Once weekly selinexor, carfilzomib and dexamethasone in carfilzomib non-refractory multiple myeloma patients

Abstract Background Proteasome inhibitors (PIs), including carfilzomib, potentiate the activity of selinexor, a novel, first-in-class, oral selective inhibitor of nuclear export (SINE) compound, in preclinical models of multiple myeloma (MM). Methods The safety, efficacy, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of selinexor (80 or 100 mg) + carfilzomib (56 or 70 mg/m2) + dexamethasone (40 mg) (XKd) once weekly (QW) was evaluated in patients with relapsed refractory MM (RRMM) not refractory to carfilzomib. Results Thirty-two patients, median prior therapies 4 (range, 1–8), were enrolled. MM was triple-class refractory in 38% of patients and 53% of patients had high-risk cytogenetics del(17p), t(4;14), t(14;16) and/or gain 1q. Common treatment-related adverse events (all/Grade 3) were thrombocytopenia 72%/47% (G3 and G4), nausea 72%/6%, anaemia 53%/19% and fatigue 53%/9%, all expected and manageable with supportive care and dose modifications. MTD and RP2D were identified as selinexor 80 mg, carfilzomib 56 mg/m2, and dexamethasone 40 mg, all QW. The overall response rate was 78% including 14 (44%) ≥ very good partial responses. Median progression-free survival was 15 months. Conclusions Weekly XKd is highly effective and well-tolerated. These data support further investigation of XKd in patients with MM.

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Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.20.02259 ◽

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.

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Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma

Blood ◽

10.1182/blood-2006-08-042275 ◽

2006 ◽

Vol 109 (7) ◽

pp. 2767-2772 ◽

Cited By ~ 137

Author(s):

Antonio Palumbo ◽

Maria Teresa Ambrosini ◽

Giulia Benevolo ◽

Patrizia Pregno ◽

Norbert Pescosta ◽

...

Keyword(s):

Multiple Myeloma ◽

Response Rate ◽

Phase 1 ◽

Progression Free Survival ◽

Complete Response ◽

Maximum Tolerated Dose ◽

Free Survival ◽

Grade 3 ◽

Dose Levels ◽

Initial Results

AbstractIn multiple myeloma (MM), the addition of thalidomide or bortezomib to the standard oral melphalan/prednisone combination significantly increased response rate and event-free survival. In this multicenter phase 1/2 trial, dosing, safety, and efficacy of the 4-drug combination, bortezomib, melphalan, prednisone, and thalidomide (VMPT) was determined. Bortezomib was administered at 3 dose levels (1.0 mg/m2, 1.3 mg/m2, or 1.6 mg/m2) on days 1, 4, 15, and 22; melphalan was given at a dose of 6 mg/m2 on days 1 through 5 and prednisone at 60 mg/m2 on days 1 through 5. Thalidomide was delivered at 50 mg on days 1 through 35. Each course was repeated every 35 days. The maximum tolerated dose of bortezomib was 1.3 mg/m2. Thirty patients with relapsed or refractory MM were enrolled; 20 patients (67%) achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good PR. Among 14 patients who received VMPT as second-line treatment, the PR rate was 79% and the immunofixation-negative complete response rate 36%. The 1-year progression-free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 nonhematologic adverse events included infections (5 patients), fatigue (1), vasculitis (1), and peripheral neuropathy (2); no grade 4 toxicities were recorded. Initial results showed that VMPT is an effective salvage therapy with a very high proportion of responses. The incidence of neurotoxicities was unexpectedly low.

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ACTR-01. PHASE I/II STUDY OF TEMOZOLOMIDE PLUS NIMUSTINE CHEMOTHERAPY FOR RECURRENT MALIGNANT GLIOMAS: KYOTO NEURO-ONCOLOGY GROUP

Neuro-Oncology ◽

10.1093/neuonc/noz175.046 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi12-vi12

Author(s):

Tomokazu Aoki ◽

Yoshiki Arakawa ◽

Tetsuya Ueba ◽

Masashi Oda ◽

Namiko Nishida ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Malignant Gliomas ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Free Survival ◽

Grade 3 ◽

Experienced Grade

Abstract The objective of this phase I/II study was to examine the efficacy and toxicity profile of temozolomide (TMZ) plus nimustine (ACNU). Patients who had received a standard radiotherapy with one or two previous chemoregimens were enrolled. In phase I, the maximum-tolerated dose (MTD) by TMZ (150 mg/m2/day) (Day 1–5) plus various doses of ACNU (30, 35, 40, 45 mg/m2/day) (Day 15) per 4 weeks was defined on a standard 3 + 3 design. In phase II, these therapeutic activity and safety of this regimen were evaluated. Forty-nine eligible patients were enrolled. The median age was 50 years-old. Eighty percent had a KPS of 70–100. Histologies were glioblastoma (73%), anaplastic astrocytoma (22%), anaplastic oligodendroglioma (4%). In phase I, 15 patients were treated at four cohorts by TMZ plus ACNU. MTD was TMZ (150 mg/m2) plus ACNU (40 mg/m2). In phase II, 40 patients were treated at the dose of cohort 3 (MTD). Thirty-five percent of patients experienced grade 3 or 4 toxicities, mainly hematologic. The overall response rate was 11% (4/37). Sixty-eight percent (25/37) had stable disease. Twenty-two percent (8/37) showed progression. Progression-free survival (PFS) rates at 6 and 12 months were 24% (95% CI, 12–35%) and 8% (95% CI, 4–15%). Median PFS was 13 months (95% CI, 9.2–17.2 months). Overall survival (OS) at 6 and 12 were 78% (95% CI, 67–89%) and 49% (95% CI, 33–57%). Median OS was 11.8 months (95% CI, 8.2–14.5 months). This phase I/II study showed a moderate toxicity in hematology and may has a promising efficacy in OS, without inferiority in PFS.

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Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14)

Journal of Clinical Oncology ◽

10.1200/jco.21.00443 ◽

2021 ◽

pp. JCO.21.00443

Author(s):

Nizar J. Bahlis ◽

Rachid Baz ◽

Simon J. Harrison ◽

Hang Quach ◽

Shir-Jing Ho ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Phase I ◽

Phase I Study ◽

Overall Response Rate ◽

Response Rate ◽

Progression Free Survival ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Grade 3

PURPOSE Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab. METHODS This phase I study ( NCT03314181 ) evaluated venetoclax with daratumumab and dexamethasone (VenDd) in patients with t(11;14) RRMM and VenDd with bortezomib (VenDVd) in cytogenetically unselected patients with RRMM. Primary objectives included expansion-phase dosing, safety, and overall response rate. Secondary objectives included further safety analysis, progression-free survival, duration of response, time to progression, and minimal residual disease negativity. RESULTS Forty-eight patients were enrolled, 24 each in parts 1 (VenDd) and 2 (VenDVd). There was one dose-limiting toxicity in part 1 (grade 3 febrile neutropenia, 800 mg VenDd). Common adverse events with VenDd and VenDVd included diarrhea (63% and 54%) and nausea (50% and 50%); grade ≥ 3 adverse events were observed in 88% in the VenDd group and 71% in the VenDVd group. One treatment-emergent death occurred in part 2 (sepsis) in the context of progressive disease, with no other infection-related deaths on study with medians of 20.9 and 20.4 months of follow-up in parts 1 and 2, respectively. The overall response rate was 96% with VenDd (all very good partial response or better [≥ VGPR]) and 92% with VenDVd (79% ≥ VGPR). The 18-month progression-free survival rate was 90.5% (95% CI, 67.0 to 97.5) with VenDd and 66.7% (95% CI, 42.5 to 82.5) with VenDVd. CONCLUSION VenDd and VenDVd produced a high rate of deep and durable responses in patients with RRMM. These results support continued evaluation of venetoclax with daratumumab regimens to treat RRMM, particularly in those with t(11;14).

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CTNI-32. PHASE I/II STUDY OF TEMOZOLOMIDE PLUS NIMUSTINE CHEMOTHERAPY FOR RECURRENT MALIGNANT GLIOMAS: KYOTO NEURO-ONCOLOGY GROUP

Neuro-Oncology ◽

10.1093/neuonc/noaa215.199 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii49-ii50

Author(s):

Tomokazu Aoki ◽

Yoshiki Arakawa ◽

Tetsuya Ueba ◽

Masashi Oda ◽

Namiko Nishida ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Malignant Gliomas ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Free Survival ◽

Grade 3 ◽

Experienced Grade

Abstract The objective of this phase I/II study was to examine the efficacy and toxicity profile of temozolomide (TMZ) plus nimustine (ACNU). Patients who had received a standard radiotherapy with one or two previous chemo-regimens were enrolled. In phase I, the maximum-tolerated dose (MTD) by TMZ (150 mg/m2/day) (Day 1–5) plus various doses of ACNU (30, 35, 40, 45 mg/m2/day) (Day 15) per 4 weeks was defined on a standard 3 + 3 design. In phase II, these therapeutic activity and safety of this regimen were evaluated. Forty-nine eligible patients were enrolled. The median age was 50 years-old. Eighty percent had a KPS of 70–100. Histologies were glioblastoma (73%), anaplastic astrocytoma (22%), anaplastic oligodendroglioma (4%). In phase I, 15 patients were treated at four cohorts by TMZ plus ACNU. MTD was TMZ (150 mg/m2) plus ACNU (40 mg/m2). In phase II, 40 patients were treated at the dose of cohort 3 (MTD). Thirty-five percent of patients experienced grade 3 or 4 toxicities, mainly hematologic. The overall response rate was 11% (4/37). Sixty-eight percent (25/37) had stable disease. Twenty-two percent (8/37) showed progression. Progression-free survival (PFS) rates at 6 and 12 months were 24% (95% CI, 12–35%) and 8% (95% CI, 4–15%). Median PFS was 13 months (95% CI, 9.2–17.2 months). Overall survival (OS) at 6 and 12 were 78% (95% CI, 67–89%) and 49% (95% CI, 33–57%). Median OS was 11.8 months (95% CI, 8.2–14.5 months). This phase I/II study showed a moderate toxicity in hematology and may has a promising efficacy in OS, without inferiority in PFS.

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Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure

Blood ◽

10.1182/blood-2008-02-141614 ◽

2008 ◽

Vol 112 (12) ◽

pp. 4445-4451 ◽

Cited By ~ 127

Author(s):

Michael Wang ◽

Meletios A. Dimopoulos ◽

Christine Chen ◽

M. Teresa Cibeira ◽

Michel Attal ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Response Rate ◽

Response Rate ◽

Progression Free Survival ◽

Efficacy And Safety ◽

Time To Progression ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Previously Treated ◽

Survival Studies

AbstractThis analysis assessed the efficacy and safety of lenalidomide + dexamethasone in patients with relapsed or refractory multiple myeloma (MM) previously treated with thalidomide. Of 704 patients, 39% were thalidomide exposed. Thalidomide-exposed patients had more prior lines of therapy and longer duration of myeloma than thalidomide-naive patients. Lenalidomide + dexamethasone led to higher overall response rate (ORR), longer time to progression (TTP), and progression-free survival (PFS) versus placebo + dexamethasone despite prior thalidomide exposure. Among lenalidomide + dexamethasone-treated patients, ORR was higher in thalidomide-naive versus thalidomide-exposed patients (P = .04), with longer median TTP (P = .04) and PFS (P = .02). Likewise for dexamethasone alone-treated patients (P = .03 for ORR, P = .03 for TTP, P = .06 for PFS). Prior thalidomide did not affect survival in lenalidomide + dexamethasone-treated patients (36.1 vs 33.3 months, P > .05). Thalidomide-naive and thalidomide-exposed patients had similar toxicities. Lenalidomide + dexamethasone resulted in higher rates of venous thromboembolism, myelosuppression, and infections versus placebo + dexamethasone, independent of prior thalidomide exposure. Lenalido-mide + dexamethasone was superior to placebo + dexamethasone, independent of prior thalidomide exposure. Although prior thalidomide may have contributed to inferior TTP and PFS compared with thalidomide-naive patients, these parameters remained superior compared with placebo + dexamethasone; similar benefits compared with placebo + dexamethasone were not evident for thalidomide-exposed patients in terms of overall survival. Studies were registered at http://www.clinicaltrials.gov under NCT00056160 and NCT00424047.

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Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: Updated Follow-Up and Improved Survival

Journal of Clinical Oncology ◽

10.1200/jco.2013.52.0023 ◽

2014 ◽

Vol 32 (7) ◽

pp. 634-640 ◽

Cited By ~ 139

Author(s):

Antonio Palumbo ◽

Sara Bringhen ◽

Alessandra Larocca ◽

Davide Rossi ◽

Francesco Di Raimondo ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Response Rate ◽

Complete Response Rate ◽

Progression Free Survival ◽

Complete Response ◽

Free Survival ◽

Grade 3 ◽

To Receive

Purpose Bortezomib-melphalan-prednisone (VMP) has improved overall survival in multiple myeloma. This randomized trial compared VMP plus thalidomide (VMPT) induction followed by bortezomib-thalidomide maintenance (VMPT-VT) with VMP in patients with newly diagnosed multiple myeloma. Patients and Methods We randomly assigned 511 patients who were not eligible for transplantation to receive VMPT-VT (nine 5-week cycles of VMPT followed by 2 years of VT maintenance) or VMP (nine 5-week cycles without maintenance). Results In the initial analysis with a median follow-up of 23 months, VMPT-VT improved complete response rate from 24% to 38% and 3-year progression-free-survival (PFS) from 41% to 56% compared with VMP. In this analysis, median follow-up was 54 months. The median PFS was significantly longer with VMPT-VT (35.3 months) than with VMP (24.8 months; hazard ratio [HR], 0.58; P < .001). The time to next therapy was 46.6 months in the VMPT-VT group and 27.8 months in the VMP group (HR, 0.52; P < .001). The 5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P = .01). Survival from relapse was identical in both groups (HR, 0.92; P = .63). In the VMPT-VT group, the most frequent grade 3 to 4 adverse events included neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). All of these, except for thrombocytopenia, were significantly more frequent in the VMPT-VT patients. Conclusion Bortezomib and thalidomide significantly improved OS in multiple myeloma patients not eligible for transplantation.

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MP0250 Combined with Bortezomib and Dexamethasone in Multiple Myeloma Patients Previoulsy Exposed to Proteasome Inhibitors and Immunomodulatory Drugs

Blood ◽

10.1182/blood-2018-99-112859 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1980-1980

Author(s):

Stefan Knop ◽

Hartmut Goldschmidt ◽

Marc S Raab ◽

Monika Szarejko ◽

Artur Jurczyszyn ◽

...

Keyword(s):

Multiple Myeloma ◽

Half Life ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Proteasome Inhibitors ◽

Immunomodulatory Drugs ◽

Multiple Cycles ◽

Grade 3 ◽

To Receive

Abstract Background MP0250 is a first-in-class selective tri-specific multi-DARPin® drug candidate neutralizing VEGF-Α and HGF as well as binding to human serum albumin to increase its plasma half-life. Preclinical studies have shown that MP0250 enhances sensitivity of Multiple Myeloma (MM) cells to bortezomib, inhibits tumor growth and reduces bone destruction. In this clinical phase 2 trial (NCT03136653), we are investigating the safety, tolerability and efficacy of the combination of MP0250 plus bortezomib and dexamethasone (dex) in patients (pts) with relapsed/refractory (RR) MM previously exposed to proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). Aims To study the efficacy and safety of MP0250 in combination with bortezomib and dexamethasone in patients with RRMM. Trial Design This trial is recruiting adults ≥18 years of age with RRMM who have progressed after at least two prior treatment regimens including bortezomib and an IMiD. A dose-escalation phase (part 1) consisting of two cohorts will define a safe dose of the combination of MP0250 plus bortezomib + dex followed by a dose-expansion phase (part 2). Patients were enrolled to receive iv MP0250 on day 1 + subcutaneous bortezomib 1.3 mg/m² on days 1, 4, 8, 11, oral dexamethasone (dex) 20 mg on days 1-2, 4-5, 8-9, 11-12 of each 21-day cycle. Up to 40 patients will be enrolled. Patients will receive treatment until there is documented disease progression or unacceptable toxicity. Methods The primary endpoint is efficacy in terms of overall response rate (ORR) per International Myeloma Working Group criteria. Secondary endpoints include safety, immunogenicity, progression free survival (PFS) and duration of response (DOR). Exploratory endpoints include overall survival, pharmacokinetics and potential biomarkers that include MM specific markers and cytokines monitoring bone homeostasis. The safety analysis set (SAF) is defined as patients who have received at least 1 dose of the combination of MP0250 plus bortezomib + dex. Results Data cut off was 21 July 2018. 8 pts have been treated in cohort 1 and 3 pts in cohort 2. Median time from initial diagnosis to first dose was 4.8 years (range, 1-10). Median number of prior therapies was 3 (range, 2-5). All 11 pts had prior exposure to IMiDs and PIs and 4 pts were considered PI refractory. Four patients received PI immediately prior to receive MP250 in combination. The most frequent drug-related grade ≥ 3 AEs: hypertension in 3 pts, thrombocytopenia in 6 pts, proteinuria in 2 pts and transient liver enzyme elevation in 1 patient. One dose-limiting toxicity has been reported in cohort 1 (grade 3 hypertension) and two in cohort 2 (grade 3 epistaxis, grade 3 proteinuria). There were no infusion-related reactions. Best response achieved in the 8 efficacy evaluable pts in cohort 1 was VGPR in 1 and PR in 4 for an overall response rate (ORR, ≥PR) of 62.5%. In cohort 2, 1 patient achieved Minimal Response (MR), 1 patient stable disease and 1 progressive disease. Three of four patients who were coming immediately from a PI based regimen achieved a response. Pharmacokinetics data in cohort 1 show sustained exposure over multiple cycles with a mean half-life of 11 days, and no indication of ADA mediated drug clearance was observed. Data from cohort 1 patients show accumulation of MP0250-HGF complexes over multiple cycles confirming the stable binding of MP0250 to HGF suggesting that all circulating HGF is neutralized. Summary Data from cohort 1 (8 mg/Kg q3w) suggest that MP0250 can be safely combined with bortezomib and dex in patients with relapsed and refractory MM. Durable responses were seen in patients who came from PI based pretreatment suggesting that MP0250 might be capable to reverse PI resistance. Disclosures Knop: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Goldschmidt:Sanofi: Consultancy, Research Funding; ArtTempi: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding. Raab:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Dürig:Janssen: Consultancy, Honoraria; Celgene: Honoraria; Roche: Honoraria, Speakers Bureau. Castellano Acosta:Molecular Partners AG: Employment. Lemaillet:Molecular Partners AG: Employment. Cortijo:Molecular Partners AG: Employment. Sudhir:Molecular Partners AG: Employment.

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How I manage frontline transplant-eligible multiple myeloma in Italy

Hematology Reports ◽

10.4081/hr.2020.8954 ◽

2020 ◽

Vol 12 (s1) ◽

Author(s):

Vittorio Montefusco ◽

Giovanni Martinelli ◽

Claudio Cerchione

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Overall Response Rate ◽

Response Rate ◽

Progression Free Survival ◽

Clinical Results ◽

Second Primary ◽

Induction Phase ◽

Free Survival ◽

Second Primary Malignancies

The treatment of transplant-eligible multiple myeloma patients in Italy consists in an induction phase based on bortezomib plus thalidomide plus dexamethasone (VTd), followed by a single or tandem autologous stem cell transplantation (ASCT), followed by lenalidomide maintenance. This approach offers an overall response rate of 93% and a CR rate of 58% with acceptable toxicity. Lenalidomide maintenance adds a significant increase in disease control, with a progression free survival after ASCT of 53 months, and an overall survival of 86 months. Second primary malignancies represent the most concerning toxicity of lenalidomide maintenance with a 6.9% incidence. However, the benefit in terms of increased myeloma control largely outweigh this complication. The incorporation of daratumumab in this treatment schema will further improve these clinical results.

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A Phase I/II Study of the Tolerability of Lenalidomide and Low Dose Dexamethasone in Previously Treated Multiple Myeloma Patients with Impaired Renal Function: Pre1003, a Precog LLC Study

Blood ◽

10.1182/blood.v120.21.1856.1856 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1856-1856

Author(s):

Joseph R. Mikhael ◽

Judith Manola ◽

Amylou Constance Dueck ◽

Suzanne R Hayman ◽

Kurt Oettel ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Renal Function ◽

Renal Insufficiency ◽

Impaired Renal Function ◽

Response Rate ◽

Progression Free Survival ◽

Free Survival ◽

Previously Treated ◽

Grade 3

Abstract Abstract 1856 Background: Lenalidomide has proven to be a highly effective treatment in relapsed multiple myeloma (MM), particularly when used in combination with dexamethasone. However, over 30% of patients with myeloma have renal insufficiency and as lenalidomide is renally excreted, little information is available about its use in myeloma patients with impaired kidney function. Defining a safe and effective dose of lenalidomide in this context is critical. Objective: We undertook this study to establish the maximum tolerated dose of lenalidomide in three cohorts of patients with different levels of impaired renal function: Group A - patients with creatinine clearance (CrCl) between 30 and 60 mL/min, Group B - patients with CrCl <30 mL/min not on dialysis, and Group C - patients with CrCl < 30mL/min who are on dialysis. Secondary endpoints included response rate, progression free survival and overall survival. Methods: Eligible patients had previously treated MM with renal impairment defined as creatinine clearance < 60 mL/min measured within 21 days prior to registration. Patients previously treated with lenalidomide were required to demonstrate clinical response (any duration) or stable disease with progression-free interval of > 6 months from start of that therapy. All patients received dexamethasone 40 mg orally on days 1, 8, 15 and 22 of a 28-day cycle. Prophylactic anticoagulation consisted of either 81 mg or 325 mg per day of aspirin. Patients also received lenalidomide orally every 1 or 2 days on days 1 through 21 of a 28-day cycle, as described below (Table 1). Starting doses were as in US Product Insert. Dose escalation follows a standard 3+3 design. Results: There have been 23 patients enrolled into groups and cohorts as shown in Table 1. Median age was 73 (range 49–89) and 13 (57%) were women. ISS stage was advanced in all patients, 0 in stage 1, 4 (18%) in stage 2 and 19 (82%) in stage 3. The regimen was well tolerated. Indeed, the MTD has not been reached in any of the groups, as no DLTs have occurred to date. The most commonly reported clinical adverse events (all grades, independent of attribution) across all patients included infections, hyperglycemia, constipation, dizziness, hyponatremia, hypocalcemia and tremor. Hematological toxicities (grade 3–4) occurred in 13 out of 21 pts (62%), mostly neutropenia and thrombocytopenia. Grade 3–4 events at least possibly related to the regimen occurred in 70% and included pneumonia (26%) and otitis media (9%). Response was seen in 14 patients, resulting in an overall response rate of 61%. CR was seen in 1 patient (4%), VGPR in 2 patients (9%), PR in 11 patients (43%), and SD for 9 patients. With median follow-up of 15.5 months, median progression-free survival is 9.8 months and median overall survival is 22 months. Conclusion: Lenalidomide and dexamethasone is a safe and effective regimen in patients with multiple myeloma and renal insufficiency. It is also very well tolerated, although cytopenias are common but manageable. MTD has yet to be reached in each group, allowing for higher doses to be given than previously thought, including 25mg daily (for 21/28 days) in patients with CrCl 30–60 mL/min, 25 mg every other day (for 21/28 days) in patients with CrCl < 30 mL/min not on dialysis, and 10mg daily (for 21/28 days) in patients with CrCl < 30 mL/min on dialysis. These results will provide needed, clinically relevant dosing for lenalidomide in MM patients with renal insufficiency. Disclosures: Kaufman: Millenium: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Novartis: Consultancy.

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