Outcomes of bendamustine- or cyclophosphamide-based first-line chemotherapy in older patients with indolent B-cell lymphoma

Clinical trials comparing bendamustine/rituximab (BR) with cyclophosphamide-based regimens (RCHOP/RCVP) have pooled various histologies of indolent B-cell lymphomas. We examined real-life outcomes of older patients with follicular (FL), mantle cell (MCL), or marginal zone/lymphoplasmacytic lymphoma (MZL/LPL), treated with these first-line regimens. We identified Medicare beneficiaries with FL, MCL, or MZL/LPL, who received either first-line BR or RCHOP/RCVP in 2009-2016, and matched groups using a propensity score. Outcomes of claims-based event-free survival (EFS), overall survival (OS), toxicity, secondary cancers, and costs were compared in the aggregate cohort (N = 2736), and in separately matched histology-specific subcohorts. In the aggregate cohort, EFS was better with BR than with RCHOP/RCVP (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.70-0.87). Acute toxicity was lower with BR, including rates of hospitalizations (33% vs 45%), infections (21% vs 30%), cardiovascular events, and transfusions, yet OS did not differ (HR, 1.03; 95% CI, 0.91-1.17) and Medicare spending was higher. There was no difference in the cumulative incidence of secondary cancers (subhazard ratio, 1.11; 95% CI, 0.83-1.48). The EFS advantage of BR was pronounced in MCL (N = 690; HR, 0.64; 95% CI, 0.54-0.76), but less so in FL (N = 1330; HR, 0.83; 95% CI, 0.69-0.98) and absent in MZL/LPL (N = 574; HR, 0.92; 95% CI, 0.73-1.17). Despite improved EFS and lower toxicity, the shift from RCHOP/RCVP to BR in clinical practice did not improve OS for older patients with indolent B-cell lymphomas. Frequent infections and hospitalizations underscore the need for safer treatment approaches in this population. Secondary cancers do not appear to be increased after BR compared with RCHOP/RCVP.     

A phase 2 study of modified lenalidomide,bortezomib and dexamethasone in transplant‐ineligible multiple myeloma

We sought a regimen that incorporates optimal novel agents and balances efficacy with toxicity in transplant‐ineligible multiple myeloma (MM) patients. Our study evaluated modified lenalidomide‐bortezomib‐dexamethasone (RVD lite) in this population and was administered over a 35‐day cycle. Lenalidomide 15 mg was given orally on days 1–21; bortezomib 1·3 mg/m² weekly subcutaneously on days 1, 8, 15 and 22; and dexamethasone 20 mg orally was given on the day of and day after bortezomib for 9 cycles followed by 6 cycles of consolidation with lenalidomide and bortezomib. The primary objective was to evaluate the overall response rate (ORR); secondary objectives included safety, progression‐free survival (PFS) and overall survival (OS). Fifty‐three eligible patients were screened between April 2013 and May 2015; 50 received at least one dose of therapy. Median age at study entry was 73 years (range 65–91). The ORR was 86% and 66% of patients achieved a very good partial response or better. Median PFS was 35·1 months (95% confidence interval 30·9–not reached) and median OS was not reached at a median follow‐up of 30 months. Peripheral neuropathy was reported in 31 (62%) patients with only 1 patient experiencing grade 3 symptoms. RVD lite is a well‐tolerated and highly effective regimen, with robust PFS and OS, in the transplant‐ineligible MM population.     

Bortezomib,cyclophosphamide, dexamethasone versus lenalidomide,cyclophosphamide, dexamethasone in multiple myeloma patients at first relapse

Bortezomib- and lenalidomide-containing regimens are well-established therapies in multiple myeloma (MM). However, despite their extensive use, head-to-head comparisons have never been performed. Therefore, we compared bortezomib and lenalidomide in fixed-duration therapies. In this open-label, phase III study, we randomized MM patients at first relapse to receive either nine cycles of bortezomib plus cyclophosphamide plus dexamethasone (VCD) or lenalidomide plus cyclophosphamide plus dexamethasone (RCD). The primary endpoint was achievement of a very good partial response (VGPR) or better at six weeks after nine treatment cycles. From March 2011 to February 2015, 155 patients were randomized. VGPR or better was achieved by 12 patients (15%) in the VCD arm and 14 patients (18%) in the RCD arm (P = 0·70). Median progression-free survival (PFS) was 16·3 (95% CI: 12·1–22·4) with VCD and 18·6 months (95% CI: 14·7–25·5) with RCD, and the two-year overall survival (OS) was 75% (95% CI: 66–86%) and 74% (95% CI: 64–85%) respectively. In subgroup analyses, no differences in PFS were observed in bortezomib- and lenalidomide-naïve patients, nor in patients who received a bortezomib-based regimen in first line. Adverse events were consistent with the well-established safety profiles of both drugs. Bortezomib and lenalidomide treatments were equally effective in terms of depth of response, PFS, and OS in MM patients at first relapse.     

Lenalidomide before and after autologous stem cell transplantation for transplant-eligible patients of all ages in the randomized,phase III,Myeloma XI trial

The optimal way to use immunomodulatory drugs as components of induction and maintenance therapy for multiple myeloma is unresolved. We addressed this question in a large phase III randomized trial, Myeloma XI. Patients with newly diagnosed multiple myeloma (n=2,042) were randomized to induction therapy with cyclophosphamide, thalidomide, and dexamethasone (CTD) or cyclophosphamide, lenalidomide, and dexamethasone (CRD). Additional intensification therapy with cyclophosphamide, bortezomib, and dexamethasone (CVD) was administered before autologous stem-cell transplantation to patients with a suboptimal response to induction therapy using a response-adapted approach. After receiving high-dose melphalan with autologous stem cell transplantation, eligible patients were further randomized to receive either lenalidomide alone or observation alone. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS). The CRD regimen was associated with significantly longer PFS (median: 36 vs. 33 months; hazard ratio [HR], 0.85; 95% confidence interval [CI]: 0.75-0.96; P=0.0116) and OS (3-year OS: 82.9% vs. 77.0%; HR, 0.77; 95% CI: 0.63-0.93; P=0.0072) compared with CTD. The PFS and OS results favored CRD over CTD across all subgroups, including patients with International Staging System stage III disease (HR for PFS, 0.73; 95% CI: 0.58-0.93; HR for OS, 0.78; 95% CI: 0.56-1.09), high-risk cytogenetics (HR for PFS, 0.60; 95% CI: 0.43-0.84; HR for OS, 0.70; 95% CI: 0.42-1.15) and ultra-high-risk cytogenetics (HR for PFS, 0.67; 95% CI: 0.41-1.11; HR for OS, 0.65; 95% CI: 0.34-1.25). Among patients randomized to lenalidomide maintenance (n=451) or observation (n=377), maintenance therapy improved PFS (median: 50 vs. 28 months; HR, 0.47; 95% CI: 0.37-0.60; P<0.0001). Optimal results for PFS and OS were achieved in the patients who received CRD induction and lenalidomide maintenance. The trial was registered with the EU Clinical Trials Register (EudraCT 2009-010956-93) and ISRCTN49407852.     

Long‐term outcomes of primary systemic light chain (AL) amyloidosis in patients treated upfront with bortezomib or lenalidomide and the importance of risk adapted strategies

Bortezomib and lenalidomide are increasingly used in patients with AL amyloidosis, but long term data on their use as primary therapy in AL amyloidosis are lacking while early mortality remains significant. Thus, we analyzed the long term outcomes of 85 consecutive unselected patients, which received primary therapy with bortezomib or lenalidomide and we prospectively evaluated a risk adapted strategy based on bortezomib/dexamethasone to reduce early mortality. Twenty‐six patients received full‐dose bortezomib/dexamethasone, 36 patients lenalidomide with oral cyclophosphamide and low‐dose dexamethasone and 23 patients received bortezomib/dexamethasone at a dose and schedule adjusted to the risk of early death. On intent to treat, 67% of patients achieved a hematologic response (24% hemCRs) and 34% an organ response; both were more frequent with bortezomib. An early death occurred in 20%: in 36% of those treated with full‐dose bortezomib/dexamethasone, in 22% of lenalidomide‐treated patients but only in 4.5% of patients treated with risk‐adapted bortezomib/dexamethasone. Activity of full vs. adjusted dose bortezomib/dexamethasone was similar; twice weekly vs. weekly administration of bortezomib also had similar activity. After a median follow up of 57 months, median survival is 47 months and is similar for patients treated with bortezomib vs. lenalidomide‐based regimens. However, risk adjusted‐bortezomib/dexamethasone was associated with improved 1‐year survival vs. full‐dose bortezomib/dexamethasone or lenalidomide‐based therapy (81% vs. 56% vs. 53%, respectively). In conclusion, risk‐adapted bortezomib/dexamethasone may reduce early mortality and preserve activity while long term follow up indicates that remissions obtained with lenalidomide or bortezomib may be durable, even without consolidation with alkylators.Am. J. Hematol. 90:E60–E65, 2015. © 2015 Wiley Periodicals, Inc.     

Proteomic profiling of naïve multiple myeloma patient plasma cells identifies pathways associated with favourable response to bortezomib‐based treatment regimens

Toward our goal of personalized medicine, we comprehensively profiled pre‐treatment malignant plasma cells from multiple myeloma patients and prospectively identified pathways predictive of favourable response to bortezomib‐based treatment regimens. We utilized two complementary quantitative proteomics platforms to identify differentially‐regulated proteins indicative of at least a very good partial response (VGPR) or complete response/near complete response (CR/nCR) to two treatment regimens containing either bortezomib, liposomal doxorubicin and dexamethasone (VDD), or lenalidomide, bortezomib and dexamethasone (RVD). Our results suggest enrichment of ‘universal response’ pathways that are common to both treatment regimens and are probable predictors of favourable response to bortezomib, including a subset of endoplasmic reticulum stress pathways. The data also implicate pathways unique to each regimen that may predict sensitivity to DNA‐damaging agents, such as mitochondrial dysfunction, and immunomodulatory drugs, which was associated with acute phase response signalling. Overall, we identified patterns of tumour characteristics that may predict response to bortezomib‐based regimens and their components. These results provide a rationale for further evaluation of the protein profiles identified herein for targeted selection of anti‐myeloma therapy to increase the likelihood of improved treatment outcome of patients with newly‐diagnosed myeloma.     

Residual disease detected by flow cytometry is an independent predictor of survival in childhood acute myeloid leukaemia; results of the NOPHO‐AML 2004 study

Early response after induction is a prognostic factor for disease outcome in childhood acute myeloid leukaemia (AML). Residual disease (RD) detection by multiparameter flow cytometry (MFC) was performed at day 15 and before consolidation therapy in 101 patients enrolled in the Nordic Society of Paediatric Haemato‐Oncology AML 2004 study. A multicentre laboratory approach to RD analysis was used. Event‐free survival (EFS) and overall survival (OS) was significantly different in patients with and without RD at both time points, using a 0·1% RD cut‐off level. RD‐negative and ‐positive patients after first induction showed a 5‐year EFS of 65 ± 7% and 22 ± 7%, respectively (P < 0·001) and an OS of 77 ± 6% (P = 0·025) and 51 ± 8%. RD‐negative and ‐positive patients at start of consolidation therapy had a 5‐year EFS of 57 ± 7% and 11 ± 7%, respectively (P < 0·001) and an OS of 78 ± 6% and 28 ± 11%) (P < 0·001). In multivariate analysis only RD was significantly correlated with survival. RD before consolidation therapy was the strongest independent prognostic factor for EFS [hazard ratio (HR):5·0; 95% confidence interval (CI):1·9–13·3] and OS (HR:7·0; 95%CI:2·0–24·5). In conclusion, RD before consolidation therapy identifies patients at high risk of relapse in need of intensified treatment. In addition, RD detection can be performed in a multicentre setting and can be implemented in future trials.     

Results of a randomized trial in children with Acute Myeloid Leukaemia: medical research council AML12 trial

The Medical Research Council Acute Myeloid Leukaemia 12 (MRC AML12) trial (children) addressed the optimal anthracenedione/anthracycline in induction and the optimal number of courses of consolidation chemotherapy. 504 children (<16 years) with AML were randomized between mitoxantrone/cytarabine/etoposide or daunorubicin/cytarabine/etoposide as induction chemotherapy and 270 entered a second randomization between a total of four or five courses of treatment. Ten‐year event‐free (EFS) and overall survival (OS) was 54% and 63% respectively; the relapse rate was 35%. There was no difference in complete remission rate between the induction regimens, but there was a benefit for mitoxantrone with regard to relapse rate [32% vs. 39%; Hazard ratio (HR) 0·73; 95% confidence interval (CI) 0·54, 1·00] and disease‐free survival (DFS; 63% vs. 55%; HR 0·72; 95% CI 0·54, 0·96). However, this did not translate into a better EFS or OS (HR 0·84; 95% CI 0·63, 1·12). Results of the second randomization did not show a survival benefit for a fifth course of treatment (HR 1·01; 95% CI 0·63, 1·62), suggesting a ceiling of benefit for conventional chemotherapy and demonstrating the need for new agents. EFS was superior compared to the preceding trial AML10, partly due to fewer deaths in remission, highlighting the importance of supportive care.     

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.     

Bortezomib‐Cyclophosphamide‐Dexamethasone (VCD) versus Bortezomib‐Thalidomide‐Dexamethasone (VTD) ‐based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta‐analysis

Three‐drug induction regimens have become the standard of care in newly diagnosed transplant‐eligible multiple myeloma patients. Two frequently used protocols are bortezomib, cyclophosphamide and dexamethasone (VCD) and bortezomib, thalidomide and dexamethasone (VTD). Comparisons between the two are lacking. The present study aimed to identify the differences in response rate and toxicity between the two regimens. Databases were searched using the terms ‘VTD’ or ‘VCD’ and ‘induction regimens for newly diagnosed multiple myeloma’. Prospective trials evaluating initial response in transplant eligible patients were included. The main outcome measures were response rates and adverse events. Eight clinical trials were eligible for analysis. Overall 672 patients were treated with either VCD (n = 157) or VTD (n = 515) as induction therapy. Patients treated with VTD presented with a significantly higher complete/near complete response (34% vs. 6%, P = 0·002) as well as a higher very good partial response rate or better, following induction therapy (62% vs. 27%, P < 0·0001). Although grade 3–4 neurotoxicity was more frequent during VTD therapy (11% vs. 6%, P = 0·057), a higher incidence of overall grade 3–4 adverse events was found in the VCD‐treated patients (74% vs. 51%, P < 0·001). VTD induction therapy may be superior in achieving deeper response rate following induction therapy, and is better tolerated.     

Systematic review of the addition of vincristine plus steroid pulses in maintenance treatment for childhood acute lymphoblastic leukaemia – an individual patient data meta‐analysis involving 5659 children

Vincristine plus steroid pulses have long been a part of maintenance treatment in many protocols for childhood acute lymphoblastic leukaemia (ALL). A collaborative individual patient data meta‐analysis of all randomised trials of the addition of vincristine plus prednisone/prednisolone (VP) pulses in childhood ALL was updated and extended to include trials comparing vincristine plus dexamethasone (VD) pulses to maintenance without pulses. VP pulses improved event‐free survival (EFS) (70·1% vs. 62·0% at 5 years; odds ratio (OR) = 0·71; 95% confidence interval (CI) = 0·61–0·84; P = 0·00004); VD pulses did not have a significant effect (80·9% vs. 79·9% 5 year EFS; OR = 0·94; 95% CI = 0·80–1·11; P = 0·5). Heterogeneity between groups (VP or VD) was significant (P = 0·02). Neither treatment clearly affected overall survival. The difference between the VP and VD results is probably due to the greater early intensity of the backbone of the VD trial protocols and improved outcome seen in the VD trials, which were more recent. Pulses may still be useful in cases where less intensive early therapy is used and the balance between these treatments in terms of both effectiveness and toxicity needs to be considered.     

Cranial radiation for pediatric T‐lineage acute lymphoblastic leukemia: A systematic review and meta‐analysis

There are heterogeneous approaches to cranial radiation therapy (CRT) for T‐lineage acute lymphoblastic leukemia (T‐ALL). We performed a systematic review of studies that specified a radiation strategy and reported survival for pediatric T‐ALL. Our analysis included 62 publications reporting 78 treatment groups (patient n = 5844). The average event‐free survival (EFS) was higher by 6% per 5 years (P < 0.001). Adjusting for year, EFS differed by radiation strategy. Compared to the reference group (CRT for all) which had a year‐adjusted EFS of 65% (95% confidence interval, CI: 61–69%) the adjusted EFS was significantly worse (rate difference (RD) = ?9%, 95% CI: ?15 to ?2%) among studies that used a risk‐directed approach to CRT (P = 0.004). The adjusted EFS for the other strategies were not significantly different compared to the reference group: CRT for central nervous system positive patients only (RD = ?3%, 95% CI: ?14 to 7%, P = 0.49); CRT omitted for all patients (RD = 5%, 95% CI: ?4 to 15%, P = 0.33). CRT may not be necessary with current chemotherapy for T‐ALL. These findings, however, are susceptible to bias and caution should be applied in drawing conclusions on the comparative effectiveness of alternative CRT strategies. Am. J. Hematol. 89:992–997, 2014. © 2014 Wiley Periodicals, Inc.     

Phase 2 study of two sequential three‐drug combinations containing bortezomib,cyclophosphamide and dexamethasone,followed by bortezomib,thalidomide and dexamethasone as frontline therapy for multiple myeloma

Novel sequential combination therapy for induction may improve the quality of response and therefore prolong survival in newly diagnosed multiple myeloma (MM) patients. We report results from a phase 2 study of two sequential three‐drug combinations. Forty‐four previously untreated, symptomatic MM patients received: bortezomib 1·3 mg/m² (days 1, 4, 8, 11), cyclophosphamide 300 mg/m² (days 1, 8), plus dexamethasone 40 mg (day of and day after bortezomib) for three 21‐day cycles, followed by bortezomib 1·0 mg/m², dexamethasone 40 mg and thalidomide 100 mg daily for three cycles. Overall response rate for 42 evaluable patients was 95%, including 19% stringent complete response (sCR), 26% CR, and 57%≥ very good partial response. Twenty‐two patients have undergone stem‐cell transplantation. After a median follow‐up of 20·9 months, five patients have died; none was induction therapy‐related. Median event‐free survival (EFS) and overall survival (OS) have not been reached; estimated 1‐year EFS and OS rates were 81% and 91% respectively. Both three‐drug combinations were well tolerated; 82% of patients completed all six cycles. Toxicities were predictable and manageable; the most‐commonly reported grade 3/4 toxicity was neuropathy (11%). This novel sequential three‐drug combination therapy is effective and well‐tolerated in previously untreated MM patients.     

Elevated monoclonal and polyclonal serum immunoglobulin free light chain as prognostic factors in B‐ and T‐cell non‐Hodgkin lymphoma

The serum immunoglobulin free light chain (FLC) assay quantitates free kappa (κ) and lambda (λ) light chains. FLC elevations in patients with diffuse large B‐cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and chronic lymphocytic leukemia (CLL) are associated with an inferior survival. These increases in FLC can be monoclonal (as in myeloma) or polyclonal. The goal was to estimate the frequency of these elevations within distinct types of B‐cell and T‐cell non‐Hodgkin lymphoma (NHL) and whether the FLC measurements are associated with event‐free survival (EFS). We studied serum for FLC abnormalities using normal laboratory reference ranges to define an elevated κ or λ FLC. Elevations were further classified as polyclonal or monoclonal. Four hundred ninety‐two patients were studied: 453 B‐cell and 34 T‐cell NHL patients. Twenty‐nine % (142/453) of patients had an elevated FLC of which 10% were monoclonal elevations. Within B‐cell NHL, FLC abnormalities were most common in lymphoplasmacytic (79%), mantle cell (68%), and lymphomas of mucosa associated lymphoid tissue (31%); they were least common in follicular (15%). The hazard ratio (HR) for EFS in all patients was 1.41 (95% CI; 1.11–1.81); in all B‐cell NHL the HR was 1.44 (95% CI 1.11–1.96); in all T‐cell NHL the HR was 1.17 (95% CI 0.55–2.49). FLC abnormalities predicted an inferior OS (HR = 2.75, 95% CI: 1.93–3.90, P < 0.0001). The serum FLC assay is useful for prognosis in both B‐cell and T‐cell types of NHL. In B‐cell NHL further discrimination between a monoclonal and polyclonal elevation may be helpful and should be analyzed in prospective clinical trials. Am. J. Hematol. 89:1116–1120, 2014. © 2014 Wiley Periodicals, Inc.     

Efficacy of daratumumab‐based therapies in patients with relapsed,refractory multiple myeloma treated outside of clinical trials

Outside of clinical trials, experience with daratumumab‐based combination therapies (DCTs) using bortezomib (V)/lenalidomide (R)/pomalidomide (P), and dexamethasone (d) in relapsed/refractory multiple myeloma (RRMM) is limited. We reviewed the outcomes of 126 patients who received ≥ 1 cycle of any DCT. Median age at DCT initiation was 67 (range, 43‐93) years. High‐risk cytogenetics was present in 33% patients. Median number of prior therapies was 4 (range, 1‐14) and time to first DCT from diagnosis was 4.3 years (range, 0.4‐13.0). Seventeen (13%) patients were refractory to single agent daratumumab. Fifty‐two (41%), 34 (27%), 23 (18%), and 17 (14%) received DPd, DRd, DVd and “other” DCTs, respectively. Overall response rate was 47%. Median follow‐up was 5.5 months (95% CI, 4.2‐6.1). Median progression‐free survival (PFS) was 5.5 months (95% CI, 4.2‐7.8). Median overall survival was not reached (NR) with any regimen. Median PFS (months) was worst for penta‐refractory MM (n = 8) vs quadruple refractory MM (n = 18) and others (n = 100) (2.2 [95% CI, 1‐2.4] vs 3.1 [95% CI, 2.1‐NR] vs 5.9 [95% CI, 5.0‐NR]; P < .001); those who were refractory to ≥1 agents used in the DCT vs others (4.9 [95% CI, 3.1‐6.0] vs 8.2 [95% CI, 4.6‐NR]; P = .02); and those who received >2 prior therapies vs others (5.0 months [95% CI, 3.7‐5.9] vs NR [95% CI, NR‐NR]; P = .002). Non‐hematologic toxicities included infections (38%), fatigue (32%), and infusion reactions (18%). Grade 3 or higher hematological toxicities were seen in 41% of patients. DCTs are effective in RRMM. ORR and PFS in heavily pretreated patients are lower than those reported in clinical trials.     

Comparison of venous thromboembolism incidence in newly diagnosed multiple myeloma patients receiving bortezomib,lenalidomide, dexamethasone (RVD) or carfilzomib,lenalidomide, dexamethasone (KRD) with aspirin or rivaroxaban thromboprophylaxis

Incidence of venous thromboembolism (VTE) varies across different regimens in newly diagnosed multiple myeloma (NDMM) patients. Limited data exist on the use of direct oral anticoagulants as thromboprophylaxis in the setting of haematologic malignancies, specifically multiple myeloma. In this retrospective study of 305 NDMM patients, VTE rates in those treated with carfilzomib, lenalidomide, dexamethasone (KRD) + aspirin (ASA), bortezomib, lenalidomide, dexamethasone (RVD) + ASA, and KRD + rivaroxaban were statistically significant, 16·1%, 4·8%, and 4·8%, respectively. The findings confirm a higher incidence of VTE when using KRD induction compared to RVD induction and reveal that the use of low-dose rivaroxaban thromboprophylaxis can mitigate this risk without an observable increase in bleeding rates.     

Efficacy of VDT PACE‐like regimens in treatment of relapsed/refractory multiple myeloma

Experience with intensive chemotherapy for relapsed/refractory multiple myeloma (RRMM) using VDT PACE regimen and its modifications (VDT PACE‐like regimens: VPLRs) outside TOTAL THERAPY trials is limited. We analyzed the outcomes of 141 patients with RRMM who received VPLRs at our center between 2006 and 2017 in an intent‐to‐treat analysis. Median age was 59.7 years and 66.7% of patients were male. A median of 2.2 years (range 0.02‐11.4) separated diagnosis of myeloma and inititation of VPLR. High‐risk cytogenetics were present in 52.4% patients. Patients received a median of 4 (range 1‐14) prior therapies, including stem cell transplant (SCT) in 66.7% patients. Ninety‐five (67.4%) patients received VDT PACE, 20 (14.2%) patients received VD PACE and 26 (18.4%) patients received other VPLRs. Patients received a median of 1 cycle (range 1‐9) of VPLR. We observed ≥ minimal response in 68.4%, ≥ partial response (PR) in 54.4% and ≥ very good PR in 10.3% patients. Median progression‐free survival was 3.1 months (95% CI, 1.9‐3.9) and median overall survival (OS) was 8.1 months (CI, 6.2‐9.9). One‐hundred and sixteen (82.3%) patients received some therapy after VPLR; 71 (61.2%) received systemic chemotherapy, while 45 (38.8%) underwent SCT. Median OS for those who received SCT after VPLR was 15.1 months (CI, 10.3‐20.8). Age ≥ 60 years (hazard ratio [HR] 2.3 [CI, 1.4‐3.7]; P = 0.0008) and R‐ISS III stage (HR‐ 2.4 [CI, 1.3‐4.0]; P = 0.003) predicted shorter OS in patients receiving VPLR. VPLRs are effective in heavily pre‐treated RRMM. In fit patients, SCT can be used to consolidate the response to VPLR.     

Ki‐67 expression as a prognostic factor in diffuse large B‐cell lymphoma patients treated with rituximab plus CHOP

Background: Assessment of tumor cell proliferation based on Ki‐67 expression yielded conflicting prognostic predictions of patients with diffuse large B‐cell lymphoma (DLBCL). The introduction of rituximab to the DLBCL treatment regime has led to alterations in the significance of previous prognostic factors. Methods: We analyzed Ki‐67 expression and its correlation with prognosis in 144 patients with DLBCL treated with rituximab plus CHOP (R‐CHOP) between July 2003 and January 2008. Results: The complete response (CR) rates following R‐CHOP administration were not significantly different, based on Ki‐67 expression status (P = 0.104). However, higher rates of relapse were observed in the high Ki‐67 expression group (Ki‐67 ≥ 85%, n = 46) with 25.0%, compared to 10.0% in the low Ki‐67 expression group (Ki‐67 < 85%, n = 88) (P = 0.040). The 2‐yr event‐free survival (EFS) rates were 44.3% and 74.1% in the high and low Ki‐67 expression groups, respectively (P = 0.011). The 2‐yr overall survival (OS) rate was 66.4% in the high Ki‐67 expression group and 82.2% in the low Ki‐67 expression group (P = 0.016). In multivariate analysis, Ki‐67 expression was a significant prognostic factor for EFS [hazard ratio (HR) = 2.909; 95% confidence interval (CI) 1.261–6.708; P = 0.012]. Ki‐67 was associated with OS but with borderline significance (HR = 2.876; 95% CI, 0.972–8.508; P = 0.056). Conclusion: Elevated Ki‐67 expression seems to be associated with higher relapse after CR and inferior EFS in patients with DLBCL treated with R‐CHOP.     

Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial

The combination of lenalidomide and low-dose dexamethasone is an effective treatment for multiple myeloma (MM). Addition of alkylating agents to lenalidomide or thalidomide results in increased response rates and deeper responses. We designed this trial to study the combination of cyclophosphamide, lenalidomide, and dexamethasone (CRd) as initial therapy for MM. Fifty-three patients with previously untreated symptomatic MM was enrolled. Patients received 4-week treatment cycles consisting of lenalidomide (25 mg daily for 3 weeks), dexamethasone (40 mg weekly), and cyclophosphamide (300 mg/m(2) weekly for 3 weeks). A partial response or better was seen in 85% of patients including 47% with a very good partial response or better. The toxicities were manageable with over 80% of planned doses delivered; six patients went off study for toxicity. The median progression free survival (PFS) for the entire group was 28 months (95% CI: 22.7-32.6) and the overall survival (OS) at 2 years was 87% (95% CI: 78-96). Importantly, 14 patients with high-risk MM had similar PFS and OS as the standard-risk patients (n = 39). CRd is an effective and well-tolerated regimen for upfront therapy of MM with high response rates and excellent 2-year OS, and is suitable for long-term therapy.     

Daratumumab monotherapy compared with historical control data in heavily pretreated and highly refractory patients with multiple myeloma: An adjusted treatment comparison

Daratumumab is a human CD38‐directed monoclonal antibody approved in the United States as monotherapy for patients with multiple myeloma (MM) who have received ≥3 prior lines of therapy (LOTs), including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double refractory to a PI and an IMiD, and in combination with lenalidomide/dexamethasone or bortezomib/dexamethasone for patients with MM who have received ≥1 prior LOT. This study compared the efficacy of daratumumab monotherapy versus historical controls through adjusted treatment comparison. Patient‐level data were pooled from two daratumumab monotherapy studies (16 mg/kg; GEN501 and SIRIUS) and two independent US databases (IMS LifeLink and OPTUM), which reflect treatments used in real‐world patients with MM who received ≥3 prior LOTs or were double refractory to a PI and an IMiD. Using a multivariate proportional hazards regression model, the relative treatment effect of daratumumab versus historical controls was estimated, adjusting for imbalances in characteristics between cohorts. Baseline characteristics that differed between patients treated with daratumumab (N = 148) and historical control (N = 658) were prior treatment with pomalidomide (55% vs 15%) or carfilzomib (41% vs 28%) and triple/quadruple refractory status (64% vs 14%). The adjusted overall survival–hazard ratio (OS‐HR) for daratumumab versus historical control was 0.33 (95% confidence interval, 0.24‐0.46) compared with 0.46 (0.35‐0.59) for unadjusted HR. Impact of adjustment was mainly driven by refractory status and prior pomalidomide/carfilzomib exposure. This adjusted treatment comparison suggests that daratumumab demonstrates improved OS compared with historical control data in heavily pretreated and highly refractory MM patients.