Author(s):  
Paul G. Richardson ◽  
S. Jagannath ◽  
D.E. Avigan ◽  
M. Alsina ◽  
R.L. Schlossman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combination Therapy ◽  
Phase 1 ◽  
Toxicity Assessment ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Dose Escalation Study ◽  
Heavily Pretreated ◽  
Anticoagulant Prophylaxis ◽  
Dose Reductions

Abstract Background: Bortezomib (VELCADE®, Vel) and lenalidomide (Revlimid®, Rev) are both highly effective agents in multiple myeloma (MM). Preclinical studies show Rev sensitizes MM cells to Vel and dexamethasone (Dex), suggesting combination therapy may enhance clinical activity. This phase 1 dose-escalation study aimed to determine MTD and activity of Rev-Vel +/− Dex combination therapy in patients (pts) with relapsed and/or refractory MM. Methods: Eight cohorts (≥3 pts each) were planned, with dosing of Vel 1.0 or 1.3mg/m2 (d 1, 4, 8, 11) and Rev 5, 10, 15, or 20mg (d 1–14), in 21-d cycles. Dex 40mg (on day of and day after each Vel dose) could be added in pts with PD. NCI CTCAE v3.0 was used for toxicity assessment; DLT was defined as any grade (G) ≥3 non-hematologic toxicity, G4 neutropenia for ≥5 d and/or neutropenic fever, or platelets <10,000/mm3 on >1 occasion despite transfusion. Response was assessed by modified EBMT criteria. Results: 28 pts were enrolled in cohorts 1–6 (Rev 5–15mg, Vel 1.0–1.3mg/m2) plus 10 additional pts at the MTD (Dose Level 5), including 12 with relapsed and 26 with relapsed and refractory MM (n=38). Among 25 men and 13 women, median age was 60yrs (range: 37–79), and median no. of prior therapies was 5 (range: 1–13), including 23 pts with prior SCT, 23 with prior Vel, 6 with prior Rev, and 36 with prior thalidomide (Thal). One DLT was observed in cohort 4 (Rev 10mg–Vel 1.3mg/m2; transient G3 hyponatremia). DLT was reached in cohort 6 (Rev 15mg–Vel 1.3mg/m2) with 1 episode of G3 HZV reactivation (successfully treated with acyclovir) and 1 G4 neutropenia (reversed with GCSF support and dose reduction). MTD was therefore declared at Rev 15mg–Vel 1.0mg/m2. In total, 5 pts had dose reductions for Vel, 6 pts for Rev, and 5 pts for both Rev and Vel. No significant (G≥3) fatigue or peripheral neuropathy has been seen. No anticoagulant prophylaxis was required and only 1 pt had DVT while on Rev alone. In 36 evaluable pts, the overall response rate (CR+PR+MR) is 58% (90% CI: 46%, 75%), including 6% CR/nCR (Table) after a median of 6 cycles (range: 4–17). Responses were durable (median 6 months, range: 1–26), and 11 pts remain on therapy beyond 1 year. Dex has been added in 14 pts with PD, resulting in PR/MR/SD in 10 (71%), with just 1 pt experiencing Dex-related G2 diarrhea and fatigue, which prompted discontinuation of therapy. Conclusions: Rev-Vel +/− Dex is well tolerated and very active with durable responses seen in pts with heavily pretreated relapsed and/or refractory MM, including pts who have had prior Rev, Vel, Thal and SCT. An MTD of Rev 15mg–Vel 1.0mg/m2 has been defined, with Phase 2 studies now ongoing in both newly diagnosed and relapsed/refractory MM. Best responses by Rev-Vel cohort (EBMT criteria) Cohort Rev-Vel dose Vel 1.0mg/m2 Vel 1.3mg/m2 1–2 Rev 5mg 2PR, 1MR 1CR, 2PR 3–4 Rev 10mg 1nCR, 2PR 2PR, 2MR, 1SD, 1PD 5–6 Rev 15mg 2PR, 4MR, 7SD, 1PD 2 PR, 5SD

scholarly journals OCEAN: a randomized Phase III study of melflufen + dexamethasone to treat relapsed refractory multiple myeloma

2020 ◽  
Vol 16 (11) ◽  
pp. 631-641 ◽  
Author(s):  
Fredrik Schjesvold ◽  
Pawel Robak ◽  
Ludek Pour ◽  
Johan Aschan ◽  
Pieter Sonneveld
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Open Label ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Duration Of Response ◽  
Secondary Endpoints ◽  
Phase Iii Study

Melflufen is a novel peptide–drug conjugate that rapidly delivers a cytotoxic payload into tumor cells. It has emerged as a potential new multiple myeloma treatment, particularly for late-stage forms of the disease. Here we describe the rationale and design of OCEAN (NCT03151811), a randomized, head-to-head, superiority, open-label, global, Phase III study evaluating the efficacy and safety of melflufen + dexamethasone versus pomalidomide + dexamethasone. Eligible patients with relapsed refractory multiple myeloma have received 2–4 previous treatments and are refractory to both lenalidomide and their last treatment. Patients are excluded if they have previously received pomalidomide. The primary endpoint is progression-free survival, and key secondary endpoints include overall response rate, duration of response and overall survival.

Phase I/II Trial Assessing Bortezomib and Melphalan Combination Therapy for the Treatment of Patients With Relapsed or Refractory Multiple Myeloma

2006 ◽  
Vol 24 (6) ◽  
pp. 937-944 ◽  
Author(s):  
James R. Berenson ◽  
Hank H. Yang ◽  
Karen Sadler ◽  
Supol G. Jarutirasarn ◽  
Robert A. Vescio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Free Survival ◽  
Dose Cohort ◽  
Refractory Multiple Myeloma ◽  
Promising Treatment ◽  
Grade 3 ◽  
Dose Limiting Toxicity

Purpose Bortezomib has shown synergy with melphalan in preclinical models. We assessed the safety, tolerability, and response rate in a dose-escalation study of this combination for relapsed or refractory multiple myeloma patients. Methods Bortezomib was administered from 0.7 to 1.0 mg/m2 on days 1, 4, 8, and 11 of a 28-day cycle for up to eight cycles. Oral melphalan was administered in escalating doses from 0.025 to 0.25 mg/kg on days 1 to 4. Results Thirty-five patients with relapsed or refractory myeloma were enrolled, 34 of whom were assessable for response. Dose-limiting toxicity of grade 4 neutropenia in two of six patients in the highest dose cohort led to the assignment of bortezomib 1.0 mg/m2 and melphalan 0.10 mg/kg as the maximum-tolerated dose (MTD). Responses (minimal [MR], partial [PR], or complete [CR]) occurred in 23 of 34 patients (68%), including two CRs (6%), three immunofixation-positive CRs (9%), 11 PRs (32%), and seven MRs (21%). Responses were observed in five of six assessable patients (83%) at the MTD. Median progression-free survival for all patients was 8 months (range, 2 to 18 months). Grade ≥ 3 toxicities were related mostly to myelosuppression. Among the 15 patients with grade 1/2 neuropathy at baseline, it resolved during treatment in one, worsened in four, and remained stable in 10 patients. Eight other patients developed grade 1/2 neuropathy during the study. Conclusion Bortezomib plus melphalan given on a 28-day schedule showed encouraging activity with manageable toxicity and represents a promising treatment for myeloma patients.

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