Lenalidomide, Bortezomib, and Dexamethasone in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Encouraging Response Rates and Tolerability with Correlation of Outcome and Adverse Cytogenetics in a Phase II Study.

Abstract Background: Bortezomib (VELCADE®, Bz) is approved for the treatment of multiple myeloma (MM). Lenalidomide (Revlimid®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed MM pts following ≥ 1 prior therapy. In a phase 1 study, Len/Bz (maximum tolerated dose [MTD] 15 mg/1.0 mg/m2) with or without Dex (20–40 mg) was well tolerated and resulted in a response rate (CR+PR+MR) of 58% in relapsed and/or refractory MM pts. The aim of this multi-center phase 2 study was to evaluate the efficacy and safety of Len/Bz/Dex (RVD) at the phase 1 MTD. Methods: Pts with relapsed or relapsed and refractory MM with 1–3 prior lines of therapy received up to eight 21-day cycles of Bz 1.0 mg/m2 (days 1, 4, 8, 11) Len 15 mg (days 1–14) and Dex 40/20 mg (cycles 1–4/5–8) on days of/after Bz dosing. After cycle 8, pts with stable or responding disease received maintenance therapy on a 21-day cycle; Bz (days 1 and 8) and Len (days 1–14) at the dose levels tolerated at the end of cycle 8, with Dex at 10 mg (days 1, 2, 8, 9) until disease progression or unacceptable toxicity. Pts received concomitant anti-thrombotic (aspirin 81 or 325 mg/day) and anti-viral prophylaxis. Pts with Grade (G) ≥ 2 peripheral neuropathy (PNY) were excluded. Response was assessed according to modified EBMT and Uniform Criteria with toxicities assessed using NCI CTCAE v3.0. Primary end point was time to progression (TTP). Results: 64 pts have been enrolled; 38 (59%) with relapsed and 26 (41%) with relapsed and refractory MM. Median number of prior therapies was two, including Len (8%), Bz (55%), Dex (92%), thalidomide (77%), and stem cell transplant (SCT; 36%). Pts received a median of 8 cycles; 31 (48%) completed 8 cycles, 24 continue on maintenance. 4 pts proceeded to stem cell collection (median CD34+ yield of 4.58x106/kg after median of 8 cycles of therapy) and 3 pts proceeded to stem cell transplant, with the 4th pt currently undergoing salvage therapy to restore disease control. 19 pts discontinued prior to completing 8 cycles due to: progressive disease (10), toxicities (3) or other reason (2). Toxicities were manageable, consisting primarily of G1–2 myelosuppression. Attributable non-hematologic toxicities included deep vein thrombosis (two pts; attributed to Len, both pts remain on-study after antithrombotic therapy), and two episodes of atrial fibrillation (G3) prompting Dex dose reduction. G3 PNY was reported in one pt attributed to Bz and leading to treatment discontinuation despite Bz dose reduction. Dose reductions were required for: Len (13 pts); Bz (9 pts) and Dex (26 pts). One on-study death (thought to be due to fungal pneumonia) was reported during cycle 3: this was not attributed to either Bz or Len, but possibly Dex. In 63 response-evaluable pts, the overall response rate (CR/nCR+VGPR+ PR+ MR) is currently 86%, including 24% CR/nCR and 67% CR/nCR/VGPR/PR. Response rates according to baseline cytogenetics, disease stage, and prior therapies showed no significant differences according to adverse risk (Table). Similarly, analysis of evaluable pts with chromosome 13 deletion by FISH showed no significant difference in response rate compared to those without. Median DOR in responding pts is 21 weeks; range 6–72 weeks. Median TTP and overall survival have not yet been reached. Conclusions: RVD is very active and well tolerated in pts with relapsed and/or refractory MM, including pts who have received prior Len, Bz, thalidomide, and SCT. Responses appeared independent of adverse cytogenetics, advanced disease stage at diagnosis, prior treatment, and being refractory to prior therapy. Durable responses have been observed. Surrogates and correlative studies are in progress. Response rates* by baseline cytogenetics, disease stage at diagnosis, and prior treatment Cytogenetics (n= 60) ORR (≥ MR) ≥ PR ≥ VGPR CR/nCR * Response assessed by Uniform Criteria. †Abnormal cytogenetics by metaphase analysis Normal (n=38) 84% 63% 29% 18% Abnormal† (n=22) 91% 73% 41% 32% ISS disease stage (n=44) Stage l (n=15) 80% 67% 40% 33% Stage ll (n=15) 87% 67% 20% 13% Stage lll (n=14) 86% 71% 57% 36% Response to RVD according to type of prior therapy Bortezomib (n=35) 77% 57% 31% 17% Len/Thalidomide (n=54) 81% 57% 22% 15% Response by Relapsed/Refractory Relapsed (n=38) 84% 66% 34% 26% Relapsed/Refractory (n=26) 85% 65% 31% 19%

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Results From the Phase II Dose Expansion of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.445.445 ◽

2012 ◽

Vol 120 (21) ◽

pp. 445-445 ◽

Cited By ~ 4

Author(s):

Joseph R. Mikhael ◽

Craig B. Reeder ◽

Edward N. Libby ◽

Luciano J. Costa ◽

P. Leif Bergsagel ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Phase Ii ◽

Initial Phase ◽

Stem Cell Transplant ◽

Response Rate ◽

Phase Ii Trial ◽

Cell Transplant ◽

Newly Diagnosed ◽

Grade 3

Abstract Abstract 445 Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its target and has a favorable toxicity profile that has shown significant activity in relapsed multiple myeloma (MM), leading to recent FDA accelerated approval. To achieve rapid and deep response in patients eligible for stem cell transplant, we combined carfilzomib with the regimen of cyclophosphamide-thalidomide-dexamethasone (CTD). We recently reported the results of the Phase I component of the trial (in which no MTD was reached) followed by the initial Phase II trial; however, with increasing evidence for the safe and effective use of higher doses of carfilzomib, we now report results from dose escalation extension of the Phase II trial. Methods: Newly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with Carfilzomib IV Days 1,2,8,9,15,16 (see Table 1 below for dosing per cohort) along with Cyclophosphamide 300 mg/m2 PO Days 1,8,15, Thalidomide 100 mg PO Days 1–28 and Dexamethasone 40 mg PO Days 1,8,15,22. We initially conducted a Phase I run in trial of 6 patients with no DLT observed before expanding to the Phase II portion of the study. The initial phase II regimen is shown below – as no DLTs were observed, we have now fully accrued to the Phase II dose level +1. Treatment was for 4 cycles with expected SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results: A total of 38 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II, and the remaining at dose escalated cohorts. We are reporting the 27 patients who have completed therapy and will update with the dose escalated cohorts. Median age was 65 (range 27–74) and 52% were female. ISS Stage was advanced (II-III) in 56%. Best overall response rate during 4 cycles of CYCLONE at dose level 0 is 96%: CR 29%, VGPR 46%, PR 21% (1 pt achieved MR). Adverse events of grade 3 or higher at least possibly related to CYCLONE occurred in 12 (44%). Most commonly reported non hematological toxicities (all grades) included fatigue (67%), constipation (56%), lethargy (41%) somnolence (37%), malaise (30%) depressed level of consciousness (22%); however, grade 3/4 toxicities occurring in >5% were uncommon: thromboembolic event 11%) and muscle weakness (7%). Two cases of pneumonia required hospitalization. Eight patients (30%) developed grade 1 sensory neuropathy; no higher grade or painful neuropathy was evident. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included neutropenia (15%) and lymphopenia (7%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. Conclusion: The 4 drug CYCLONE regimen is highly efficaceous with a response rate after only 4 cycles of 96% (75% ≥VGPR, 29% CR) at the current dosing level of carfilzomib IV 20/27 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. Increasing the dose of carfilzomib is feasible and updated results of dose escalated cohorts will be reported at 20/36 and 20/45 mg/m2. Disclosures: Bergsagel: onyx: Membership on an entity's Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

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Presentation Characteristics, Risk Profiles and Response to Thalidomide in a Public Health System, Minority Patient Population with Multiple Myeloma

Blood ◽

10.1182/blood.v112.11.5189.5189 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5189-5189

Author(s):

Shylendra B Sreenivasappa ◽

Mousami Shah ◽

Rosalind Catchatourian ◽

Luciano Fochesatto ◽

Barbara Yim

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Side Effects ◽

Overall Response Rate ◽

Stem Cell Transplant ◽

Response Rate ◽

Cell Transplant ◽

Overall Response ◽

Duration Of Therapy ◽

Historical Controls

Abstract Background: Multiple Myeloma is a clonal plasma cell malignancy which accounts for about 10% of all hematological malignancies. Introduction of thalidomide has revolutionized the treatment. We have characterized the risk profiles and response to thalidomide in a minority cohort socio-economically ineligible for stem cell transplant. Methods: 113 patients (pts) with Multiple myeloma who were treated with thalidomide between the periods of 2002–2008 were identified and studied as a retrospective cohort. Demographics, presentation, dosage schedule, tolerability and response were analyzed. Categorical data via Fisher’s exact test and time to progression data was analyzed via Kaplan Meier life table analysis and log rank test. Results: Demographic and disease characteristics of 113 pts are as follows: 73 (64.6%) females, 40(35.4%) males, 71(62.8%) african american, 23(20.4%) hispanic, 10(8.8%) caucasian and 9(8%) others. The median age at diagnosis was 58.5 years, with 86(76.1%) being 65 or younger and 27 (23.9%) older than 65. 90(79.6%) pts had 2 or less co morbidities. 99(87.6%) pts could not receive stem cell transplant. Bone pain was the most common presenting symptom (35%). 68 had lytic lesions (60%). 21(18.6%) pts were Durie Salmon stage I, 26(23%) stage II, 56(49.5%) Stage III and 10 had missing data. 65(57.5%) had IgG disease, 27(23.8%) IgA and 20(17.7% light chain disease. 64 (56.6%) pts had received a prior therapy. Almost all patients received thalidomide and dexamethsone. Thalidomide was started at 50 or 100mg and the dose was escalated by 50 mg upon progression. 54 (47.8%) pts were started on 50 mg of thalidomide, 55 (48.7%) on 100mg, 3 (2.7%) on 200mg and 1 (0.9%) on 150mg. Thalidomide was discontinued either due to intolerance or disease progression. Patients receiving 50 mg of thalidomide as starting dose (n=54), had an overall response rate (ORR) of 61%. Of these 4 (7.4%) had VGPR, 10 (18.5%) PR and 19(35.2%) stable disease (SD). Median time to dose escalation was 4 months (range 1–36 months). 19 pts were dose escalated to 100mg and achieved an ORR of 79%. Of these 19 pts, 11(57.8%) had SD, 4 (21%) had PR and 4 (21%) had progression of disease. The mean duration of thalidomide therapy in this sub group was 9.94 months. 10 deaths were noted in the group. In pts on 100mg of thalidomide upfront, (n=55) ORR was 69.1%.1 pt (1.8%) had a CR, 3 (5.5%) had VGPR, 18 (32.7%) had PR and 16 (29.1%) had SD. The median time to dose escalation was 7 months (range 1–84 months). Thalidomide dose was increased in 8 pts and ORR of this subgroup was 50%, 1 pt (12.5%) had a CR and 3 (37.5%) had SD. The median duration of therapy in this sub group is 19.5 months and 8 deaths were noted. In the entire cohort the overall response rate to thalidomide and dexamethasone was 69.1%. The median duration of therapy was 8 months (range of 1 to 84 months) and median follow up was 22 months (range 1 to 173). The incidence of grade 3 and grade 4 toxicity are as follows: 12 (10.5%) had neurologic, 2(1.8%) had constitutional side effects, 3 (2.5%) gastrointestinal, 5 (4.4%) venous thromboembolism. 7 (6.3%) infection related complications, 3(2.7%) musculoskeletal, 3 (2.7%) had renal. We documented 18 deaths (12 stage III and 6 stage II). Aspirin for DVT prophylaxis was used in 80(70.8%) pts, coumadin in 4 (3.5%). Discussion: In our minority cohort the median age at diagnosis was much younger than the historical control (58.5 yr vs 62). More than 75% of pts were younger than 65 years and more than half presented with advanced stage. The frequency of monoclonal immunoglobulin was similar to historical controls and so was the overall response to treatment. The incidence of adverse events was much lower than historical controls and this was inspite of longer duration of thalidomide therapy. Conclusion: Ethnic minority patients present with advanced disease and at younger age. Transplant ineligible patients may benefit from a stepwise increment in the dosing of thalidomide and this may account for fewer side effects even on prolonged therapy. Step wise dosing schedule needs to be tested in a prospective randomized trial.

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Lenalidomide in Combination with Dexamethasone Is More Effective Than Dexamethasone at First Relapse in Relapsed Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.3552.3552 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3552-3552 ◽

Cited By ~ 8

Author(s):

Edward Stadtmauer ◽

Donna Weber ◽

M. Dimopolous ◽

Andrew Belch ◽

Michel Attal ◽

...

Keyword(s):

Multiple Myeloma ◽

Salvage Therapy ◽

Response Rate ◽

Response Rates ◽

High Dose ◽

Cell Transplant ◽

Second Line ◽

Prior Therapy ◽

First Relapse ◽

Line Of Therapy

Abstract Background: High-dose dexamethasone (Dex) remains a standard therapy for relapsed or refractory multiple myeloma (MM). Lenalidomide is a novel, orally administered, immunomodulatory drug (IMiD) that has single-agent activity against MM and additive effects when combined with Dex. At the interim analysis, lenalidomide/dexamethasone achieved a significant benefit over dexamethasone, providing a longer median time to progression (TTP), higher response rates, and higher CR rates. Aim: This prospective subgroup analysis of MM-009/010 was performed to determine the potential benefit of starting lenalidomide/dexamethasone at first relapse by analyzing outcomes with lenalidomide/dexamethasone versus dexamethasone among patients who had received only 1 versus > 1 prior line of therapy. Methods: Patients who had received at least 1 prior treatment and were not refractory to dexamethasone were randomized to either receive oral lenalidomide (25 mg daily for 3 weeks every 4 weeks) plus Dex (40 mg on Days 1–4, 9–12, 17–20 every 4 weeks for 4 months, then 40 mg on Days 1–4 every cycle thereafter) or placebo plus Dex. The European Blood and Marrow Transplantation criteria were used to evaluate response. Randomization was stratified at entry by number of prior therapies (1 versus > 1). Results: Among the 248 patients who had received only 1 prior therapy, those receiving second-line lenalidomide/dexamethasone had a significantly longer median TTP (71 vs. 20 wks) and a higher response rate (complete response [CR] + partial response [PR]; 65% vs. 26%) versus those receiving second-line dexamethasone. Among the 456 patients who had received > 1 prior line of therapy, the median TTP (41 vs. 20 wks), response rate (58% vs. 20%) were higher with lenalidomide/dexamethasone compared with dexamethasone. Comparing patients who received lenalidomide/dexamethasone as second-line versus as later salvage therapy, the median TTP appeared longer and the response rates higher in patients who received lenalidomide/dexamethasone earlier, although TTP and response rates were also significantly better with lenalidomide/dexamethasone than with dexamethasone in patients who received lenalidomide/dexamethasone later. Differences in the groups included prior stem cell transplant (66% vs. 54%), thalidomide (12.5% vs. 53.2%), and bortezomib (0.4% vs. 11.6%) in the second-line versus later salvage therapy groups. No difference was observed in grade ¾ adverse events or survival with a median follow-up of 16.8 months. Conclusions: Lenalidomide/dexamethasone provided higher response rates and improved TTP compared with dexamethasone at first relapse and beyond. Response to lenalidomide/dexamethasone was superior to that to dexamethasone regardless of the type of prior therapy. TTP and response rates appeared more favorable when lenalidomide/dexamethasone was administered earlier at first relapse compared with its use as later salvage therapy. These data support the use of lenalidomide/dexamethasone for patients as second-line therapy.

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A phase 1 trial of 90Y-Zevalin radioimmunotherapy with autologous stem cell transplant for multiple myeloma

Bone Marrow Transplantation ◽

10.1038/bmt.2017.164 ◽

2017 ◽

Vol 52 (10) ◽

pp. 1372-1377 ◽

Cited By ~ 4

Author(s):

A Dispenzieri ◽

A D'Souza ◽

M A Gertz ◽

K Laumann ◽

G Wiseman ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplant ◽

Phase 1 ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Phase 1 Trial

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A Phase 1 Study of Bendamustine and Melphalan Conditioning for Autologous Stem Cell Transplant in Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.2042.2042 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2042-2042

Author(s):

Tomer M Mark ◽

Whitney Reid ◽

Ruben Niesvizky ◽

Usama Gergis ◽

Roger N Pearse ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Partial Response ◽

Stem Cell Transplant ◽

Phase 1 ◽

Complete Response ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Phase 1 Study ◽

Dose Levels

Abstract Abstract 2042 Background: Given data showing efficacy of bendamustine in treating multiple myeloma (MM), with the known toxicity profile significant for myelosuppression, we hypothesized that the addition of bendamustine to autologous stem cell transplant (ASCT) conditioning would enhance response without significant toxicity change. We now report the results of a phase 1 study of bendamustine + melphalan conditioning ASCT in MM. Methods: 21 patients were enrolled onto a 3+3 phase 1 study of bendamustine added to melphalan 200mg/m2 split on subsequent days at the following dose levels on the indicated days of melphalan: 1) 30 mg/m2 given on day 2; 2) 60 mg/m2 on day 2; 3) 90 mg/m2 on day 2; 4) 60mg/m2 on days 1 and 2; 5) 90 mg/m2 on day 1 and 60mg/m2 on day 2; 6) 125 mg/m2 on day 1 and 100mg/m2 on day 2. Stem cell infusion of > 2 million × 106 CD34+ cells/kg was performed at 24–48 hours after final chemotherapy. Patients received G-CSF with standard supportive care until engraftment, defined as absolute neutrophil count > 500/ml and a platelet count > 20,000/ml. Bone marrow biopsy and skeletal imaging were prior to and 100 days after ASCT to assess baseline and post-ASCT disease status. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis in accordance with international uniform myeloma reporting criteria. Results: Twenty-one patients completed ASCT over 6 cohorts: 3 in dose level 1, 6 at dose level 2, and 3 each in dose levels 3, 4, 5, and 6. Median number of days (range) to wbc engraftment and platelet engraftment was 11 (9–13) and 12.5 (10–22), respectively. Toxicities were graded according to the Bearman scale. There was only one Grade 3 toxicity: a patient with respiratory decompensation in the setting of neutropenic fever in cohort 2 (a pulmonary dose limiting toxicity-DLT). Other toxicities noted in patients (%) (Grade 1 / Grade 2 respectively) were Cardiac: 6 (29%) / 2 (10%); Pulmonary 1 (5%) / 1 (5%); CNS 0 / 1 (5%); Stomatitis 15 (71%) / 0; GI 10 (48%) / 1 (5%). The CNS toxicity was narcotic-related psychosis. Eight patients had neutropenic fever, with 3 cases of bacteremia. No transplant-related mortality occurred. At present, there are 18 evaluable Day +100 myeloma responses: disease progression in 5 (24%), stable disease in 1 (6%), partial response 1 (6%), very good partial response in 2 (11%), and complete response in 9 (50%). Four patients (19%) died from MM, all with disease progression at 100 days post-ASCT, and all with pre-existing extramedullary disease. Summary: Bendamustine added to ASCT conditioning in MM does not exacerbate expected toxicities. The maximum tolerated dose of bendamustine in combination with melphalan 200mg/m2 was not found after a series of 6 treatment cohorts. The relatively high complete response rate and good regimen tolerability has prompted an extension phase 2 trial at the cohort 6 dosing to further evaluate regimen efficacy. Disclosures: Off Label Use: The study evaluates bendamustine safety in transplantation for myeloma; there is no FDA-label for this. Niesvizky:Merck: Research Funding.

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