Long-term Results of Response to Therapy, Time to Progression, and Survival With Lenalidomide Plus Dexamethasone in Newly Diagnosed Myeloma

ArticleinMayo Clinic Proceedings 82(10):1179-84 · November 2007with23 Reads
DOI: 10.4065/82.10.1179 · Source: PubMed
Abstract
To determine the long-term effects of a combined regimen of lenalidomide and dexamethasone (Rev-Dex) on time to progression, progression-free survival, and overall survival (OS) in patients with multiple myeloma. From March 2004 through October 2004, 34 patients were registered for the study. They were treated with 25 mg/d of lenalidomide on days 1 through 21 of a 28-day cycle and 40 mg/d of dexamethasone on days 1 through 4, 9 through 12, and 17 through 20 of each cycle. After 4 cycles of therapy, patients were allowed to discontinue treatment to pursue autologous stem cell transplant (SCT). Treatment beyond 4 cycles was permitted at the physician s discretion. Thirteen patients proceeded to SCT after initial therapy and were censored at that time point for purposes of calculation of response. Thirty-one patients achieved an objective response, defined as a partial response or better (91%; 95% confidence interval, 79%-98%), with a complete response plus very good partial response rate of 56%. The complete response plus very good partial response among the 21 patients who received Rev-Dex without SCT was 67%. The 2-year progression-free survival rates for patients proceeding to SCT and patients remaining on Rev-Dex were 83% and 59%, respectively; the OS rates were 92% and 90% at 2 years and 92% and 85% at 3 years, respectively. The 3-year OS rate for the whole cohort was 88%. The Rev-Dex regimen is highly active in the treatment of newly diagnosed multiple myeloma. Responses are durable with a low progression rate at 2 years. Randomized trials that incorporate quality-of-life measures are needed to determine if this and other combination regimens are better used early in therapy or should be reserved for later interventions.
    • "Data from 150 patients with newly diagnosed, active MM participating in three consecutive Phase II trials at Mayo Clinic and Princess Margaret Hospital from 2004 to 2008 were retrospectively analysed. Analysis of RD (n = 34), CRD (n = 53), and CyBorD (n = 63) was performed after all patients had completed four cycles of therapy (Kumar et al, 2007; Lacy et al, 2007; Reeder et al, 2009). Each study received approval from the Mayo Clinic Institutional Review Board. "
    [Show abstract] [Hide abstract] ABSTRACT: Novel agents are considered standard components of induction therapy for newly diagnosed patients with multiple myeloma. We retrospectively compared the results of three consecutive phase 2 clinical trials; RD (lenalidomide/dexamethasone, n=34), CRD (cyclophosphamide/lenalidomide/dexamethasone, n=53) and CyBorD (cyclophosphamide/bortezomib/dexamethasone, n=63) (N=150). Response rates after four cycles of treatment were: ≥near complete response (nCR), 12% vs. 2% vs. 41%, P<0·0001 and very good partial response or better, 35% vs. 30% vs. 65%, P=0·0003, respectively. With all cycles of therapy considered, ≥nCR was 35%, 15% and 41%, P=0·006. However, there is no evidence that one regimen produced superior progression-free survival (PFS) (median: 3·2 vs. 2·3 vs. 2·7years, P=0·11) or overall survival (3-year: 88% vs. 79% vs. 88%, P=0·23). Transplantation did not impact PFS (median: 2·7 vs. 2·3 years, P=0·41) but was associated with improved OS (3-year: 93% vs. 75%, P≤0·001). High genetic risk patients (n=40) had earlier relapse despite lenalidomide or bortezomib (median: 2·1 vs. 2·7years, P=0·45). Grade 3/4 toxicities were least with CyBorD while CRD had most toxicity. In conclusion, CyBorD demonstrated superior responses and less frequent serious toxicity but more neuropathy when compared to RD and CRD. Importantly, 80% of patients treated with modern therapeutic approaches are alive at 4years.
    Full-text · Article · Nov 2011
    • "The impact of pre-transplantation induction regimens with novel agents including thalidomide (such in VTD regimen [35,36]) or lenalidomide on the post-transplantation outcome is being investigated in several large phase III trials, as well as in maintenance therapy [37]. For elderly patients, the combination of " old " therapies with thalidomide or lenalidomide has resulted in the melphalan–prednisone–thalidomide [38,39], melphalan–prednisone–lenalidomide [40] and lenalido- mide/dexamethasone [41] regimens, which are highly effective. Moreover, promising results have been reported with both thalidomide and lenalidomide maintenance [37]. "
    [Show abstract] [Hide abstract] ABSTRACT: Single nucleotide polymorphisms (SNPs) in 12 genes involving multidrug resistance, drug metabolic pathways, DNA repair systems and cytokines were examined in 28 patients with relapsed/refractory multiple myeloma (MM) treated with single agent thalidomide and the results were correlated with response, toxicity and overall survival (OS). The response rate was higher in patients with SNPs in ERCC1 (rs735482) (p=0.006), ERCC5 (rs17655) (p=0.04) or XRCC5 (rs1051685) (p=0.013). Longer OS was associated with the SNP in ERCC1 (rs735482) (p=0.005) and XRCC5 (rs1051685) (p=0.02). Finally, polymorphism in GSTT1 (rs4630) was associated with a lower frequency of thalidomide-induced peripheral neuropathy (p=0.04).
    Full-text · Article · Mar 2011
    • "Abbreviations: BiRD = biaxin (clarithromycin)/revlimid (lenalidomide)/dexamethasone; CBD = cyclophosphamide/bortezomib/dexamethasone; CNHT = cumulative main nonhematologic toxicity; CR = complete remission; CTD = cyclophosphamide/thalidomide/dexamethasone; DTPACE = dexamethasone/thalidomide/platinum/doxorubicin/cyclophosphamide/etoposide; Dvd-T = doxil/vincristine/low-dose dexamethasone; L = lenalidomide; MHT = maximal hematologic toxicity; MPT = melphalan/prednisone/thalidomide; MPR = melphalan/prednisone/lenalidomide; ORR = overall response rate; OS = overall survival; PAD = bortezomib/doxorubicin/dexamethasone; PFS = progression-free survival; PR = partial remission; RCd = lenalidomide/cyclophosphamide /low-dose dexamethasone; RD = lenalidomide/dexamethasone; T = thalidomide; TD = thalidomide/dexamethasone; T-VADoxil = thalidomide/vincristine/doxorubicin/dexamethasone/doxil; V = velcade; VBMCP = vincristine/BCNU/melphalan/cyclophosphamide; VCD-VTD = velcade/cyclophosphamide/dexamethasone–velcade/thalidomide/dexamethasone; VDCR = velcade/ dexamethasone/cylophosphamide/lenalidomide; VDD = velcade/doxil/dexamethasone; VMP = velcade/melphalan/prednisone; VMPT = velcade/melphalan/prednisone/thalidomide; VT = velcade/ thalidomide; VTP = velcade/thalidomide/prednisone Dingli et al, 2005 12 Jagannath et al, 2005 13 Cavo et al, 2005 14 Wu et al, 2006 15 Offidani et al, 2006 16 Hussein et al, 2006 17 Mateos et al, 2006 18 Macro et al, 2006 19 Barlogie et al, 2006 20 Lacy et al, 2007 21 Wang et al, 2007 22 Rosinol et al, 2007 23 Jakubowiak et al, 2007 24 Belch et al, 2007 25 Palumbo et al, 2007 26 Zonder et al, 2007 27 Zervas et al, 2007 28 Facon et al, 2007 29 Palumbo et al 2007 30 Popat et al, 2008 31 Popat et al, 2008 31 Reeder et al, 2008 32 Kumar et al, 2008 33 Bensinger, 2008 34 Kumar et al 2008 35 Rosignol et al, 2008 36 Rosignol et al, 2008 36 Rosignol et al, 2008 36 "
    [Show abstract] [Hide abstract] ABSTRACT: The introduction of new drugs such as thalidomide, lenalidomide, and bortezomib has led to novel treatment strategies and significantly improved the outcome of patients with multiple myeloma (MM). The enhanced knowledge of myeloma pathogenesis has allowed the identification of new therapeutic targets and many clinical trials are either planned or in progress to evaluate these more selective drugs in the near future. The results of these studies, however, will have to be compared with the results of existing novel therapies for the treatment of MM in order to define whether new protocols do not duplicate current new standards and constitute a real improvement. We reviewed the results of a series of phase I, II, III studies with thalidomide, lenalidomide, and bortezomib combinations for newly diagnosed MM in order to define a reasonable standard in terms of activity, efficacy, and toxicity and to have a potentially useful starting point for comparisons with future investigational trials. Three-drug regimens appear to double the complete remission (CR) rate (20%), though regimens containing 4 drugs triple the CR rate (30%), compared with those containing only 2 agents (10%). These improvements in the depth and quality of response translate into a progressive increase in the progression-free survival rate at 2 years (from approximately 54%-62% to 75%, respectively). Conversely, by using additional agents, a marked increase in hematologic toxicity has been described (8%, 28%, and 28% respectively), whereas nonhematologic toxicity appears to be similar (26%, 24%, and 27%, respectively). These results suggest that new trials in the future will constitute significant progress if they can improve on the current relatively favorable efficacy/toxicity ratio. Nonetheless, exciting new combinations in development do hold promise and results from these studies are eagerly awaited.
    Full-text · Article · Oct 2010
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