A Pilot Study of Pomalidomide and Dexamethasone in Previously Treated Light Chain Amyloidosis Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3854-3854 ◽  
Author(s):  
Angela Dispenzieri ◽  
Morie A Gertz ◽  
Suzanne R. Hayman ◽  
Francis Buadi ◽  
Shaji Kumar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Median Time ◽  
Light Chain ◽  
Research Funding ◽  
M Protein ◽  
Autonomic Nerve ◽  
Nerve Involvement ◽  
Previously Treated ◽  
Grade 3

Abstract Abstract 3854 Poster Board III-790 Background Primary systemic amyloidosis (AL) is an incurable plasma cell disorder. Lenalidomide, especially in conjunction with dexamethasone, has been shown to be active in patients with multiple myeloma. Pomalidomide is a derivative of thalidomide that acts as an immunomodulator. Preliminary data in multiple myeloma demonstrate that this agent is highly active and well tolerated. Methods Eligible patients were accrued into an IRB approved treatment trial with pomalidomide and dexamethasone after signing informed consent. Pomalidomide (2 mg) and dexamethasone (40 mg) were scheduled to be taken orally, the former on a continuous schedule and the latter once weekly. All patients were instructed to take an aspirin daily. Patients were eligible if they had previously treated, biopsy proven, symptomatic AL. Patients were required to have measurable hematologic disease, defined as either a serum M-protein greater than 1 g/dL, a urinary M-protein greater than 200 mg/24-hours, or a serum immunoglobulin free light chain greater than 10 mg/dL. Other eligibility criteria included an ECOG PS>=2, adequate hematologic reserve (ANC>=1000/uL, platelets>=75/uL) and adequate renal function (creatinine <=2.5 mg/dL). They also were required to comply with contraceptive requirements. Patients were excluded if they had uncontrolled infection, another active malignancy, NYHA classification III or IV, a serum troponin T >0.1 ng/mL, >=grade 3 peripheral neuropathy, untreated active thrombosis, or other chemotherapy within 2 weeks of study enrollment. Thirty-four patients are to be enrolled to allow for 2 possible cancels and to provide 90% power to detect a true hematologic response rate of at least 20%. Between 11/24/08-7/28/09, 20 patients have been enrolled. Baseline characteristics and adverse events are available for 17 of the 20 enrolled patients. Results Median age was 63 years (range 52 78), with 60% male. The median time from diagnosis to study entry was 45 months (range 4.5-103). Eighty-two percent had cardiac involvement; 41% renal involvement; 18% peripheral nerve involvement; and 12% autonomic nerve involvement. The cardiac biomarker staging breakdown was: I, 13%; II, 56%; and III, 31%. Patients were heavily treated, with 100% having received prior alkylator (including prior transplant in 9), 44% prior lenalidomide, 31% prior thalidomide, and 37% prior bortezomib. Thirty-three percent of patients had non-hematological adverse events (AEs) >=grade 3 (severe) that were deemed to be at least possibly related to therapy. Thirty-three percent had >=grade 3 hematologic AEs. Neutropenia was most the most common severe hematologic AE; severe thrombocytopenia was observed in only 1 patient, and there was no severe anemia. The most common severe non-hematologic AE was fatigue, which was observed in 3 patients. The only other severe AEs, each of which was observed in one subject each, were pneumonia, weakness, dyspnea, and ascites. As of 8/14/09, 17 patients remain on active therapy. Median time on study is only 3.7 months (range 0.2-8.1). Three patients have discontinued therapy: two progressions; and one death 5 days into treatment, presumably due to cardiac amyloidosis. At the time of this writing response rates could not be calculated given the short follow-up, but hematologic responses have been observed, and details on efficacy will be presented at the meeting. Conclusions Pomalidomide is well tolerated in previously treated AL patients. More information about its activity will be provided at the meeting. Disclosures: Dispenzieri: Celgene: Research Funding. Gertz:Celgene: Honoraria. Kumar:Celgene: Research Funding. Rajkumar:Celgene: Research Funding. Witzig:Novartis: Research Funding. Greipp:Celgene: Research Funding. Fonseca:Celgene: Consultancy. Bergsagel:Celgene: Consultancy. Mikhael:Celgene: Research Funding. Roy:Celgene: Research Funding. Lacy:Celgene: Research Funding.

A Phase-2 Study of Pomalidomide and Dexamethasone In Previously-Treated Light-Chain (AL) Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 987-987
Author(s):  
Angela Dispenzieri ◽  
Morie Abraham A. Gertz ◽  
Suzanne R. Hayman ◽  
Francis Buadi ◽  
Shaji Kumar ◽  
...  
Keyword(s):  
Median Time ◽  
Light Chain ◽  
Research Funding ◽  
Troponin T ◽  
Renal Involvement ◽  
Al Amyloidosis ◽  
Severe Thrombocytopenia ◽  
Previously Treated ◽  
Grade 3 ◽  
Dose Reductions

Abstract Abstract 987 Background: IMiD® compounds are effective in immunoglobulin light-chain amyloidosis (AL), a systemic plasma cell disorder related to multiple myeloma (MM). Pomalidomide is a new IMiD® compound. Methods: Persons with symptomatic, biopsy-proved, previously-treated AL were eligible for treatment with pomalidomide if they had measurable hematologic disease, ECOG PS≥2, adequate hematologic reserve and creatinine ≤2.5 mg/dL. Pomalidomide, 2 mg/d, and dexamethasone, 40 mg/w, were given orally along with low-dose aspirin. Dose-escalation to 4 mg/d was allowed for non-responders. Exclusion-criteria were uncontrolled infection, cancer, NYHA classification >II, serum troponin-T >0.1 ng/mL, ≥grade-3 neuropathy, thrombosis or other AL therapy within 2 weeks of enrollment. 31 subjects enrolled, but only 29 are evaluble for toxicity and response due to recent enrollment. Results: Median age was 66 y (range, 52 82 y); 19 were male. Median time from diagnosis to study-entry was 36 mo (range, 0.9–104.1 mo). 24 had cardiac involvement, 10, renal involvement and 8, nerve involvement. Cardiac biomarker staging was: I, N=3, II, 21, and III, N=7. Subjects were extensively pretreated: 28 received an alkylator (including an autotransplant in 13), 15, prior lenalidomide or thalidomide and 12, prior bortezomib. 193 cycles of pomalidomide were given to 29 subjects. 11 subjects had protocol-specified dose-increases (no response) and 16, dose-reductions (AEs). 20 subjects had dexamethasone dose-reductions. ≥Grade-3 AE's ≥possibly attributed to therapy occurred in 21 subjects. 7 of these subjects had only hematologic AE's. Neutropenia was the most common severe AE (N=10); severe thrombocytopenia occurred in 2 subjects. Other grade-3/-4 AEs included infection/fever (N=3); fatigue (N=4), and pleural effusion, ascites/edema, and edema each in one patient. 1 subject each had dyspnea, increased creatinine, thrombosis, muscle weakness, atrial tachycardia, and diarrhea. There were 2 episodes of syncope attributed to AL rather than therapy. A subject died 5 d after beginning therapy presumably from cardiac AL. As of 7/27/010, median time on-study is 8.4 mo (range, 0.2–16.2 mo). 18 subjects discontinued therapy for: progression/death (N=9); consent withdrawal (N=4), AE (N=3) and physician choice (N=2). Overall hematologic response rate (N=29) is 38% (95% CI, 20–58%) There were 8 PRs and 3 VGPRs including 4 PRs and 2 VGPRs among 14 subjects failing prior lenalidomide and/or thalidomide. 3 subjects had confirmed organ responses (2 heart and 1 kidney) and 4 unconfirmed organ responses. 1 y survival and PFS are 77% (95% CI, 60–98) and 56% (95% CI, 36–85). Conclusion: These data suggest that pomalidomide could provide a safe and effective therapy in previously-treated persons with AL including those failing lenalidomide and/or thalidomide. Disclosures: Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Off Label Use: Non-FDA approved indication. Gertz:Celgene: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Fonseca:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding; Genzyme: Consultancy; Onyx: Research Funding; Otsuka: Consultancy; Medtronic: Consultancy. Bergsagel:Celgene: Consultancy; Centocor: Consultancy; Genentech: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Stewart:Millennium: Consultancy; Celgene: Honoraria. Lacy:Celgene: Research Funding.

scholarly journals Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Hang Quach ◽  
Simon J Harrison ◽  
Je-Jung Lee ◽  
Nichloas Murphy ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Research Funding ◽  
Open Label ◽  
Advisory Committees ◽  
Open Label Phase ◽  
Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

A Clinical Pharmacology and Exploratory Study of Azacitidine Administered Subcutaneously or Intravenously In Japanese Patients with Myelodysplastic Syndrome

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4964-4964
Author(s):  
Yukio Kobayashi ◽  
Michinori Ogura ◽  
Kiyoshi Ando ◽  
Kensei Tobinai ◽  
Toshiki Uchida ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Median Time ◽  
Research Funding ◽  
Treatment Protocol ◽  
Japanese Patients ◽  
Hematologic Response ◽  
Transfusion Requirements ◽  
Grade 3 ◽  
To Receive

Abstract Abstract 4964 [Background and Purpose]: Azacitidine is a pyrimidine nucleoside analog of cytidine with hypomethylating and cytotoxic activity. Although azacitidine is currently approved for subcutaneous (SC) injection and intravenous(IV) administration for the treatment of myelodysplastic syndromes (MDS) in the US, there are limited data available on the treatment effects of IV versus SC administration. To compare the safety, pharmacokinetics (PK), and efficacy of IV with SC administration, a phase I/II study of azacitidine in Japanese patients with MDS was conducted. [Patients and Method]: Patients with RA, RA with ringed sideroblasts (RARS), RAEB, or RAEB-t defined by the French-American-British (FAB) classification were enrolled. RA and RARS must fulfill the additional criteria of significant marrow dysfunction (defined by cytopenias and/or transfusion requirements). Eligible patients were at least 20 years of age but younger than 80 and had a ECOG PS between 0 and 2. The patients were alternately assigned to receive azacitidine SC or IV (10-minutes) at 75 mg/m2/day for 7 days every 4 weeks for a minimum of 4 cycles. Patients who achieved a complete response (CR) received additional 3 cycles of azacitidine and were followed up without treatment. Subjects with a partial response (PR) or hematologic improvement (HI) received azacitidine until disease progression with a maximum of 18 cycles. Ten patients received azacitidine by both SC and IV administration on the different cycle and PK parameters were compared on day 1 of each cycle. The primary endpoints of this study were the safety, PK and HI according to the International Working Group (IWG 2006) criteria for MDS, respectively. [Results]: A total of 54 patients (10 in phase I portion and 44 in phase II portion) were enrolled between October 2007 and November 2008. Of these, 53 patients received at least one dose of azacitidine; 17 patients (32 %) were female; the median age was 65 years (range 35–77 years). FAB MDS subtypes were: RA (16/53, 30%); RARS (3/53, 6%); RAEB (20/53, 38%); RAEB-t (14/53, 26%). IPSS risk groups were: Low (0%); Int-1(23/53, 43%); Int-2(15/53, 28%); High(15/53, 28%). IPSS cytogenetic groups were: good (24/53, 45%); intermediate (13/53, 25%); poor (16/53, 30%). Fifty-one patients have completed the treatment protocol to date. The median number of treatment cycles was 7(range 1 – 18). Seven patients have completed 18 cycles of treatment. Two patients are continuing to receive treatment in their cycles 16 and 17. HI was observed in 53% (26/49) of patients. Median time to HI was 55 days (range 20–217). Of the 27 patients who were RBC transfusion dependent at baseline, 15 (56%) became transfusion independent. Hematologic response (CR, PR, or marrow CR) was achieved in 29% (15/51) of patients. Median time to hematologic response was 113 days (range 49–247). HI rate in SC and IV administration was 50 % (12/24) and 56 % (14/25), respectively. Hematologic response rate in SC and IV administration was 29% (7/24) and 30% (8/27), respectively. There were no significant differences between SC and IV administration of azacitidine for HI and hematologic response. The Cmax following IV administration was approximately 4-fold of that obtained following SC administration; however, the AUC(0-∞) following SC administration was 92.3 ± 15.8% compared to that of IV, indicating good bioavailability following SC administration. Overall, the PK profile was similar to that of the previously reported study. The most common grade 3 or 4 adverse events included neutropenia 80% (41/51), leukopenia 76% (39/51), hemoglobin decreased 71% (36/51) and thrombocytopenia 65% (33/51). Grade 3 or 4 non-hematologic adverse events which were observed more than 10% included pneumonia 12% (6/51) and hypophosphatemia 16%(8/51). There was no death during the study that occurred within 29 days of last dose of azacitidine. The safety profile did not differ significantly different between SC and IV administration with the exception of injection site reactions observed with SC administration, only. [Conclusions]: Azacitidine is generally well tolerated and demonstrated a beneficial effect in Japanese patients with MDS. The higher Cmax of IV dose was not translated into clinical outcomes; no difference was shown in both efficacy and safety profiles between SC and IV administration. Both IV and SC azacitidine are promising therapeutic options for Japanese patients with MDS. Disclosures: Kobayashi: Nippon Shinyaku Co., Ltd.: Research Funding. Ogura: Nippon Shinyaku Co., Ltd: Research Funding. Ando: Nippon Shinyaku Co., Ltd.: Research Funding. Tobinai: Nippon Shinyaku Co., Ltd.: Research Funding. Uchida: Nippon Shinyaku Co., Ltd.: Research Funding. Ogawa: Nippon Shinyaku Co., Ltd.: Research Funding. Ishikawa: Nippon Shinyaku Co., Ltd.: Research Funding. Ohashi: Nippon Shinyaku Co., Ltd.: Research Funding. Hata: Nippon Shinyaku Co., Ltd.: Research Funding. Usui: Nippon Shinyaku Co., Ltd.: Research Funding. Taniwaki: Nippon Shinyaku Co., Ltd.: Research Funding. Ohnishi: Nippon Shinyaku Co., Ltd.: Research Funding. Akiyama: Nippon Shinyaku Co., Ltd.: Research Funding. Ozawa: Nippon Shinyaku Co., Ltd.: Research Funding. Ohyashiki: Nippon Shinyaku Co., Ltd.: Research Funding. Okamoto: Nippon Shinyaku Co., Ltd.: Research Funding. Tomita: Nippon Shinyaku Co., Ltd.: Research Funding. Nakao: Nippon Shinyaku Co., Ltd.: Research Funding. Hotta: Nippon Shinyaku Co., Ltd.: Research Funding.

Lenalidomide (Revlimid), Bortezomib (Velcade) and Dexamethasone (RVD) for Heavily Pretreated Relapsed or Refractory Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2936-2936
Author(s):  
Victor H Jimenez-Zepeda ◽  
Donna E. Reece ◽  
Suzanne Trudel ◽  
Christine Chen ◽  
Vishal Kukreti
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Phase 1 ◽  
Prior Exposure ◽  
Rank Test ◽  
Continuous Variables ◽  
Previously Treated ◽  
Grade 3

Abstract Abstract 2936 Almost all patients (pts) with multiple myeloma eventually relapse and remission duration decreases with each regimen. The median Progression Free Survival (PFS) and Overall Survival (OS) in pts with relapsed myeloma refractory to lenalidomide (len) and bortezomib (btz) is poor at 5 and 9 months respectively. A phase 1 study of len plus btz in pts with relapsed or relapsed, refractory MM (RRMM) demonstrated favorable toxicity and promising response and survival further confirmed in a phase 2 study with len, btz and dexamethasone (dex) [RVD]. In this retrospective study, we assessed the efficacy and toxicity profile of RVD therapy for pts with advanced RRMM. We retrospectively reviewed the records of all pts with RRMM treated with RVD at Princess Margaret Hospital between 03/09 and 05/11. Relapse was defined according to the Uniform International Criteria. Pts were given RVD therapy as previous described by Anderson et al and must have completed at least one cycle of RVD therapy. Primary endpoints were response rate (RR), PFS, OS, and toxicity. Pts discontinued therapy if they experienced PD, no additional benefit or unacceptable toxicity. Definitions of response and progression were used according to the EBMT modified criteria with a category of very good partial response (VGPR). To examine variables independently prognostic for PFS and OS, multivariate Cox analysis was performed. Differences in continuous variables between groups were compared using Mann-Whitney or Kruskal-Wallis tests. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. Thirty pts with RRMM received RVD therapy. Clinical characteristics are seen in Table 1. Median age at RVD initiation was 57 yrs (37–76 yrs), and 46.7% were male. Pts received a median of 3 prior therapies (1–6). In many instances, pts previously treated with len had len added to btz + dex at progression (n=6), or pts previously treated with btz had btz added to len + dex, at progression (n=5). Thalidomide (thal), len and btz containing regimens were previously used in 60%, 73.3% and 80% of pts respectively. PR or better was observed in 46.6%. After a median of 4.6 cycles (1–14), VGPR was seen in 4.8%, PR in 33% and SD in 14%. Pts who achieved PR or better experienced a significant improvement in PFS. There was no difference in terms of RR between those pts according to prior exposure to either btz or len (p=0.7 and 0.9 respectively). Eight pts experienced non-hematological grade 3/4 adverse events (26%), including muscle weakness, sepsis and pneumonia but there was no worsening of peripheral neuropathy. Grade 3–4 neutropenia and/or thrombocytopenia were commonly seen in 70% of pts (n=21). Disease progression was seen in 19 pts at a median of 3.9 months. Median PFS for pts previously exposed to len was 2.3 months vs 2.9 months for those with no prior exposure (p=0.75). On the other hand, median PFS for pts previously exposed to btz was 2.1 months vs 3.4 months for those with no prior exposure (p=0.9) In addition, median PFS for pts who achieved at least PR was significantly better at 5.9 vs 2.0 months for those who did not (p<0.005). (Figure 1) FISH cytogenetics studies were available in 19 out of 30 patients at relapse: 5 -normal, 4–13q deletion, 3-p53 deletion and 2 - t(4, 14). High-risk MM pts had a median PFS significantly lower of 0.6 months (CI 95%, 0–1.99) vs 4.7 months for those without high-risk features (CI 2.5–7.0) (p=0.008) (Figure 2) At the time of submission, 13 pts are alive (43.3%) and 7 pts (23%) continue on RVD therapy.Table 1.Clinical characteristics of patients with RRMM treated with RVDClinical characteristic N=30MedianRange%Age5737-76Male46.7%Female53.3%Hemoglobin (g/L)10571-155Creatinine (mmol/L)99.936-383Beta-2 microglobulin (mmol/L)280119-1440Lactate dehydrogenase (U/L)18189-255IgG56.6% (17)IgA23.3% (7)IgM3.3% (1)Light Chain16.6% (5)Kappa (mg/L)4005.3-346063.3% (19)Lambda (mg/L)5145.1-530036.7% (11)KappaLambda*BMPC57%6-95%M-spike serum (g/L)300-77M-spike urine (g/d)0.890-7.9Prior therapies31-6ASCT83.3% (25)Thal60% (18)Len73.3% (22)Btz80% (24)*BMPC, Bone marrow plasma cells In conclusion, RVD is active and well tolerated in pts with RRMM, including pts who have received prior len, btz, thal and ASCT but PFS is short at 3.9 months in this highly advanced disease group of patients. We question whether response is dependent on recognized risk factors such as adverse cytogenetics. Disclosures: Jimenez-Zepeda: J & J: Honoraria. Reece:Bristol, Meyers, Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Johnson&Johnson: Research Funding; Merck: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Millennium: Research Funding; Amgen: Honoraria. Kukreti:Celgene: Honoraria.

Phase 1/2 Trial Of Lenalidomide In Combination With Cyclophosphamide and Prednisone (REP) In Patients With Lenalidomide-Refractory Multiple Myeloma (REPEAT-study)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 287-287 ◽  
Author(s):  
Inger S. Nijhof ◽  
Sonja Zweegman ◽  
Mark-David Levin ◽  
Harry R. Koene ◽  
Aart Beeker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Oral Cyclophosphamide ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Grade 3 ◽  
Dose Levels

Abstract Background The outcome of multiple myeloma (MM) patients who are no longer responding to thalidomide, lenalidomide (LEN) and bortezomib (BORT) is very poor, with a median event-free survival of 5 months and median overall survival (OS) of 9 months (Kumar SK et al, Leukemia 2012; 26;149-157). We have previously shown in a small retrospective study that the combination of continuous low dose oral cyclophosphamide (endoxan) and prednisone combined with lenalidomide (REP) had remarkable activity in heavily pretreated LEN-refractory multiple myeloma patients (median 6 lines of previous chemotherapy) (vd Donk et al; Br J Haematol 2010;148(2):335-7). To determine the optimal dose of lenalidomide with continuous cyclophosphamide and prednisone, we initiated a prospective study to evaluate the maximum tolerated dose (MTD) of the REP regimen and to assess its efficacy and safety in LEN-refractory MM patients. Here we report safety and efficacy data from the phase 1 dose-escalation part of the REPEAT-study (NCT01352338). Patients and Methods Patients aged ≥ 18 years with LEN-refractory MM, ECOG-performance status 0-3 and adequate kidney, liver and hematologic function were included. Five dose levels were evaluated using a standard 3+3 design, based on dose-limiting toxicities (DLTs) occurring in cycle 1. Patients received LEN in doses ranging from 10-25 mg/day on days 1-21 of 28-day cycle, while oral cyclophosphamide (50 or 100 mg) and prednisone (20 mg) were given continuously. Therapy was continued until progression. The MTD for the phase 2 part is defined as the highest dose level with 0 or 1 DLT's observed in 6 patients. Results Up till now, 35 patients were enrolled (22 in phase 1 and 13 in phase 2) from August 2011 to June 2013. The phase 2 part is still recruiting and data are not evaluable yet. One patient in phase 1 was excluded because of study violation and is not included in the analysis. The median age of the 21 evaluable patients in phase 1 was 69 years (range 41-73); 76% were male. The median duration of the disease from diagnosis was 41 months (range 18-96), median number of prior therapies was 3 (range 2-6), and 12 patients (57%) had previously received autologous SCT. All patients were LEN-refractory, 19 (90%) had prior BORT treatment, and 16 (76%) had BORT-refractory MM. Fifty-five % of the patients were considered high risk by FISH. At the time of analysis, 16 of 21 patients in phase 1 have discontinued treatment because of disease progression (13), alternative treatment (allo-SCT) (1), or adverse events (2). The MTD was defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously (dose level 4), based on three patients experiencing a DLT: two developed pneumonia (in dose levels 4 and 5; CTC grade 3), and one patient at dose level 5 experienced CTC grade 3 dyspnea. Neutropenia (18%) and thrombocytopenia (18%) were the most common grade 3 hematological adverse events (AEs), which were managed with growth factor support and/or dose modification. There were no grade 4 hematologic AEs. Grade 3 respiratory tract infections (29%) and grade 2 fatigue (19%) were the most common non-hematological AEs. Venous thromboembolism occurred in 1 patient. Figure 1 shows a waterfall plot of the responses of the patients that participated in the phase 1 part of the study. Overall response rate (≥ PR) was 67% with 6 out of 21 (29%) patients achieving at least VGPR. In addition 2 patients achieved MR (≥ MR: 76%). Median PFS and OS were 6.3 and 15.5 months respectively. Similar results were achieved in the subset of patients with LEN- and BORT-refractory disease. Interestingly, laboratory experiments with purified myeloma cells from these patients suggest synergism between LEN and cyclophosphamide. Conclusions The REP regimen induces high response rates and prolonged PFS and OS in LEN-refractory patients with acceptable toxicity. The MTD is defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously. Phase 2 is enrolling patients and evaluates efficacy and safety of the REP regimen at the MTD. REP should be considered a valuable salvage option for LEN-refractory MM patients. We will present an updated follow-up at ASH. Disclosures: Sonneveld: Onyx: Research Funding; Millenium: Research Funding; Janssen-Cilag: Research Funding; Onyx: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Celgene: Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. van de Donk:Celgene: Research Funding.

Phase 1 Study of the Investigational Proteasome Inhibitor Ixazomib Alone or in Combination with Lenalidomide–Dexamethasone (Rd) in Japanese Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5752-5752 ◽  
Author(s):  
Hiroshi Handa ◽  
Kenshi Suzuki ◽  
Takaaki Chou ◽  
Takafumi Matsushima
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Japanese Patients ◽  
M Protein ◽  
Phase 3 ◽  
Grade 3 ◽  
Ongoing Phase

Background Ixazomib is the first oral proteasome inhibitor to be investigated clinically for the treatment of MM. Phase 1 studies have shown single-agent activity and manageable toxicities in RRMM (Kumar et al. Blood 2014) and phase 1/2 studies have suggested the feasibility and activity of weekly oral ixazomib plus Rd in previously untreated MM (Kumar et al. ASH 2012; Richardson et al. ASH 2013). These findings have led to ongoing phase 3 trials of weekly ixazomib 4 mg + Rd in RRMM and previously untreated MM. However, the early-phase studies were conducted in Western pts. This phase 1, open-label multicenter study aimed to determine the safety, tolerability, and pharmacokinetics (PK) of weekly ixazomib alone or with Rd in Japanese pts with RRMM (Japic Clinical Trials Information no. 121822). Methods Primary objectives were to evaluate the safety and tolerability, including dose-limiting toxicities (DLTs) and adverse events (AEs), and the PK of ixazomib alone or with Rd. A secondary objective was evaluation of antitumor activity. Japanese pts aged ≥20 years with RRMM who had received at least 2 prior regimens, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, were eligible. All had measurable disease and ECOG performance status of 0–2. Pts with grade ≥2 peripheral neuropathy or grade ≥2 diarrhea at study entry were excluded. Pts received ixazomib 4 mg on days 1, 8, and 15 of 28-day cycles, alone or with Rd (lenalidomide 25 mg on days 1–21, dexamethasone 40 mg on days 1, 8, 15, and 22), per the regimen used in the ongoing phase 3 trials. AEs were graded per NCI-CTCAE v4.03. Blood samples for PK analysis were taken at multiple time points prior to and after dosing on days 1 and 15 of cycle 1. Responses were assessed per IMWG uniform response criteria. Results Fourteen pts were enrolled; 8 (57%) were male, median age was 62.5 yrs (range 53–71), 4 pts were aged ≥65 yrs, median number of prior therapies was 7. Seven pts received single-agent ixazomib and 7 received ixazomib + Rd. One pt in each cohort was excluded from the DLT-evaluable population. Two patients experienced DLTs in cycle 1: 1 pt receiving single-agent ixazomib had grade 4 thrombocytopenia and grade 3 diarrhea, hypertension, hypokalemia, hyponatremia, and nausea; 1 pt in the ixazomib + Rd cohort had grade 4 thrombocytopenia and neutropenia. All events were considered treatment-related. At data cut-off (Jan 6 2014), 6 pts remained on treatment and 8 had discontinued due to: progressive disease (PD; n=3), AEs (n=3), symptomatic deterioration, and protocol violation (each n=1). At data cut-off, pts (n=14) had received a median of 6 cycles of ixazomib (range 1–21); the 7 pts in the ixazomib + Rd cohort had received a median of 4 cycles (range 1–12) of ixazomib + Rd. Thirteen (93%) pts experienced treatment-related AEs; the most common were neutropenia (71%), thrombocytopenia (71%), leukopenia (64%), lymphopenia (57%), and diarrhea (50%). There were no cases of peripheral neuropathy. Nine (64%) pts had grade ≥3 AEs; the most common were lymphopenia (50%), neutropenia (43%), and thrombocytopenia (36%). Two (14%) pts (single-agent cohort) had serious AEs (grade 2 bronchitis in 1 pt, and grade 4 thrombocytopenia and grade 3 hypokalemia in 1 pt). Three pts discontinued due to AEs; 1 due to diarrhea in the single-agent cohort, and 1 due to neutropenia and 1 due to thrombocytopenia in the ixazomib + Rd cohort. There were no deaths. PK data showed ixazomib was rapidly absorbed with a Tmax at 1.08–1.83 hrs. Terminal half-life (geometric mean) was 5.7 days for single-agent ixazomib and 5.2 days for ixazomib + Rd. There were no substantial differences in the ixazomib PK profile between the two cohorts. Thirteen pts were response-evaluable. One pt (ixazomib + Rd cohort) had a partial response; at data cut-off, this pt remained in response with a 100% M-protein reduction (unconfirmed VGPR) and duration of response of ~10.8 months. Seven pts had stable disease (including 3 with M-protein reductions of 25–50%), 2 had PD, and 3 were not assessable. Conclusions These data suggest that ixazomib 4 mg alone or with Rd is feasible and tolerable in Japanese pts with RRMM. The AEs were manageable, reflecting the AE profile seen in Western populations, supporting the use of this dose and schedule in Japanese pts. Disclosures Handa: Celgene: Research Funding; Yakult: Research Funding; Kirin: Research Funding; Chugai: Research Funding. Off Label Use: Investigational agent ixazomib for the treatment of Japanese patients with relapsed and/or refractory multiple myeloma.. Matsushima:Takeda Pharmaceutical Company Limited : Employment.

Preliminary Safety and Efficacy Results from an International Phase 3b Study for Expanded Access to Bortezomib in 624 Patients with Relapsed and/or Refractory Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3530-3530 ◽  
Author(s):  
Joseph R. Mikhael ◽  
Andrew Belch ◽  
Miles Prince ◽  
Maria Nambo Lucio ◽  
Angelo Maiolino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Median Time ◽  
Stable Disease ◽  
Progressive Disease ◽  
Karnofsky Performance Status ◽  
M Protein ◽  
Significant Activity ◽  
Expanded Access ◽  
Grade 3

Abstract Background: Bortezomib (VELCADE®) is a first-in-class, reversible proteasome inhibitor with activity in multiple myeloma (MM) and other malignancies. Bortezomib showed significant activity in previous phase 2 and 3 studies in patients (pts) with previously treated MM. This international multicenter open-label phase 3b study allowed expanded access to bortezomib therapy in pts with relapsed/refractory MM treated with ≥ 2 previous lines of therapy. Methods: Pts with MM were eligible if they had received ≥ 2 prior lines of therapy and required treatment due to relapsed or progressive disease. Pts with grade ≥ 2 peripheral neuropathy (PN) were excluded. Pts received 1.3 mg/m2 IV bolus bortezomib on days 1, 4, 8, and 11 of each 3-week cycle for up to 8 cycles; dexamethasone (20 mg/d PO on the day of and day after bortezomib dose) could be added after cycle 2 for progressive disease or after cycle 4 for stable disease. Adverse events (AEs) were assessed beginning at the start of treatment and continuing until 30–42 days after treatment and were graded based on NCI-CTC version 2.0. Efficacy assessment was performed based on changes in disease burden as measured by monoclonal (M)-protein concentration in serum and urine every 2 cycles (6 weeks). Response was assessed using modified SWOG criteria: complete response (CR) was a 100% reduction in M-protein; very good partial response (VGPR), 75–99% reduction; partial response (PR), 50–74% reduction; minimal response (MR), 25–49% reduction; and stable disease, < 25% reduction. Increasing M-protein levels indicated progressive disease. Results: 624 pts in 93 centers from 21 countries received at least 1 dose of treatment and were evaluable for safety (55.3% male; median age 62.7 years). 68% of pts received 3–11 lines of previous therapy. Karnofsky performance status was ≤70 in 25.6% of pts; 141 pts (22.6%) were ≥ 70 years of age. Pts completed a median of 5 cycles of therapy (range 0–13); 39.3% of pts completed all 8 planned cycles. Grade 3/4 treatment-emergent (related and unrelated) AEs were reported in 430 pts (68.9%), with thrombocytopenia (29.2%), neutropenia (13.3%), and anemia (11.7%) the most common hematologic AEs. Grade 3/4 PN was reported in 8.2% of pts. Overall, 165 pts (26.4%) discontinued therapy due to treatment-related AEs. Best responses among evaluable pts (n = 593) included 12.0% CR, 23.1% VGPR, 19.1% PR, and 16.5% MR, for an overall response rate of 70.7%. Median time to first response was 42 days (range 7–125), and median time to best response was 63 days (range 7–235). Conclusions: Bortezomib 1.3 mg/m2 administered biweekly q3 weeks was well tolerated with manageable toxicities in pts with relapsed and/or refractory MM. Response rates with bortezomib were high, even in heavily pretreated pts, inducing > 25% CR/VGPR. This study confirms results from initial clinical trials in a broader population.

Bortezomib, Lenalidomide and Dexamethasone Vs. Lenalidomide and Dexamethasone in Patients (Pts) with Previously Untreated Multiple Myeloma without an Intent for Immediate Autologous Stem Cell Transplant (ASCT): Results of the Randomized Phase III Trial SWOG S0777

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 25-25 ◽  
Author(s):  
Brian Durie ◽  
Antje Hoering ◽  
S. Vincent Rajkumar ◽  
Muneer H. Abidi ◽  
Joshua Epstein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Rank Test ◽  
P Value ◽  
Advisory Committees ◽  
Significance Level ◽  
Grade 3

Abstract Background: Lenalidomide with dexamethasone (Rd) is a standard of care for patients with previously untreated multiple myeloma. SWOG S0777, a randomized phase III trial, has compared Rd with bortezomib, lenalidomide and dexamethasone (VRd). The primary end point is progression-free survival (PFS) using a pre-specified one-sided stratified log rank test at a significance level of 0.02. The stratification factors are International Staging System (ISS) stage (I, II or III) and intent to transplant (yes or no), a total of 6 strata. Overall response rate (ORR), overall survival (OS) and safety are secondary end points. Methods: This analysis includes 474 patients evaluable for survival endpoints: 232 patients were randomized to Rd and 242 patients to VRd. Rd patients received lenalidomide 25 mg/day on days 1-21 and dexamethasone 40 mg/day on days 1, 8, 15 and 22 of a 28-day cycle. VRd patients received lenalidomide 25 mg/day on days 1-14 and dexamethasone 20/mg/day on days 1, 2, 4, 5, 8, 9, 11 and 12 plus bortezomib 1.3 mg/m2 IV push on days 1, 4, 8 and 11 of a 21-day cycle. All patients received aspirin 325 mg/day and VRd patients received HSV prophylaxis per institutional standard. Induction was six 28-day cycles of Rd and eight 21-day cycles of VRd followed by Rd maintenance for all patients until progression, unacceptable toxicity or withdrawal of consent. Initial analyses utilized the pre-specified one-sided stratified log rank test. Results: Data are presented for VRd followed by Rd throughout. Between 2008 and 2012, 525 patients from 48 institutions were randomized. Fifty-one patients, 29 randomized to Rd and 22 randomized to RVd, were ineligible for the following reasons: missing, insufficient or early or late baseline labs (40); not meeting requirements of measurable disease (6); inadequate marrow function (1); inadequate creatinine clearance (1); prior malignancy (1); prior therapy (1); and more than 2 weeks of prior steroid therapy (1). The pre-specified significance level of 0.02 was reached in the log rank testing. The stratified hazard ratio (HR) was 0.742 (96% Wald confidence interval: 0.579, 0.951), and the one-sided stratified log rank p-value for PFS (VRd vs. Rd) was 0.0066. The OS was improved for VRd vs. Rd with HR = 0.666; two-sided log-rank p-value = 0.0114. The PFS and OS survival charts are displayed below. Median PFS was 43 months (VRd) versus 31 months (Rd). Median OS was not reached (VRd) versus 63 months (Rd). Patient characteristics were well-matched between VRd and Rd with the exception of fewer women (37% vs. 47%: P = 0.033) and fewer older patients (≥ 65 years 38% vs. 48%: P = 0.042) receiving VRd. With univariate Cox regression analysis correlates of better PFS/OS were: use of VRd (HR 0.72/0.65; P = 0.006); hemogoblin ≥10 g/dl (HR 1.17/1.43; P = 0.2/0.026) and lower ISS disease stage (HR 1.35/1.98; P = 0.014/< 0.001). The ORR for VRd was 71.07% versus 63.79% for Rd. The adverse events by CTC category and toxicity category were fairly well balanced. The most common hematologic adverse events (≥ Grade 3 and at least possibly attributable to therapy) were low hemoglobin (RVd=13%; Rd=16%), leukopenia (RVd=14%; Rd=16%), lymphopenia (RVd=23%; Rd=18%), neutropenia (RVd=19%; Rd=21%), and thrombocytopenia (RVd=18%; Rd=14%). The most common non-hematologic adverse events (≥ Grade 3 and at least possibly attributable to therapy) were: fatigue (RVd=16%; Rd=14%), sensory neuropathy (RVd=23%; Rd=3%), hyperglycemia (RVd=7%; Rd=11%), thrombosis/embolism (RVd=8%; Rd=9%), hypokalemia (RVd=9%; Rd=6%), muscle weakness (RVd=7%; Rd=4%), diarrhea (RVd=8%; Rd=2%), and dehydration (RVd=8%; Rd=2%). As expected ≥ Grade 3 neuropathy was more frequent with VRd (24% vs. 5%: P < 0.0001). Sixteen patients experienced a second primary malignancy, 7 (3%) on VRd and 9 (4%) on Rd. Conclusion: The addition of bortezomib to lenalidomide dexamethasone for induction therapy in previously untreated myeloma results in a statistically significant and clinically meaningful improvement in PFS as well as better OS. VRd had an acceptable safety and tolerability profile despite increased neurotoxicity and represents a potential new standard of care. Support: NIH/NCI/NCTN grants CA180888, CA180819, CA180821, CA180820; and in part by Millennium Pharmaceuticals, Inc., The Takeda Oncology Company, for provision of study drug. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Durie: Johnson & Johnson: Consultancy; Takeda: Consultancy; Onyx: Consultancy; Celgene: Consultancy. Abidi:Millennium: Research Funding. Epstein:University of Arkansas for Medical Sciences: Employment. Reu:Takeda/Millennium: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Orlowski:BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Acetylon: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Forma Therapeutics: Consultancy; Array BioPharma: Consultancy, Research Funding. Barlogie:Dana Farber Cancer Institute: Other: Travel Stipend; International Workshop on Waldenström's Macroglobulinemia: Other: Travel Stipend; ComtecMed- World Congress on Controversies in Hematology: Other: Travel Stipend; European School of Haematology- International Conference on Multiple Myeloma: Other: Travel Stipend; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Myeloma Health, LLC: Patents & Royalties: Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC; Multiple Myeloma Research Foundation: Other: Travel Stipend.

scholarly journals Prevalence of Smoldering Multiple Myeloma: Results from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 151-151
Author(s):  
Sigrun Thorsteinsdottir ◽  
Gauti Kjartan Gislason ◽  
Thor Aspelund ◽  
Sæmundur Rögnvaldsson ◽  
Jon Thorir Thorir Oskarsson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Risk Stratification ◽  
Light Chain ◽  
Research Funding ◽  
Plasma Cells ◽  
Population Based ◽  
M Protein ◽  
Screening Study

Abstract Background Smoldering multiple myeloma (SMM) is an asymptomatic precursor condition to multiple myeloma (MM). Emerging data from clinical trials indicate that - compared to watchful monitoring - initiation of therapy at the SMM stage might be indicated. Currently, there is no established screening for SMM in the general population and therefore patients are identified incidentally. Here, we define for the first time, epidemiological and clinical characteristics of SMM in the general population based on a large (N&gt;75,000) population-based screening study. Methods The iStopMM study (Iceland Screens Treats or Prevents Multiple Myeloma) is a nationwide screening study for MM precursors where all residents in Iceland over 40 years of age and older were invited to participate. Participants with a positive M-protein on serum protein electrophoresis (SPEP) or an abnormal free light chain (FLC) analysis entered a randomized controlled trial with three arms. Participants in arm 1 continued care in the Icelandic healthcare system as though they had never been screened. Arms 2 and 3 were evaluated at the study clinic with arm 2 receiving care according to current guidelines. In arm 3 bone marrow testing and whole-body low-dose CT (WBLDCT) was offered to all participants. SMM was defined as 10-60% bone marrow plasma cells on smear or trephine biopsy and/or M-protein in serum ≥3 g/dL, in the absence of myeloma defining events. Participants in arm 3 were used to estimate the prevalence of SMM as bone marrow biopsy was performed in all participants of that arm when possible. The age- and sex-specific prevalence was determined with a fitted function of age and sex, and interaction between those. Diagnosis at baseline evaluation of the individuals in the study was used to define the point prevalence of SMM. Results Of the 148,704 individuals over 40 years of age in Iceland, 75,422 (51%) were screened for M-protein and abnormal free light chain ratio. The 3,725 with abnormal screening were randomized to one of the three arms, and bone marrow sampling was performed in 1,503 individuals. A total of 180 patients were diagnosed with SMM, of which 109 (61%) were male and the median age was 70 years (range 44-92). Of those, a total of 157 (87%) patients had a detectable M-protein at the time of SMM diagnosis with a mean M-protein of 0.66 g/dL (range 0.01-3.5). The most common isotype was IgG in 101 (56%) of the patients, 44 (24%) had IgA, 2 (1%) had IgM, and 5 (3%) had biclonal M-proteins. A total of 24 (13%) patients had light-chain SMM. Four patients (2%) had a negative SPEP and normal FLC analysis at the time of SMM diagnosis despite abnormal results at screening. A total of 131 (73%) patients had 11-20% bone marrow plasma cells at SMM diagnosis, 32 (18%) had 21-30%, 9 (5%) had 31-40%, and 8 (4%) had 41-50%. Bone disease was excluded with imaging in 167 (93%) patients (MRI in 25 patients, WBLDCT in 113 patients, skeletal survey in 27 patients, FDG-PET/CT in 1 patient), 13 patients did not have bone imaging performed because of patient refusal, comorbidities, or death. According to the proposed 2/20/20 risk stratification model for SMM, 116 (64%) patients were low-risk, 47 (26%) intermediate-risk, and 17 (10%) high-risk. A total of 44 (24%) had immunoparesis at diagnosis. Using the PETHEMA SMM risk criteria on the 73 patients who underwent testing with flow cytometry of the bone marrow aspirates; 39 (53%) patients were low-risk, 21 (29%) patients were intermediate-risk, and 13 (18%) patients were high-risk. Out of the 1,279 patients randomized to arm 3, bone marrow sampling was performed in 970, and 105 were diagnosed with SMM (10.8%). The prevalence of SMM in the total population was estimated to be 0.53% (95% CI: 0.49-0.57%) in individuals 40 years of age or older. In men and women, the prevalence of SMM was 0.70% (95% CI: 0.64-0.75%) and 0.37% (95% CI: 0.32-0.41%), respectively, and it increased with age in both sexes (Figure). Summary and Conclusions Based on a large (N&gt;75,000) population-based screening study we show, for the first time, that the prevalence of SMM is 0.5% in persons 40 years or older. According to current risk stratification models, approximately one third of patients have an intermediate or high risk of progression to MM. The high prevalence of SMM has implications for future treatment policies in MM as treatment initiation at the SMM stage is likely to be included in guidelines soon and underlines the necessity for accurate risk stratification in SMM. Figure 1 Figure 1. Disclosures Kampanis: The Binding Site: Current Employment. Hultcrantz: Daiichi Sankyo: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science LLC: Consultancy; Intellisphere LLC: Consultancy. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy. Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Janssen: Research Funding; Janssen: Other: IDMC; Celgene: Research Funding; Takeda: Other: IDMC; Janssen: Honoraria; Amgen: Honoraria; Amgen: Research Funding; GSK: Honoraria. Kristinsson: Amgen: Research Funding; Celgene: Research Funding.

A Phase II Trial of Lenalidomide, Cyclophosphamide and Dexamethasone (RCD) in Patients with Light Chain Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3853-3853 ◽  
Author(s):  
Shaji Kumar ◽  
Suzanne R. Hayman ◽  
Francis Buadi ◽  
Jacob Allred ◽  
Kristina Laumann ◽  
...  
Keyword(s):  
Median Time ◽  
Plasma Cell ◽  
Light Chain ◽  
Research Funding ◽  
Cardiac Involvement ◽  
Response Rate ◽  
Stage I ◽  
Stage Iii ◽  
Light Chains ◽  
Previously Treated

Abstract Abstract 3853 Poster Board III-789 Background Light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by progressive multiorgan deposition of amyloid fibrils derived from immunoglobulin light chains. Treatment strategies for AL have typically targeted the clonal plasma cell and have paralleled that for myeloma, with recent clinical trials evaluating the role of novel agents such as immune modulatory drugs (IMiDs). Lenalidomide has activity in patients with AL, and given the synergy seen with alkylating agents, we designed a phase 2 clinical trial of cyclophosphamide added to lenalidomide and dexamethasone. Methods Patients (Pts) with newly diagnosed or previously treated AL, with adequate hematological and organ function, were enrolled between December 2007 and November 2008. Treatment consisted of 28-day cycles with Lenalidomide at 15 mg daily (days 1-21), oral cyclophosphamide 300 mg (days 1, 8, 15) and dexamethasone 40 mg weekly. All patients received aspirin for thromboprophylaxis. Hematological and organ responses were assessed using conventional response criteria. Results Thirty-five pts, 11 (31%) previously treated, with a median age of 64 yrs (range 44-82) were enrolled. Median time from diagnosis to trial enrollment was 1.6 mos (range; 0.1- 129) and 23 (66%) were alive at the time of analysis with a median follow up of 8.7 mos (range; 1.5-17.6). Three or more organs were involved in 10 (28%) pts with cardiac and renal involvement present in 22 (63%) and 27 (77%) respectively. Fifteen pts (44%) had advanced stage III disease by the troponin/ NT-ProBNP staging system. Seven (20%) pts had previous stem cell transplant, one pt had thalidomide and others had melphalan, dexamethasone or a combination of the two. The median duration on study was 6.5 months and the median number of cycles administered was 6, with 27 (77%) patients completing at least 3 cycles of therapy. Thirteen patients still remain on study, with the most common reason for study discontinuation being toxicity (10 pts, 45%). There were 15 (43%) and 24 (69%) episodes of Grade 3 or 4 hematologic and non-hematologic adverse events respectively. The most common non-hematologic toxicities seen were fatigue, edema, constipation and rash. Six patients died while on study due to sepsis (1), multiorgan failure (1), arrhythmia (1), or heart failure (3). The overall hematologic response rate was 60% (21 pts; CR (2), VGPR (10) and PR (9)); 79% for stage I and II pts and 40% for stage III patients. Among those patients receiving at least four cycles, the response rate was 20/23 (87%); 2CR, 10 VGPR and 8 PR. At least one organ response was documented in 8 (24%) patients. The median overall survival (OS) for all enrolled patients is 16.1 mos (95% CI; 10.8-NR). The median OS was not reached for stage I and stage II patients, and was 7 mos (95% CI; 4.6 - 16.1) for stage III pts. The median time to hematologic progression was 16.1 mos and to hematologic or organ progression was 6.7 mos (95% CI; 6.3, 16.1). The median OS among those with a hematologic response was 16.1 mos, and not reached among the group with a VGPR or better. Among the 31 patients with measurable FLC, those (n=24) with a ≥50% decrease in the difference between light chains had superior OS compared to the rest (16.1 mos vs. 4.3 mos). The six patients who died on study all had cardiac involvement and significantly higher NT-ProBNP/ BNP compared to the rest. Conclusion The combination of cyclophosphamide, lenalidomide and dexamethasone has significant activity in patients with light chain amyloidosis. Toxicity is manageable with dose reductions, but patients with advanced cardiac involvement are at a higher risk for toxicity and early discontinuation of therapy. Future trials with this combination should compare this regimen with other treatment approaches in selected patients, as well as pursue a dose-adapted strategy in those with advanced cardiac involvement. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Celgene: Research Funding.

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