The phase 2 LYSA study of prednisone, vinblastine, doxorubicin, and bendamustine for untreated Hodgkin lymphoma in older patients.

ABSTRACT: Older patients with classical Hodgkin lymphoma (cHL) require more effective and less toxic therapies than younger patients. In this multicenter, prospective, phase 2 study, we investigated a new firstline therapy regimen comprising 6 cycles of prednisone (40 mg/m2, days 1-5), vinblastine (6 mg/m2, day 1), doxorubicin (40 mg/m2, day 1), and bendamustine (120 mg/m2, day 1) (PVAB regimen) every 21 days for patients with newly diagnosed cHL aged ≥61 years with an advanced Ann Arbor stage. A Mini Nutritional Assessment score ≥17 was the cutoff value for patients aged ≥70 years. The primary end point was the complete metabolic response (CMR) rate after 6 cycles. The median age of the 89 included patients was 68 years (range, 61-88 years), with 35 patients (39%) aged ≥70 years. Seventy-eight patients (88%) completed the 6 cycles. The toxicity rate was acceptable, with a 20% rate of related serious adverse events. CMR was achieved by 69 patients (77.5%; 95% confidence interval [CI], 67-86). After a median follow-up of 42 months, 31 patients progressed or relapsed (35%), and 24 died (27%) from HL (n = 11), toxicity during treatment (n = 4), secondary cancers (n = 6), or other causes (n = 3). The 4-year progression-free survival (PFS) and overall survival rates were 50% and 69%, respectively. Multivariate analysis showed that liver involvement (P = .001), lymphopenia (P = .001), CRP (P = .0005), and comedications (P = .003) were independently associated with PFS. The PVAB regimen yielded a high CMR rate with acceptable toxicity. Over long-term follow-up, survival end points were influenced by unrelated lymphoma events. This trial was registered at www.clinicaltrials.gov as #NCT02414568 and at EudraCT as 2014-001002-17.

RAS/RAF landscape in monoclonal plasma cell conditions.

ABSTRACT: Multiple myeloma is characterized by a huge heterogeneity at the molecular level. The RAS/RAF pathway is the most frequently mutated, in ∼50% of the patients. However, these mutations are frequently subclonal, suggesting a secondary event. Because these genes are part of our routine next-generation sequencing panel, we analyzed >10 000 patients with different plasma cell disorders to describe the RAS/RAF landscape. In this large cohort of patients, almost 61% of the patients presented a RAS/RAF mutation at diagnosis or relapse, but much lower frequencies occurred in presymptomatic cases. Of note, the mutations were different from that observed in solid tumors (higher proportions of Q61 mutations). In 29 patients with 2 different mutations, we were able to perform single-cell sequencing, showing that in most cases, mutations occurred in different subclones, suggesting an ongoing mutational process. These findings suggest that the RAS/RAF pathway is not an attractive target, both on therapeutic and residual disease assessment points of view.

Biallelic deletion of 1p32 defines ultra-high-risk myeloma, but monoallelic del(1p32) remains a strong prognostic factor.

Cytogenetic abnormalities (CAs) are known to be the preponderant prognostic factor in multiple myeloma. Our team has recently developed a prognostic score based on 6 CAs, with which del(1p32) appears to be the second worst abnormality after del(17p). This study aimed to confirm the adverse effect of 1p32 deletion in patients with newly diagnosed multiple myeloma (NDMM). Among 2551 patients with newly diagnosed multiple myeloma, 11% were harboring del(1p32). Their overall survival (OS) was significantly inferior compared with patients without del(1p32) (median OS: 49 months vs 124 months). Likewise, progression-free survival was significantly shorter. More importantly, biallelic del(1p32) conferred a dramatically poorer prognosis than a monoallelic del(1p32) (median OS: 25 months vs 60 months). As expected, the OS of patients with del(1p32) significantly decreased when this abnormality was associated with other high-risk CAs [del(17p), t(4;14), or gain(1q)]. In the multivariate analysis, del(1p32) appeared as a negative prognostic factor; after adjustment for age and treatment, the risk of progression was 1.3 times higher among patients harboring del(1p32), and the risk of death was 1.9 times higher. At the dawn of risk-adapted treatment strategies, we have confirmed the adverse effect of del(1p32) in multiple myeloma and the relevance of its assessment at diagnosis.

Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial.

BACKGROUND: CASSIOPEIA part 1 demonstrated superior depth of response and prolonged progression-free survival with daratumumab in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) alone as an induction and consolidation regimen in transplant-eligible patients newly diagnosed with myeloma. In CASSIOPEIA part 2, daratumumab maintenance significantly improved progression-free survival and increased minimal residual disease (MRD)-negativity rates versus observation. Here, we report long-term study outcomes of CASSIOPEIA. METHODS: CASSIOPEIA was a two-part, open-label, phase 3 trial of patients done at 111 European academic and community-based centres. Eligible patients were aged 18-65 years with transplant-eligible newly diagnosed myeloma and an Eastern Cooperative Oncology Group performance status of 0-2. In part 1, patients were randomly assigned (1:1) to pre-transplant induction and post-transplant consolidation with D-VTd or VTd. Patients who completed consolidation and had a partial response or better were re-randomised (1:1) to intravenous daratumumab maintenance (16 mg/kg every 8 weeks) or observation for 2 years or less. An interactive web-based system was used for both randomisations, and randomisation was balanced using permuted blocks of four. Stratification factors for the first randomisation (induction and consolidation phase) were site affiliation, International Staging System disease stage, and cytogenetic risk status. Stratification factors for the second randomisation (maintenance phase) were induction treatment and depth of response in the induction and consolidation phase. The primary endpoint for the induction and consolidation phase was the proportion of patients who achieved a stringent complete response after consolidation; results for this endpoint remain unchanged from those reported previously. The primary endpoint for the maintenance phase was progression-free survival from second randomisation. Efficacy evaluations in the induction and consolidation phase were done on the intention-to-treat population, which included all patients who underwent first randomisation, and efficacy analyses in the maintenance phase were done in the maintenance-specific intention-to-treat population, which included all patients who were randomly assigned at the second randomisation. This analysis represents the final data cutoff at the end of the study. The trial is registered with ClinicalTrials.gov, NCT02541383. FINDINGS: Between Sept 22, 2015 and Aug 1, 2017, 1085 patients were randomly assigned to D-VTd (n=543) or VTd (n=542); between May 30, 2016 and June 18, 2018, 886 were re-randomised to daratumumab maintenance (n=442) or observation (n=444). At the clinical cutoff date, Sept 1, 2023, median follow-up was 80·1 months (IQR 75·7-85·6) from first randomisation and 70·6 months (66·4-76·1) from second randomisation. Progression-free survival from second randomisation was significantly longer in the daratumumab maintenance group than the observation-alone group (median not reached [95% CI 79·9-not estimable (NE)] vs 45·8 months [41·8-49·6]; HR 0·49 [95% CI 0·40-0·59]; p<0·0001); benefit was observed with D-VTd with daratumumab maintenance versus D-VTd with observation (median not reached [74·6-NE] vs 72·1 months [52·8-NE]; 0·76 [0·58-1·00]; p=0·048) and VTd with daratumumab maintenance versus VTd with observation (median not reached [66·9-NE] vs 32·7 months [27·2-38·7]; 0·34 [0·26-0·44]; p<0·0001). INTERPRETATION: The long-term follow-up results of CASSIOPEIA show that including daratumumab in both the induction and consolidation phase and the maintenance phase led to superior progression-free survival outcomes. Our results confirm D-VTd induction and consolidation as a standard of care, and support the option of subsequent daratumumab monotherapy maintenance, for transplant-eligible patients with newly diagnosed multiple myeloma. FUNDING: Intergroupe Francophone du Myélome, Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research & Development.

Primary plasma cell leukemias displaying t(11;14) have specific genomic, transcriptional, and clinical features.

Primary plasma cell leukemia (pPCL) is an aggressive form of multiple myeloma (MM) that has not benefited from recent therapeutic advances in the field. Because it is very rare and heterogeneous, it remains poorly understood at the molecular level. To address this issue, we performed DNA and RNA sequencing of sorted plasma cells from a large cohort of 90 newly diagnosed pPCL and compared with MM. We observed that pPCL presents a specific genomic landscape with a high prevalence of t(11;14) (about half) and high-risk genomic features such as del(17p), gain 1q, and del(1p32). In addition, pPCL displays a specific transcriptome when compared with MM. We then wanted to characterize specifically pPCL with t(11;14). We observed that this subentity displayed significantly fewer adverse cytogenetic abnormalities. This translated into better overall survival when compared with pPCL without t(11;14) (39.2 months vs 17.9 months, P = .002). Finally, pPCL with t(11;14) displayed a specific transcriptome, including differential expression of BCL2 family members. This study is the largest series of patients with pPCL reported so far.

del(17p) without TP53 mutation confers a poor prognosis in intensively treated newly diagnosed patients with multiple myeloma.

Despite tremendous improvements in the outcome of patients with multiple myeloma in the past decade, high-risk patients have not benefited from the approval of novel drugs. The most important prognostic factor is the loss of parts of the short arm of chromosome 17, known as deletion 17p (del(17p)). A recent publication (on a small number of patients) suggested that these patients are at very high-risk only if del(17p) is associated with TP53 mutations, the so-called "double-hit" population. To validate this finding, we designed a much larger study on 121 patients presenting del(17p) in > 55% of their plasma cells, and homogeneously treated by an intensive approach. For these 121 patients, we performed deep next generation sequencing targeted on TP53. The outcome was then compared with a large control population (2505 patients lacking del(17p)). Our results confirmed that the "double hit" situation is the worst (median survival = 36 months), but that del(17p) alone also confers a poor outcome compared with the control cohort (median survival = 52.8 months vs 152.2 months, respectively). In conclusion, our study clearly confirms the extremely poor outcome of patients displaying "double hit," but also that del(17p) alone is still a very high-risk feature, confirming its value as a prognostic indicator for poor outcome.

A fixed-duration, measurable residual disease-guided approach in CLL: follow-up data from the phase 2 ICLL-07 FILO trial.

Trials assessing first-line, fixed-duration approaches in chronic lymphocytic leukemia (CLL) are yielding promising activity, but few long-term data are available. We report follow-up data from a phase 2 trial (ICLL07 FILO) in previously untreated, medically fit patients (N = 135). Patients underwent obinutuzumab-ibrutinib induction for 9 months; then, following evaluation (N = 130 evaluable), those in complete remission and with bone marrow measurable residual disease (BM MRD) <0.01% (n = 10) received ibrutinib for 6 additional months; those in partial remission and/or with BM MRD ≥0.01%, the majority (n = 120), also received 4 cycles of immunochemotherapy (fludarabine/cyclophosphamide-obinutuzumab). Beyond end of treatment, responses were assessed every 3 month and peripheral blood MRD every 6 months. At median follow-up 36.7 months from treatment start, progression-free and overall survival rates (95% confidence interval) at 3 years were 95.7% (92.0% to 99.5%) and 98% (95.1% to 100%), respectively. Peripheral blood MRD <0.01% rates were 97%, 96%, 90%, 84%, and 89% at months 16, 22, 28, 34, and 40, respectively. No new treatment-related or serious adverse event occurred beyond end of treatment. Thus, in previously untreated, medically fit patients with CLL, a fixed-duration (15 months), MRD-guided approach achieved high survival rates, a persistent MRD benefit beyond the end of treatment, and low long-term toxicity. This trial was registered at www.clinicaltrials.gov as #NCT02666898.

Heterogeneity in long-term outcomes for patients with Revised International Staging System stage II, newly diagnosed multiple myeloma.

In the era of personalized treatment in multiple myeloma, high-risk patients must be accurately identified. The International Myeloma Working Group recommends using the Revised International Staging System (R-ISS) to pick out high-risk patients. The main purpose of our work was to explore the heterogeneity of outcome among R-ISS stage II patients assessing the impact of International Staging System (ISS) stage, chromosomal abnormalities and lactate dehydrogenase level in this subgroup. Data were collected from 1,343 patients up to 65 years old with newly diagnosed myeloma, enrolled in three clinical trials implemented by the Intergroupe Francophone du Myélome. All patients were eligible for intensive treatment. Patients in R-ISS stage II but ISS stage I had 1.6 times higher risk of death than patients in R-ISS stage I (adjusted hazard ratio=1.6; 95% confidence interval: 1.1-2.2; P=0.01) and patients in R-ISS stage II but with ISS stage III had a better overall survival than patients in R-ISS stage III (adjusted hazard ratio=0.7; 95% confidence interval: 0.4-0.9, P=0.02). However, among patients classified in R-ISS II, ISS stage and chromosomal abnormalities (del[17p] and t[4;14]) were still relevant prognostic factors for death. Dividing R-ISS stage II into three subgroups: ISS I with standard-risk chromosomal abnormalities, ISS II or III with standard-risk chromosomal abnormalities and patients with high-risk chromosomal abnormalities, median overall survival times were, respectively, not reached, 112 months and 71 months (P<0.001). In conclusion, stratification of patients in the R-ISS stage II group can be improved by taking into account chromosomal abnormalities and ISS. However, this does not improve predictive performance of survival models.

Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial.

BACKGROUND: CASSIOPEIA part 1 showed superior depth of response and significantly improved progression-free survival with daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) as induction and consolidation in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed multiple myeloma. In part 2, we compared daratumumab maintenance versus observation only. METHODS: CASSIOPEIA is a two-part, open-label, randomised, phase 3 trial of patients aged 18-65 years with newly diagnosed multiple myeloma and Eastern Cooperative Oncology Group performance status 0-2, done in 111 European academic and community practice centres. In part 1, patients were randomly assigned (1:1) to induction and consolidation with D-VTd or VTd. Patients still on study who had a partial response or better were randomly assigned (1:1) by an interactive web-response system to daratumumab 16 mg/kg intravenously every 8 weeks (a reduced frequency compared with standard daratumumab long-term dosing) or observation only for up to 2 years. Stratification factors were induction treatment and depth of response in part 1. The part 2 primary endpoint was progression-free survival from second randomisation. This preplanned interim analysis of progression-free survival was done after 281 events and shall be considered the primary analysis of progression-free survival. Sponsor personnel and designees who were involved in the analysis were masked to treatment group until the independent data monitoring committee recommended that the preplanned interim analysis be considered the main analysis of progression-free survival in part 2. Otherwise, treatment assignments were unmasked. The interaction between induction and consolidation and maintenance was tested at a two-sided significance level of 0·05 by a stratified Cox regression model that included the interaction term between maintenance treatment and induction and consolidation treatment. Efficacy analyses were done in the maintenance-specific intention-to-treat population, which comprised all patients who underwent second randomisation. Safety was analysed in all patients in the daratumumab group who received at least one dose and all patients randomly assigned to observation only. This trial is registered with ClinicalTrials.gov, NCT02541383. Long-term follow-up is ongoing and the trial is closed to new participants. FINDINGS: Between May 30, 2016, and June 18, 2018, 886 patients (458 [84%] of 543 in the D-VTd group and 428 [79%] of 542 in the VTd group) were randomly assigned to daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35·4 months (IQR 30·2-39·9) from second randomisation, median progression-free survival was not reached (95% CI not evaluable [NE]-NE) with daratumumab versus 46·7 months (40·0-NE) with observation only (hazard ratio 0·53, 95% CI 0·42-0·68, p<0·0001). A prespecified analysis of progression-free survival results showed a significant interaction between maintenance and induction and consolidation therapy (p<0·0001). The most common grade 3 or 4 adverse events were lymphopenia (16 [4%] of 440 patients in the daratumumab group vs eight [2%] of 444 patients in the observation-only group), hypertension (13 [3%] vs seven [2%]), and neutropenia (nine [2%] vs ten [2%]). Serious adverse events occurred in 100 (23%) patients in the daratumumab group and 84 (19%) patients in the observation-only group. In the daratumumab group, two adverse events led to death (septic shock and natural killer-cell lymphoblastic lymphoma); both were related to treatment. INTERPRETATION: Daratumumab maintenance every 8 weeks for 2 years significantly reduced the risk of disease progression or death compared with observation only. Longer follow-up and other ongoing studies will shed further light on the optimal daratumumab-containing post-ASCT maintenance treatment strategy. FUNDING: Janssen Research & Development, the Intergroupe Francophone du Myélome, and the Dutch-Belgian Cooperative Trial Group for Hematology Oncology.

Adverse outcome in follicular lymphoma is associated with MYC rearrangements but not MYC extra copies.

Follicular lymphomas (FLs) with MYC rearrangements (MYC-R) and extra copies of MYC (MYC-EC) are rare and the prognosis impact is uncertain. We conducted a retrospective study including 321 FL patients, among whom 259 (81%) had no 8q24 alterations and 62 (19%) were assigned to 8qAlt. Forty-five cases were classified as MYC-EC and six as MYC-R. MYC-R patients were significantly older (P = 0·008), had higher follicular lymphoma international prognostic index (FLIPI) stage (P = 0·05) and ß2-microglobulin (ß2m; P = 0·05). Among patients treated with immuno-chemotherapy, four presented a MYC-R and 25 a MYC-EC. Univariate analysis showed the absence of significant difference between MYC-EC and normal MYC (MYC-NL) regarding progression-free survival (PFS; HR1·3; 95% CI [0·4-1·6]) and specific overall survival (SOS; HR 1·6; 95% CI [0·4-5·7]). Those results were compared to data from the PRIMA trial. This confirmed that MYC-EC had no impact on PFS (P = 0·86) or SOS (P = 0·9). Conversely, MYC-R was associated with a trend to inferior outcome regarding PFS (HR : 6·1; 95% CI [2·2-17·1]; P = 0·00026), lymphoma-related death (SOS; HR 13·6; 95% CI [2·9-65]; P = 0·00014) and risk of transformation (transformation-free survival (TFS); HR 82·7; 95% CI [14·8-463·4]; P < 0·0001). In conclusion, MYC-EC has no prognostic impact in FL but MYC-R FL tended to be associated with an increased risk of transformation and poorer outcome.

Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study.

BACKGROUND: Bortezomib, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. We evaluated whether the addition of daratumumab to VTd before and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed multiple myeloma. METHODS: In this two-part, randomised, open-label, phase 3 CASSIOPEIA trial, we recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in combination with daratumumab (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, number NCT02541383. FINDINGS: Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1·60, 95% CI 1·21-2·12, p=0·0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10-5 sensitivity threshold, assessed by multiparametric flow cytometry; both p<0·0001). Median progression-free survival from first randomisation was not reached in either group (hazard ratio 0·47, 95% CI 0·33-0·67, p<0·0001). 46 deaths on study were observed (14 vs 32, 0·43, 95% CI 0·23-0·80). The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%). INTERPRETATION: D-VTd before and after autologous stem-cell transplantation improved depth of response and progression-free survival with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma. FUNDING: The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology.

Pomalidomide, cyclophosphamide, and dexamethasone for relapsed multiple myeloma.

It is important to have an effective therapy for patients with multiple myeloma (MM) at first relapse, particularly if an autologous stem cell transplant (ASCT) is considered at this stage. This multicenter, phase 2 trial evaluated the efficacy and safety of weekly oral pomalidomide-cyclophosphamide-dexamethasone (PCD) in patients with MM in first relapse after treatment with lenalidomide-bortezomib-dexamethasone (RVD). All patients had received RVD as induction and consolidation therapy, plus lenalidomide maintenance for 1 year (arm A). Half had also received an ASCT after induction (arm B). At MM relapse, all patients received 4 oral cycles of pomalidomide 4 mg (days 1-21), cyclophosphamide 300 mg (days 1, 8, 15, and 22), and dexamethasone 40 mg (days 1-4 and days 15-18 of a 28-day cycle; PCD). Responding patients in arm A underwent ASCT and received 2 additional cycles of PCD, whereas those in arm B received 5 cycles of PCD. All patients received pomalidomide-dexamethasone maintenance until disease progression. Primary end point was partial remission or better after the initial 4 cycles of PCD. Responses were obtained in 82/97 (85%) patients evaluated: complete remission (n = 1; 1%), very good partial remission (n = 32; 33%), and partial remission (n = 49; 51%). Three patients (3%) had stable disease, and 6 (6%) had disease progression (6 response failures). Forty-five (94%) of the 48 patients in arm A underwent planned ASCT. PCD was effective therapy after first relapse with RVD. After 4 cycles, the rate of partial remission or better was 85%, and 94% of planned ASCTs were performed. Toxicity was mostly hematologic and manageable. This trial was registered at www.clinicaltrials.gov as #NCT02244125.

Apixaban for the prevention of thromboembolism in immunomodulatory-treated myeloma patients: Myelaxat, a phase 2 pilot study.

The risk of venous thromboembolism (VTE) is higher in myeloma patients receiving immunomodulatory compounds. A VTE prophylaxis using low-molecular-weight heparin or aspirin is therefore proposed. Apixaban is an oral direct anti-Xa. Several studies have shown the efficacy and safety of apixaban in VTE prophylaxis compared to enoxaparin. The objective of this prospective phase 2 pilot study was to assess the risk of VTE and bleeding in patients with myeloma treated with immunomodulatory compounds lenalidomide (len) or thalidomide (thal), using apixaban in a preventive scheme. Myeloma patients requiring Melphalan-Prednisone-Thalidomide in the first line, or Lenalidomide-Dexamethasone in the relapse setting received apixaban, 2.5 mg x 2/day for 6 months. Venous (pulmonary embolism-PE, or symptomatic proximal or distal deep vein thrombosis-DVT, or all proximal asymptomatic events detected by systematic proximal bilateral compression ultrasound) or arterial thrombotic events, and bleeding events (ISTH 2005) were registered. One hundred and four patients were enrolled (mean age 69.8 ± 7.8 years), 11 in first line and 93 in relapse. Two venous thrombotic events were observed, for example, an asymptomatic proximal DVT and a symptomatic distal DVT, in the context of apixaban stopped 14 days before, due to lenalidomide-induced thrombocytopenia. No PE or arterial cardiovascular events were reported. Only one major and 11 CRNM hemorrhages were reported. These data must now be confirmed on a randomized large study.

Serum free light chains, not urine specimens, should be used to evaluate response in light-chain multiple myeloma.

Guidelines for monitoring multiple myeloma (MM) patients expressing light chains only (light-chain MM [LCMM]) rely on measurements of monoclonal protein in urine. Alternatively, serum free light chain (sFLC) measurements have better sensitivity over urine methods, however, demonstration that improved sensitivity provides any clinical benefit is lacking. Here, we compared performance of serum and urine measurements in 113 (72κ, 41λ) newly diagnosed LCMM patients enrolled in the Intergroupe Francophone du Myélome (IFM) 2009 trial. All diagnostic samples (100%) had an abnormal κ:λ sFLC ratio, and involved (monoclonal) FLC (iFLC) expressed at levels deemed measurable for monitoring (≥100 mg/L). By contrast, only 64% patients had measurable levels of monoclonal protein (≥200 mg per 24 hours) in urine protein electrophoresis (UPEP). After 1 and 3 treatment cycles, iFLC remained elevated in 71% and 46% of patients, respectively, whereas UPEP reported a positive result in 37% and 18%; all of the patients with positive UPEP at cycle 3 also had elevated iFLC levels. Importantly, elevated iFLC or an abnormal κ:λ sFLC ratio after 3 treatment cycles associated with poorer progression-free survival (P = .006 and P < .0001, respectively), whereas positive UPEP or urine immunofixation electrophoresis (uIFE) did not. In addition, patients with an abnormal κ:λ sFLC ratio had poorer overall survival (P = .022). Finally, early normalization of κ:λ sFLC ratio but not negative uIFE predicted achieving negative minimal residual disease, as determined by flow cytometry, after consolidation therapy (100% positive predictive value). We conclude that improved sensitivity and prognostic value of serum over urine measurements provide a strong basis for recommending the former for monitoring LCMM patients.

Understanding the role of hyperdiploidy in myeloma prognosis: which trisomies really matter?

The prognosis of multiple myeloma is mainly dependent upon chromosomal changes. The 2 major abnormalities driving poor outcome are del(17p) and t(4;14). However, the outcome of these high-risk patients is not absolutely uniform, with some patients presenting long survival. We hypothesized that these better outcomes might be related to concomitant "good-risk" chromosomal changes exploring hyperdiploidy. We analyzed a large series of 965 myeloma patients, including 168 patients with t(4;14) and 126 patients with del(17p), using high-throughput single-nucleotide polymorphism arrays after plasma cell sorting. As expected, trisomic chromosomes were highly associated. Using the LASSO model, we found that only chromosome 3, when trisomic, was associated with a longer progression-free survival and that 3 trisomies modulated overall survival (OS) in myeloma patients: trisomies 3 and 5 significantly improved OS, whereas trisomy 21 worsened OS. In patients with t(4;14), trisomies 3 and/or 5 seemed to overcome the poor prognosis. For the first time, using a specific modeling approach, we show that not all trisomies display the same prognostic impact. This finding could be important for routine assessment of prognosis in myeloma, and some high-risk patients with a traditional evaluation could in fact be standard-risk patients.

miR-125b and miR-532-3p predict the efficiency of rituximab-mediated lymphodepletion in chronic lymphocytic leukemia patients. A French Innovative Leukemia Organization study.

The underlying in vivo mechanisms of rituximab action remain incompletely understood in chronic lymphocytic leukemia. Recent data suggest that circulating micro-ribonucleic acids correlate with chronic lymphocytic leukemia progression and response to rituximab. Our study aimed at identifying circulating micro-ribonucleic acids that predict response to rituximab monotherapy in chronic lymphocytic leukemia patients. Using a hierarchical clustering of micro-ribonucleic acid expression profiles discriminating 10 untreated patients with low or high lymphocyte counts, we found 26 micro-ribonucleic acids significantly deregulated. Using individual real-time reverse transcription polymerase chain reaction, the expression levels of micro-ribonucleic acids representative of these two clusters were further validated in a larger cohort (n=61). MiR-125b and miR-532-3p were inversely correlated with rituximab-induced lymphodepletion (P=0.020 and P=0.001, respectively) and with the CD20 expression on CD19+ cells (P=0.0007 and P<0.0001, respectively). In silico analyses of genes putatively targeted by both micro-ribonucleic acids revealed a central role of the interleukin-10 pathway and CD20 (MS4A1) family members. Interestingly, both micro-ribonucleic acids were negatively correlated with MS4A1 expression, while they were positively correlated with MS4A3 and MSA47 Our results identify novel circulating predictive biomarkers for rituximab-mediated lymphodepletion efficacy in chronic lymphocytic leukemia, and suggest a novel molecular mechanism responsible for the rituximab mode of action that bridges miR-125b and miR-532-3p and CD20 family members. (clinicaltrials.gov Identifier: 01370772).

Nodular lymphocyte predominant Hodgkin lymphoma: a Lymphoma Study Association retrospective study.

Nodular lymphocyte predominant Hodgkin lymphoma represents a distinct entity from classical Hodgkin lymphoma. We conducted a retrospective study to investigate the management of patients with nodular lymphocyte predominant Hodgkin lymphoma. Clinical characteristics, treatment and outcome of adult patients with nodular lymphocyte predominant Hodgkin lymphoma were collected in Lymphoma Study Association centers. Progression-free survival (PFS) and overall survival (OS) were analyzed, and the competing risks formulation of a Cox regression model was used to control the effect of risk factors on relapse or death as competing events. Among 314 evaluable patients, 82.5% had early stage nodular lymphocyte predominant Hodgkin lymphoma. Initial management consisted in watchful waiting (36.3%), radiotherapy (20.1%), rituximab (8.9%), chemotherapy or immuno-chemotherapy (21.7%), combined modality treatment (12.7%), or radiotherapy plus rituximab (0.3%). With a median follow-up of 55.8 months, the 10-year PFS and OS estimates were 44.2% and 94.9%, respectively. The 4-year PFS estimates were 79.6% after radiotherapy, 77.0% after rituximab alone, 78.8% after chemotherapy or immuno-chemotherapy, and 93.9% after combined modality treatment. For the whole population, early treatment with chemotherapy or radiotherapy, but not rituximab alone (Hazard ratio 0.695 [0.320-1.512], P=0.3593) significantly reduced the risk of progression compared to watchful waiting (HR 0.388 [0.234-0.643], P=0.0002). Early treatment appears more beneficial compared to watchful waiting in terms of progression-free survival, but has no impact on overall survival. Radiotherapy in selected early stage nodular lymphocyte predominant Hodgkin lymphoma, and combined modality treatment, chemotherapy or immuno-chemotherapy for other patients, are the main options to treat adult patients with a curative intent.

Age is a prognostic factor even among patients with multiple myeloma younger than 66 years treated with high-dose melphalan: the IFM experience on 2316 patients.

Age is a strong prognostic factor in multiple myeloma. The overall survival is shorter in patients older than 66 years, and even shorter in those older than 75 years. Whether age is also a prognostic parameter in patients younger than 66 years treated homogeneously with intensive approaches is unknown. To address this issue, we retrospectively analyzed a series of 2316 patients treated homogeneously with 3-4 cycles of induction chemotherapy followed by a high-dose melphalan course, without any consolidation or maintenance. We show that patients older than 60 years have a statistically significant shorter overall survival. The analysis of prognostic parameters did not show a higher incidence of high-risk cytogenetics, but a higher incidence of International Staging System (ISS) stages 2 and 3, mainly due to higher ß2-microglobulin levels. This study is the first to demonstrate the impact of age in the outcome of 'young' patients with multiple myeloma, and suggests that this parameter should be included in the stratification factors for future prospective clinical trials.