Patient‐reported health‐related quality of life from the phase III TOURMALINE‐MM1 study of ixazomib‐lenalidomide‐dexamethasone versus placebo‐lenalidomide‐dexamethasone in relapsed/refractory multiple myeloma

TOURMALINE‐MM1 is a phase III, randomized, double‐blind, placebo‐controlled study of ixazomib plus lenalidomide and dexamethasone (IRd) versus placebo‐Rd in patients with relapsed/refractory multiple myeloma following 1–3 prior lines of therapy. The study met its primary endpoint, demonstrating significantly longer progression‐free survival (PFS) in the IRd arm versus placebo‐Rd arm (median 20.6 vs 14.7 months, hazard ratio 0.74, P = .01), with limited additional toxicity. Patient‐reported health‐related quality of life (HRQoL) was a secondary endpoint of TOURMALINE‐MM1. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core‐30 (QLQ‐C30) and Multiple Myeloma Module 20 (QLQ‐MY20) were completed at screening, the start of cycles 1 and 2, every other cycle, the end of treatment, and every 4 weeks until progression. Over median follow‐up of 23.3 and 22.9 months in the IRd and placebo‐Rd arms, mean QLQ‐C30 global health status (GHS)/QoL scores were maintained from baseline over the course of treatment in both groups, with no statistically significant differences between groups. EORTC QLQ‐C30 function domain scores were also generally maintained from baseline; similarly, physical, emotional, and social function domains were maintained with IRd versus placebo‐Rd, with slightly higher mean change from baseline scores at earlier time points with IRd. Findings from this double‐blind study demonstrate that addition of ixazomib to Rd significantly improved efficacy while HRQoL was maintained, reflecting the limited additional toxicity seen with IRd versus placebo‐Rd, and support the feasibility of long‐term IRd administration.     

Clarithromycin overcomes resistance to lenalidomide and dexamethasone in multiple myeloma

The combination of clarithromycin, lenalidomide and dexamethasone (BiRd) has led to highly durable responses in newly diagnosed myeloma. However, the ability of clarithromycin to overcome resistance to lenalidomide and dexamethasone (Rd) is not known. To study this, we performed a retrospective analysis of 24 patients with myeloma for which clarithromycin was added to Rd at the time of progression on Rd. The median number of prior therapies was 3 (range 1–8). The best response was complete response (CR) in one (4.2%), very good partial response (VGPR) in one (4.2%) and partial response in eight (33.3%) patients. Ten patients, 41.7% (95% CI: 22.1, 63.4), achieved ≥PR. The median time to response was 4.4 months (range 1–13.6 months) and the median duration of response was 6.9 months (range 3–52.2 months). The clinical benefit rate (CR + VGPR + PR + MR) was 45.8% (95% CI 25.6, 67.2). The median progression‐free survival was 4 months. Median overall survival was 25 months with a median follow‐up of 27.5 months. The regimen was well tolerated and only 2 patients needed a clarithromycin dose reduction. Addition of clarithromycin to Rd can overcome resistance to Rd in a subset of patients and lead to durable clinical responses. Am. J. Hematol. 89:E116–E120, 2014. © 2014 Wiley Periodicals, Inc.     

Continuous treatment with lenalidomide and low‐dose dexamethasone in transplant‐ineligible patients with newly diagnosed multiple myeloma in Asia: subanalysis of the FIRST trial

The phase 3 FIRST (Frontline Investigation of REVLIMID + Dexamethasone Versus Standard Thalidomide) trial demonstrated that lenalidomide plus low‐dose dexamethasone (Rd) until disease progression (Rd continuous) is an effective treatment option for transplant‐ineligible patients with newly diagnosed multiple myeloma (NDMM). Given genetic differences between Asian and Western populations, this subanalysis of the FIRST trial examined the safety and efficacy of Rd (given continuously or for 18 cycles [Rd18]) and MPT (melphalan, prednisone, thalidomide) in 114 Asian patients from Mainland China, South Korea and Taiwan. Efficacy and safety with Rd continuous in Asian patients were consistent with those in the overall study population. The overall response rates were 77·8% for Rd continuous, 57·5% for MPT and 65·8% for Rd18. The risk of progression or death was reduced by 39% with Rd continuous versus MPT and by 35% with Rd continuous versus Rd18. Rd continuous improved the 3‐year survival rate compared with MPT (70·2% vs. 56·4%) and Rd18 (58·1%). Common grade 3/4 adverse events in the Rd continuous and MPT arms were neutropenia (25·0% vs. 43·6%), infection (19·4% vs. 28·2%) and anaemia (19·4% vs. 15·4%), respectively. Thromboembolic event rates were low, and no second primary malignancies were observed. Rd continuous is safe and effective in transplant‐ineligible Asian patients with NDMM.     

A comparison of lenalidomide/dexamethasone versus cyclophosphamide/lenalidomide/dexamethasone versus cyclophosphamide/bortezomib/dexamethasone in newly diagnosed multiple myeloma

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. 2·7 years, 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. 2·7 years, 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 4 years.     

Twice‐weekly ixazomib in combination with lenalidomide‐dexamethasone in patients with newly diagnosed multiple myeloma

Weekly ixazomib with lenalidomide‐dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma (NDMM) patients. This phase 1/2 study (NCT01383928) evaluated the recommended phase 2 dose (RP2D), pharmacokinetics, safety and efficacy of twice‐weekly ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice‐weekly oral ixazomib 3·0 or 3·7 mg plus lenalidomide 25 mg and dexamethasone 20 mg (10 mg in cycles 9–16) for up to sixteen 21‐day cycles, followed by maintenance with twice‐weekly ixazomib alone. No dose‐limiting toxicities were reported in cycle 1; the RP2D was 3·0 mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% ≥very good partial response; 24% complete response). Median progression‐free survival was 24·9 months. Responses (median duration 36·9 months for patients receiving the RP2D) deepened during treatment. Grade 3 drug‐related adverse events (AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug‐related AEs. Thirteen patients discontinued due to AEs. Twice‐weekly ixazomib‐Rd offers substantial activity with promising long‐term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly ixazomib‐Rd in this setting.     

Outcomes of lenalidomide‐ or bortezomib‐based regimens in older patients with plasma cell myeloma

The “triplet” regimen of lenalidomide, bortezomib, and dexamethasone (RVD) showed survival advantage over lenalidomide‐dexamethasone (RD) in clinical trials, but older patients with myeloma often receive doublet regimens (RD or bortezomib‐dexamethasone, VD), or VD plus cyclophosphamide (VCD). We compared these first‐line regimens using real‐world data from Medicare beneficiaries receiving therapy between 2007 and 2015. In each comparative analysis, we balanced confounding characteristics using a propensity score. Outcomes included overall (OS) and event‐free survival (EFS, reporting hazard ratios [HR] with 95% confidence intervals [CI]), adverse events, and costs. We identified 6076 patients with median age 76 and median OS of 2.6 years. In the comparison of RVD vs RD/VD doublets, RVD showed significantly better OS (HR = 0.83; 95% CI, 0.72‐0.95) and EFS (HR = 0.68; 95% CI, 0.61‐0.76). So, RVD was associated with more frequent hospitalizations, anemia, and neuropathy, but no increase in thromboembolism or secondary cancers. Costs were higher with RVD. In the comparison of RD vs VD, RD demonstrated better EFS (HR = 0.74; 95% CI, 0.68‐0.81) and marginally better OS (HR = 0.91; 95% CI, 0.83‐0.99). And, RD resulted in significantly more thromboembolic events, less neuropathy, and no significant difference in hospitalizations, transfusions, or secondary cancers. In the comparison of VCD vs VD, we observed no significant difference in any outcome. Superior survival favors RVD over doublet regimens, but even in 2015 RVD was applied for only about 25% of Medicare beneficiaries with myeloma. For patients not eligible for RVD due to toxicity, VCD offers no survival benefit over VD. Lenalidomide‐dexamethasone may be the preferred line doublet considering its advantage over VD.     

Lenalidomide and low‐dose dexamethasone (Rd) versus bortezomib,melphalan, prednisone (VMP) in elderly newly diagnosed multiple myeloma patients: A comparison of two prospective trials

There are currently no direct head‐to‐head clinical trials evaluating bortezomib‐melphalan‐prednisone (VMP) versus lenalidomide and low‐dose dexamethasone (Rd). VMP (257 cases) and Rd (222 cases) arms of two randomized phase III trials were employed to assess the treatment influence on outcome in untreated elderly MM patients. Progression free survival (PFS) and overall survival (OS) were the primary and secondary end‐points, respectively, and were investigated according to treatments administered over a 60‐months follow‐up period. While VMP significantly reduced the disease progression rate between enrolment and 12 months of follow‐up, no difference between the two schedules was found between 12 and 32 months. After 32 months, Rd‐treated patients had a lower incidence of disease progression. A statistically significant higher OS rate was seen in the VMP arm, which was maintained after data adjustment for potential confounders. Both approaches showed acceptable toxicity profiles. The profound tumor reduction by VMP over Rd justifies the initial higher PFS rate in favor of the bortezomib schedule, while the Rd regimen overcomes this evident initial drawback in reducing the tumor burden by long‐term drug administration, gaining a subsequent improved disease control. VMP is associated with a significant reduced risk of death. This study may help physicians make a more informed therapy choice.     

Overall survival of relapsed and refractory multiple myeloma patients after adjusting for crossover in the MM‐003 trial for pomalidomide plus low‐dose dexamethasone

In the phase III MM‐003 trial, pomalidomide plus low‐dose dexamethasone (POM+LoDEX) improved overall survival (OS) versus high‐dose dexamethasone (HiDEX) in 455 patients with relapsed and refractory multiple myeloma (RRMM) after treatment with bortezomib and lenalidomide. Here, a two‐stage Weibull method was used to adjust for the crossover of patients in the HiDEX arm to pomalidomide‐based therapy. The adjusted difference in median OS between patients in the POM+LoDEX and HiDEX arms was 7·0 months (12·7 vs. 5·7 months, respectively). These findings provide important evidence for understanding the clinical efficacy of pomalidomide on OS benefits seen in RRMM patients.     

Efficacy and safety of low‐dose lenalidomide plus dexamethasone in patients with relapsed or refractory POEMS syndrome

Although autologous stem cell transplantation or melphalan‐based chemotherapy has significantly improved the prognosis of POEMS syndrome, a few patients will relapse or be refractory to primary therapy, and there is a lack of studies regarding these patients. In this study, we used low‐dose lenalidomide (10 mg daily) and dexamethasone (40 mg, once weekly) to treat twelve patients with relapsed (n = 8) or refractory (n = 4) POEMS syndrome. After a median follow‐up time of 20 months, the overall hematologic response rate was 77% with 44% having a complete response. Eight (67%) patients had neurological response, and the median overall neuropathy limitation scale score was reduced from 3 (range, 1–9) to 2 (range, 0–6). Serum vascular endothelial growth factor response rate was 91% and 46% of patients had normal serum VEGF levels. One patient had progression of the disease 3 months after the end of treatment and subsequently died from the disease. Therefore, the estimated 2 year overall survival and progression‐free survival were 92%. The low‐dose lenalidomide and dexamethasone regimen was well tolerated, with no treatment‐related death or any grade 3 or 4 toxicity. In conclusion, low‐dose lenalidomide plus dexamethasone therapy is an effective and safe regimen for patients with relapsed or refractory POEMS syndrome.     

Lenalidomide plus dexamethasone vs. lenalidomide plus melphalan and prednisone: a retrospective study in newly diagnosed elderly myeloma

Background: The goal of this retrospective study was to compare the efficacy and toxicity of lenalidomide–dexamethasone (len/dex) vs. melphalan–prednisone–lenalidomide (MPR) as upfront therapy for newly diagnosed elderly patients with myeloma. Methods: Data from 51 patients enrolled in an Italian phase I/II trial and treated with MPR were analyzed and compared with data from 38 patients, seen at the Mayo Clinic, treated with len/dex and enrolled in phase II/III trials. Results: On intention‐to‐treat analysis, time to progression (median: 24.7 vs. 27.5 months in MPR and len/dex groups, respectively, P = 0.903), progression‐free survival (median: 24.7 vs. 27.5 months in MPR and len/dex groups, respectively, P = 0.926), and overall survival (2‐yr overall survival: 86.2% in MPR vs. 89.1% in len/dex, P = 0.730) were not significantly different between the two groups. Results were confirmed when the analysis was restricted to MPR and len/dex matched pair mates. Hematologic grade 3–4 toxicities were more common with MPR (neutropenia: 66.7% vs. 21.1%, P < 0.001; thrombocytopenia: 31.4% vs. 2.6%, P < 0.001). Grade 3–4 gastrointestinal events (13.2% vs. 3.9%, P = 0.132), thrombotic events (13.2% vs. 5.9%, P = 0.279), and fatigue (10.5% vs. 3.9%, P = 0.395) were more common with len/dex. Conclusions: Results show that both MPR and len/dex are efficacious regimens for elderly patients with myeloma. Randomized trials are needed to confirm these results.     

Upfront lower dose lenalidomide is less toxic and does not compromise efficacy for vulnerable patients with relapsed refractory multiple myeloma: final analysis of the phase II RevLite study

The combination of lenalidomide and dexamethasone is an established treatment for patients with multiple myeloma (MM). Increasingly, treatment attenuation is advocated for frail/elderly patients to minimize toxicity even though there have been no prospective studies to demonstrate whether lenalidomide dose attenuation impacts on response and survival outcome. This prospective multicentre phase II study assessed the efficacy and tolerability of lower dose lenalidomide (15 mg) and dexamethasone (20 mg) in 149 eligible patients with relapsed/refractory MM aged over 59 years and/or with renal impairment. The overall response rate was 71% (complete response 15%). Median (range) progression‐free survival (PFS) and overall survival (OS) were 8·9 (6·9–11·5) and 30·5 (20·0–36·2) months, respectively. Upon formal statistical comparison of these endpoints to that of a matched cohort of patients from the pivotal phase III MM009/MM010 studies who received standard‐dose lenalidomide (25 mg) and high‐dose dexamethasone (40 mg) no difference was seen in PFS (P = 0·34) and OS (P = 0·21). Importantly, grade 3–4 toxicities were reduced with low‐dose lenalidomide, mainly lower neutropenia (29% vs. 41%), infections (23% vs. 31%) and venous thromboembolism (3% vs. 13%). This study supports a strategy of lenalidomide dose reduction at the outset for at‐risk patients, and prospectively confirms that such an approach reduces adverse events while not compromising patient response or survival outcomes.     

Impact of lenalidomide use among non‐transfusion dependent patients with myelodysplastic syndromes

Chemotherapies approved for defined subgroups promise personalized oncologic care, but their off‐label impact is unclear. Lenalidomide is approved for lower‐risk, transfusion‐dependent (TD) myelodysplastic syndromes (MDS) with del(5q), but frequently used in MDS outside this indication. We characterized lenalidomide use and outcomes among non‐TD patients with MDS. Patients 65 or older diagnosed with MDS between 2007 and 2013 were identified using SEER; linked Medicare claims were evaluated for transfusions, lenalidomide use, and incident toxicities. TD was ≥2 transfusion episodes within an 8‐week period; responses were transfusion independence (TI) and ≥50% transfusion reduction (minor response). We compared overall survival for non‐TD patients receiving lenalidomide versus those not receiving lenalidomide, matched on disease and patient characteristics. We identified 676 patients who had received lenalidomide, including 275 (40.7%) TD and 401 (59.3%) non‐TD; 18.5% (125/676) had zero claims for RBC transfusion prior to receiving lenalidomide. Incident toxicities among patients prescribed lenalidomide were similar in TD and non‐TD groups, except incident thromboembolic events were higher among non‐TD patients (10.8% vs. 6.0%, P = .04). Comparing 191 non‐TD patients receiving lenalidomide within 6 months of MDS diagnosis to risk‐matched MDS controls, lenalidomide was not associated with improved OS (P = .78). Among TD patients (n = 275), 31% achieved TI, and 30% achieved minor hematologic response, with a median time to TI of 4.1 weeks. In conclusion, we confirmed the benefit of lenalidomide among TD patients with MDS; however, many non‐TD patients also received lenalidomide. These patients experienced accompanying toxicity without evidence of benefit in terms of transfusion needs or overall survival.     

Pomalidomide in combination with dexamethasone results in synergistic anti‐tumour responses in pre‐clinical models of lenalidomide‐resistant multiple myeloma

Pomalidomide is an IMiD^® immunomodulatory agent, which has shown clinically significant benefits in relapsed and/or refractory multiple myeloma (rrMM) patients when combined with dexamethasone, regardless of refractory status to lenalidomide or bortezomib. (Schey et al, 2004 ; San Miguel et al, 2013; Richardson et al, 2014; Scott, 2014 ) In this work, we present preclinical data showing that the combination of pomalidomide with dexamethasone (PomDex) demonstrates potent anti‐proliferative and pro‐apoptotic activity in both lenalidomide‐sensitive and lenalidomide‐resistant MM cell lines. PomDex also synergistically inhibited tumour growth compared with single‐agent treatment in xenografts of lenalidomide‐resistant H929 R10‐1 cells. Typical hallmarks of IMiD compound activity, including IKZF3 (Aiolos) degradation, and the downregulation of interferon regulatory factor (IRF) 4 and MYC, seen in lenalidomide‐sensitive H929 MM cell lines, were also observed in PomDex‐treated lenalidomide‐resistant H929 MM cells. Remarkably, this resulted in strong, synergistic effects on the induction of apoptosis in both lenalidomide‐sensitive and resistant MM cells. Furthermore, gene expression profiling revealed a unique differential gene expression pattern in PomDex‐treated samples, highlighted by the modulation of pro‐apoptotic pathways in lenalidomide‐resistant cells. These results provide key insights into molecular mechanisms of PomDex in the lenalidomide‐resistant setting.     

IKAROS expression in distinct bone marrow cell populations as a candidate biomarker for outcome with lenalidomide‐dexamethasone therapy in multiple myeloma

Immunomodulatory drugs (IMiDs) are a cornerstone in the treatment of multiple myeloma (MM), but specific markers to predict outcome are still missing. Recent work pointed to a prognostic role for IMiD target genes (e.g. CRBN ). Moreover, indirect activity of IMiDs on immune cells correlated with outcome, raising the possibility that cell populations in the bone marrow (BM) microenvironment could serve as biomarkers. We therefore analysed gene expression levels of six IMiD target genes in whole BM samples of 44 myeloma patients treated with lenalidomide‐dexamethasone. Expression of CRBN (R = 0.30, P = .05), IKZF1 (R = 0.31, P = .04), IRF4 (R = 0.38, P = .01), MCT ‐1 (R = 0.30, P = .05), and CD147 (R = 0.38, P = .01), but not IKZF3 (R = ?0.15, P = .34), was significantly associated with response. Interestingly, IKZF1 expression was elevated in BM environmental cells and thus selected for further investigation by multicolor flow cytometry. High IKAROS protein levels in total BM mononuclear cells (median OS 83.4 vs. 32.2 months, P = .02), CD19⁺ B cells (median OS 71.1 vs. 32.2 months, P = .05), CD3⁺ CD8⁺ T cells (median OS 83.4 vs 19.0 months, P = .008) as well as monocytes (median OS 53.9 vs 18.0 months, P = .009) were associated with superior overall survival (OS). In contrast, IKAROS protein expression in MM cells was not predictive for OS. Our data therefore corroborate the central role of immune cells for the clinical activity of IMiDs and built the groundwork for prospective analysis of IKAROS protein levels in distinct cell populations as a potential biomarker for IMiD based therapies.     

A phase 2 study of lenalidomide,rituximab, cyclophosphamide,and dexamethasone (LR‐CD) for untreated low‐grade non‐Hodgkin lymphoma requiring therapy

Patients with indolent non‐Hodgkin lymphoma (NHL) have multiple treatment options yet there is no consensus as to the best initial therapy. Lenalidomide, an immunomodulatory agent, has single agent activity in relapsed lymphoma. This trial was conducted to assess feasibility, efficacy, and safety of adding lenalidomide to rituximab, cyclophosphamide, and dexamethasone (LR‐CD) in untreated indolent NHL patients requiring therapy. This was a single institution phase II trial. Treatment consisted of IV rituximab 375 mg/m² day 1; oral lenalidomide 20 mg days 1–21; cyclophosphamide 250 mg/m² days 1, 8, and 15; and dexamethasone 40 mg days 1, 8, 15, and 22 of a 28‐day cycle. Treatment continued 2 cycles beyond best response for a maximum of 12 cycles without rituximab maintenance. Thirty‐three patients were treated. Median age was 68 (43–83 years). 39% had stage IV disease. Histologic subtypes included 8 follicular lymphoma (FL), 7 marginal zone lymphoma (MZL) (1 splenic, 2 extranodal, and 4 nodal), 15 Waldenström's macroglobulinemia (WM), 1 lymphoplasmacytic lymphoma, 1 small lymphocytic lymphoma, and 1 low‐grade B‐cell lymphoma with plasmacytic differentiation (unable to be classified better as MZL or LPL). Hematologic toxicity was the most common adverse event. Median time of follow‐up was 23.4 months (range 1.8–50.9). The overall response rate was 87.9%, with 30.3% complete response. The median duration of response was 38.7 months. The median progression free survival was 39.7 months, while median overall survival (OS) has not yet been reached. Lenalidomide can be safely added to a simple regimen of rituximab, oral cyclophosphamide, and dexamethasone and is an effective combination as initial therapy for low‐grade B‐cell NHL.     

Combination therapy with bortezomib,continuous low‐dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients

Combination therapy for longer periods but at low dose might be an effective and tolerable manner to treat patients with relapsed multiple myeloma (MM). We used bortezomib, dexamethasone and low‐dose oral cyclophosphamide as an induction regimen, followed by 1 year of maintenance consisting of bortezomib and cyclophosphamide. Relapsed MM patients were treated with six cycles of bortezomib twice weekly, cyclophosphamide 50 mg daily and dexamethasone. Maintenance therapy was given for 1 year. Primary endpoints were toxicity during re‐induction and maintenance therapy. Secondary endpoints were response to treatment and progression‐free (PFS) and overall survival (OS). This study included 59 patients. Myelosuppression and neuropathy were the most common side effects. Median follow‐up was 27·1 (0·46–54·4) months with an overall response of 71%, and a very good partial response or more of 33%. During maintenance, improved responsiveness was observed in 19% of the patients. The median PFS was 18·4 months (range 0·13–43·5) and the median OS was 28·1 months (range 0·13–54·4). In conclusion, our study demonstrates that treatment with bortezomib, dexamethasone and low‐dose cyclophosphamide is an effective and manageable regimen. Adding 1 year of maintenance was feasible, with limited side effects and an increased response rate.     

Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT‐2 follow‐up and post‐hoc analyses on progression‐free survival and tumour growth

The randomized phase III ELOQUENT‐2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab + lenalidomide/dexamethasone (ELd) versus lenalidomide/dexamethasone (Ld) in relapsed/refractory multiple myeloma. ELd reduced the risk of disease progression/death by 30% versus Ld (hazard ratio [HR] 0·70). Median time from diagnosis was 3·5 years. We present extended 3‐year follow‐up data. Endpoints included progression‐free survival (PFS), overall response rate (ORR) and interim overall survival (OS). Exploratory post‐hoc analyses included impact of time from diagnosis and prior lines of therapy on PFS, and serum M‐protein dynamic modelling. ORR was 79% (ELd) and 66% (Ld) (P = 0·0002). ELd reduced the risk of disease progression/death by 27% versus Ld (HR 0·73; P = 0·0014). Interim OS demonstrated a trend in favour of ELd (P = 0·0257); 1‐, 2‐ and 3‐year rates with ELd versus Ld were: 91% versus 83%, 73% versus 69% and 60% versus 53%. In patients with ≥ median time from diagnosis and one prior therapy, ELd resulted in a 53% reduction in the risk of progression/death versus Ld (HR 0·47). Serum M‐protein dynamic modelling showed slower tumour regrowth with ELd. Adverse events were comparable between arms. ELd provided a durable and clinically relevant improvement in efficacy, with minimal incremental toxicity.     

A phase III randomized trial of high‐dose CEOP + filgrastim versus standard‐dose CEOP in patients with non‐Hodgkin lymphoma: 10‐year follow‐up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial

Increasing dose intensity (DI) of chemotherapy for patients with aggressive non‐Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3‐weekly standard (s) or intensive (i) chemotherapy: s‐CEOP–cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m² all on day 1, and prednisolone 100 mg days 1–5; i‐CEOP–cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m² all on day 1, and prednisolone 100 mg days 1–5. Primary endpoint was 5‐year overall survival (OS). Relative to s‐CEOP patients, i‐CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5‐year OS (56.7% i‐CEOP; 55.1% s‐CEOP; P = 0.80), 5‐year progression free survival (PFS; 41% i‐CEOP; 43% s‐CEOP; P = 0.73), 5‐year time to progression (TTP; 44% i‐CEOP; 47% s‐CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i‐CEOP; 59% s‐CEOP; P = 0.64). Long‐term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i‐CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6‐month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity. Am. J. Hematol. 89:536–541, 2014. © 2014 Wiley Periodicals, Inc.     

GVHD prophylaxis using low‐dose cyclosporine improves survival in leukaemic recipients of HLA‐identical sibling transplants

Graft‐versus‐host disease (GVHD) prophylaxis of short duration (6 months) with low‐dose cyclosporine A (CsA) starting at 1 mg/kg per day i.v. and four doses of methotrexate (MTX) were given to 171 consecutive leukaemic recipients of HLA‐identical sibling transplants. In contrast, apart from MTX, retrospective controls received high‐dose CsA, starting at 5–7.5 mg/kg per day i.v. and discontinued 1 yr post‐transplant. In the low‐dose CsA group, the probability of acute GVHD grades I–II (70% vs. 53%, P < 0.01), and chronic GVHD were increased (58% vs. 25%, P < 0.01), whereas the incidences of acute GVHD grades III–IV (9% vs. 5%, P = 0.62), and non‐relapse mortality (20% vs. 22%, P = 0.58) were similar. Moreover, the probability of relapse was decreased (31% vs. 54%, P < 0.01), and both relapse‐free (56% vs. 38%, P = 0.04) and overall survival (61% vs. 40%, P = 0.04) were markedly improved using the low‐dose CsA regimen. In multivariate analyses, low‐dose CsA was strongly associated with chronic GVHD [relative hazard (RH) 2.56, P < 0.01], which decreased the risk of relapse (RH 0.46, P < 0.01) and improved the probability of survival (RH 1.84, P < 0.01). In conclusion, a low‐dose CsA regimen in leukaemic recipients of HLA‐identical sibling transplants increases the rate of chronic GVHD, which seems to attenuate the risk of relapse, thereby improving patient survival owing to enhanced graft‐versus‐leukaemia effect.     

Phase II study of pegylated liposomal doxorubicin,low‐dose dexamethasone,and lenalidomide in patients with newly diagnosed multiple myeloma

Our previous phase I/II trial of pegylated liposomal doxorubicin (PLD), low‐dose dexamethasone, and lenalidomide in patients with relapsed and refractory myeloma showed an overall response rate of 75%, with 29% achieving ≥ VGPR. Here, we investigated this combination (PLD 30 or 40 mg/m² intravenously, day 1; dexamethasone 40 mg orally, days 1–4; lenalidomide 25 mg orally, days 1–21; administered every 28 days) in a phase II study in patients with newly diagnosed symptomatic multiple myeloma to determine its efficacy and tolerability ( ClinicalTrials.gov NCT00617591). At best response, patients could proceed with high‐dose melphalan or with maintenance lenalidomide and dexamethasone. In 57 patients, we found that the overall response rate and rate of very good partial response and better on intent‐to‐treat, our primary endpoints, were 77.2% and 42.1%, respectively, with responses per the International Myeloma Working Group. Median progression‐free survival was 28 months (95% CI 18.1–34.8), with 1‐ and 2‐year overall survival rates of 98.1 and 79.6%. During induction, grade 3/4 toxicities were neutropenia (49.1%), anemia (15.8%), thrombocytopenia (7%), fatigue (14%), febrile neutropenia (8.8%), and venous thromboembolic events (8.8%). During maintenance, grade 3/4 toxicities were mainly hematologic. We found this combination to be active in patients with newly diagnosed myeloma, with results comparable to other lenalidomide‐based induction strategies without proteasome inhibition. In addition, maintenance therapy with lenalidomide was well tolerated. Am. J. Hematol. 89:62–67, 2014. © 2013 Wiley Periodicals, Inc.