Early Relapse After Autologous Transplant Is Associated With Very Poor Survival and Identifies an Ultra-High-Risk Group of Patients With Myeloma.

INTRODUCTION: Patients relapsing early after autologous stem cell transplantation (ASCT) are a particular therapeutic challenge. METHODS: This was a retrospective, single center study that included 297 consecutive patients that received first-line ASCT RESULTS: We identified 43 (14.5%) patients that relapsed within <12 months. At diagnosis, these patients had more often elevated lactate dehydrogenase, lower estimated glomerular filtration rate, hypercalcemia, and high-risk cytogenetics; the International Staging System stage distribution was similar. Consolidation and maintenance were associated with lower rates of early relapses. Progression-free survival to second-line therapy was 5 months versus 19 months for those with an early versus late relapse (P < .001), the median PFS to second-line therapy was 15.5 months versus >5 years (P < .001) and the median post-ASCT survival was 18 months versus >6 years. The survival after an early relapse has not improved significantly over time. In multivariate analysis, early relapse (hazard ratio, 14; P < .001) was the most important prognostic factor for poor survival after ASCT. CONCLUSION: Patients relapsing <12 months after ASCT comprise an ultra-high-risk group, with poor outcomes even with the application of the more recent combinations, that urgently needs more effective therapies.

Vulnerability variables among octogenerian myeloma patients: a single-center analysis of 110 patients.

In the era of an aging population, an increasing number of patients are diagnosed with multiple myeloma at an age of ≥80. The frailty of this population as a result of coexisting comorbidities and age-related organ impairment is a significant management challenge. The aim of our study was to analyze the disease characteristics, frailty scores and toxicity profile in relation to patient outcomes. Among 827 consecutive, newly diagnosed, symptomatic patients treated since 01 January 2000, we analyzed the characteristics and outcomes of the 110 who were ≥80. Median survival was 21 months, and early mortality within 2 months from diagnosis was 20%. Several factors were associated with inferior survival, whereas in the multivariate analysis, estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2 and LDH ≥250 IU/L were independently associated with poor overall survival. These patients are a distinct frail subset of the general myeloma population who require individualized approach.

Hypercalcemia remains an adverse prognostic factor for newly diagnosed multiple myeloma patients in the era of novel antimyeloma therapies.

OBJECTIVES: To evaluate the prognostic impact of hypercalcemia in newly diagnosed patients with symptomatic multiple myeloma (MM), especially after the incorporation of new agents. METHODS: we analyzed the outcomes of newly diagnosed patients with symptomatic myeloma included in the database of the Greek Myeloma Study Group for the prognostic effect of the presence of hypercalcemia (defined as corrected serum calcium ≥11 mg/dL) at diagnosis. RESULTS: Among 2129 consecutive patients with symptomatic MM, 19.5% presented with hypercalcemia at the time of diagnosis. The presence of hypercalcemia was associated with anemia, thrombocytopenia, lower estimated glomerular filtration rate (eGFR), advanced ISS stage, and presence of lytic lesions. Hypercalcemia was more common in patients with high-risk cytogenetics and was associated with inferior survival across different time periods, age groups, and primary treatments. Hypercalcemia was also associated with a twofold increase in the risk of early death. In patients without available FISH, hypercalcemia could substitute for the presence of high-risk cytogenetics and identify patients with worse prognosis along with ISS stage and elevated serum LDH. CONCLUSION: Hypercalcemia remains a poor prognostic feature in the era of novel agents despite the improvement in the outcomes of patients who present with elevated calcium.

BDR in newly diagnosed patients with WM: final analysis of a phase 2 study after a minimum follow-up of 6 years.

In this phase 2 multicenter trial, we evaluated the efficacy of the combination of bortezomib, dexamethasone, and rituximab (BDR) in 59 previously untreated symptomatic patients with Waldenström macroglobulinemia (WM), most of which were of advanced age and with adverse prognostic factors. BDR consisted of a single 21-day cycle of bortezomib alone (1.3 mg/m2 IV on days 1, 4, 8, and 11), followed by weekly IV bortezomib (1.6 mg/m2 on days 1, 8, 15, and 22) for 4 additional 35-day cycles, with IV dexamethasone (40 mg) and IV rituximab (375 mg/m2) on cycles 2 and 5, for a total treatment duration of 23 weeks. On intent to treat, 85% responded (3% complete response, 7% very good partial response, 58% partial response). After a minimum follow-up of 6 years, median progression-free survival was 43 months and median duration of response for patients with at least partial response was 64.5 months. Overall survival at 7 years was 66%. No patient had developed secondary myelodysplasia, whereas transformation to high-grade lymphoma occurred in 3 patients who had received chemoimmunotherapy after BDR. Thus, BDR is a very active, fixed-duration, chemotherapy-free regimen, inducing durable responses and with a favorable long-term toxicity profile (www.ClinicalTrials.gov #NCT00981708).

Bortezomib-based triplets are associated with a high probability of dialysis independence and rapid renal recovery in newly diagnosed myeloma patients with severe renal failure or those requiring dialysis.

Renal failure (RF) is a common and severe complication of symptomatic myeloma, associated with significant morbidity and mortality. Such patients are commonly excluded from clinical trials. Bortezomib/dexamethasone (VD)-based regimens are the backbone of the treatment of newly diagnosed MM patients who present with severe RF even those requiring dialysis. We analyzed the outcomes of 83 consecutive bortezomib-treated patients with severe RF (eGFR < 30 ml/min/1.73 m(2) ), of which 31 (37%) required dialysis. By IMWG renal response criteria, 54 (65%) patients achieved at least MRrenal, including CRrenal in 35% and PRrenal in 12%. Triplet combinations (i.e., VD plus a third agent) versus VD alone were associated with higher rates of renal responses (72 vs. 50%; P = 0.06). Fifteen of the 31 (48%) patients became dialysis independent within a median of 217 days (range 11-724). Triplets were associated with a higher probability of dialysis discontinuation (57 vs. 35%). Serum free light chain (sFLC) level ≥11,550 mg/L was associated with lower rates of major renal response, longer time to major renal response, lower probability, and longer time to dialysis discontinuation. Rapid myeloma response (≥PR within the first month) was also associated with higher rates of renal response. Patients who became dialysis-independent had longer survival than those remaining on dialysis. In conclusion, VD-based triplets are associated with a significant probability of renal response and dialysis discontinuation, improving the survival of patients who became dialysis independent. Rapid disease response is important for renal recovery and sFLCs are predictive of the probability and of the time required for renal response.

Primary therapy of Waldenstrom macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN).

In this phase 2 multicenter trial, we evaluated the activity of bortezomib, dexamethasone, and rituximab (BDR) combination in previously untreated symptomatic patients with Waldenström macroglobulinemia (WM). To prevent immunoglobulin M (IgM) "flare," single agent bortezomib (1.3 mg/m(2) IV days 1, 4, 8, and 11; 21-day cycle), was followed by weekly IV bortezomib (1.6 mg/m(2) days 1, 8, 15, and 22) every 35 days for 4 additional cycles, followed by IV dexamethasone (40 mg) and IV rituximab (375 mg/m(2)) in cycles 2 and 5. Fifty-nine patients were treated; 45.5% and 40% were high and intermediate risk per the International Prognostic Scoring System for WM. On intent to treat, 85% responded (3% complete response, 7% very good partial response, 58% partial response [PR]). In 11% of patients, an increase of IgM ≥25% was observed after rituximab; no patient required plasmapheresis. After a minimum follow-up of 32 months, median progression-free survival was 42 months, 3-year duration of response for patients with ≥PR was 70%, and 3-year survival was 81%. Peripheral neuropathy occurred in 46% (grade ≥3 in 7%); only 8% discontinued bortezomib due to neuropathy. BDR is rapidly acting, well tolerated, and nonmyelotoxic, inducing durable responses in previously untreated WM.

Diffuse pattern of bone marrow involvement on magnetic resonance imaging is associated with high risk cytogenetics and poor outcome in newly diagnosed, symptomatic patients with multiple myeloma: a single center experience on 228 patients.

Magnetic Resonance Imaging (MRI) and specific cytogenetic abnormalities offer important prognostic information for myeloma patients. However, limited data are available about the association between cytogenetic abnormalities and MRI patterns of marrow infiltration. To address this issue, we analyzed 228 consecutive newly diagnosed, symptomatic patients who were diagnosed and treated in a single center. On bone marrow MR images, 95 (41%) patients had diffuse, 94 (41%) had focal, 35 (15%) were normal, and 4 (1.7%) patients had variegated pattern of marrow infiltration. High risk cytogenetics were more commonly observed with diffuse MRI pattern (50% vs. 31% in focal and normal patterns). Patients with diffuse MRI pattern had poorer survival compared to others and responded better to novel agent-based therapies than to conventional chemotherapy (objective response: 88% vs. 46%, P < 0.001). There was a significant improvement of patients' survival with a diffuse MRI pattern when treated upfront with novel agents compared to conventional chemotherapy (47 vs. 24 months; P < 0.001). Diffuse MRI pattern along with ISS-3 and high risk cytogenetics could identify a very high risk group of patients with extremely poor median survival (21 months) and an only 35% probability of 3-year OS. Our study shows that symptomatic myeloma patients with a diffuse MRI pattern at diagnosis very often show high risk cytogenetic abnormalities and are benefiting from upfront novel agent-based therapies. Diffuse MRI pattern in combination with high risk cytogenetics and ISS-3 can identify a subset of myeloma patients with very poor prognosis who may need innovative treatment strategies and possibly more aggressive therapies.

Multiple myeloma in octogenarians: clinical features and outcome in the novel agent era.

BACKGROUND: Multiple myeloma (MM) affects mainly elderly persons and because the population of octogenarians increases, it is common to treat patients ≥ 80 years of age. These patients are often not included in clinical trials; thus, there is limited data on their characteristics and treatment outcome. PATIENTS AND METHODS: We retrospectively analyzed 682 consecutive, unselected patients with newly diagnosed symptomatic myeloma who started treatment between January 1, 2003 and December 31, 2010. RESULTS: We identified 155 (23%) patients ≥ 80 years of age. Compared to patients <80 years, octogenarians had poorer performance status (P < 0.001), anemia (P = 0.006), low serum albumin (P = 0.001), and advanced ISS (P < 0.001). The median survival of patients ≥ 80 years was 22 months, and 14% died within 2 months from therapy initiation. The median survival of patients ≥ 80 years who received upfront novel agents was 26 vs. 17 months for those who did not. ECOG performance status ≤ 1 and frontline use of novel agents were independently associated with better survival. Response to first-line therapy was associated with improved survival (29 vs. 16 months, P = 0.017). CONCLUSIONS: Patients ≥ 80 years of age present with features of advanced myeloma and impaired performance status. The addition of novel agents may improve their outcome, but careful assessment and prospective clinical trials targeting the population of elderly patients are needed.

Increased serum lactate dehydrongenase should be included among the variables that define very-high-risk multiple myeloma.

BACKGROUND: In patients who have symptomatic multiple myeloma (MM), a high serum lactate dehydrogenase (LDH) level is associated with features of advanced disease, adds prognostic value to the international staging system (ISS) and predicts for inferior survival. However, it has not been clearly defined what the impact of this abnormality is for patients treated upfront with novel agent-based regimens. PATIENTS AND METHODS: To address this issue we analyzed 203 consecutive unselected patients with symptomatic MM who received upfront treatment with novel agents in a single center. RESULTS: The median overall survival for patients with normal LDH was 54 months but in patients with increased LDH levels it was 21 months (P = .003), whereas increased serum LDH was associated with a higher probability of early death. Multivariate analysis confirmed that an increased LDH level is independently associated with poor survival. Furthermore, increased LDH levels could identify subgroups of patients within ISS-2 and ISS-3 with even worse outcome. CONCLUSION: We conclude that serum LDH is a simple, inexpensive, and readily available blood test that may be included among the variables that define very-high-risk MM.

Short progression-free survival predicts for poor overall survival in older patients with multiple myeloma treated upfront with novel agent-based therapy.

OBJECTIVES: To assess the importance of the quality of response and of early relapse in unselected elderly patients with myeloma treated upfront with novel agents. METHODS: We analyzed 135 unselected transplant-ineligible patients older than 65 yr who were treated upfront with novel agent-based regimens in a single center. RESULTS: On intent to treat, 81% of patients achieved a response (28% sCR/CR, 23% VGPR, and 30% PR). Median progression-free survival (PFS) for patients who achieved sCR/CR was 31 vs. 20 months for VGPR and 23 months for PR (P = 0.048). Median overall survival (OS) for patients with sCR/CR was 62 months, 53 months for VGPR and 38 months for patients with PR (P = 0.028). Early relapse (PFS < 12 months) was more common in patients with PR (39% vs. 21% for VGPR vs. 3% for sCR/CR). Patients who relapsed or progressed < 12 months from initiation of treatment had a median OS of 15.4 months compared with 53 months (P < 0.001) for patients who had a PFS > 12 months despite the fact that after relapse or progression most patients were treated again with novel agents. In multivariate analysis, short PFS was the most significant adverse prognostic factor affecting OS, associated with a 7.25-fold (P < 0.0001) increase in the risk of death. CONCLUSION: In newly diagnosed patients over 65 yr, treated upfront with novel agents achievement of CR and a PFS ≥ 12 months is associated with improved outcome. Patients who fail to respond or experience early relapse after primary therapy with novel agent-based regimens should be encouraged to participate in clinical trials of novel agents and combinations.

Prognostication of the high-risk WM patient.

Waldenström's macroglobulinemia is characterized by a protracted course in most patients and the median survival may be long. However, a subset of patients may present with more aggressive disease that is associated with short survival. In order to better characterize these "poor-risk" patients, we identified patients who died within 2 years from the initiation of front-line treatment. These patients were older and had more often features of aggressive disease, such as elevated LDH and low serum albumin than the standard-risk population. Furthermore, only a minority of poor-risk patient had a response to initial therapy. However, conventional clinical factors or even the lack on response could not adequately identify poor-risk patients, indicating the need for novel molecular or other markers that would be able to effectively recognize patients at greatest need for aggressive therapies.

No significant improvement in the outcome of patients with Waldenström's macroglobulinemia treated over the last 25 years.

The treatment of Waldenström's macroglobulinemia (WM) has changed over the last decades, mainly because of the introduction of nucleoside analogues and of rituximab while novel agents such as bortezomib have been recently introduced. We performed an analysis to investigate whether the outcome of patients with WM has improved over the last years, compared to that of patients who started treatment before new drugs became widely available, especially as part of the frontline treatment. We analyzed 345 symptomatic patients with WM: 130 who initiated treatment before and 215 who started treatment after January 1, 2000. Patients who started treatment in the latter group were older and had more often elevated beta2-microglobulin but the other characteristics were similar between the two groups. Most patients who started treatment before January 1, 2000 were treated upfront with alkylating agent-based regimens and most patients who started treatment after January 1, 2000 received rituximab-based regimens as initial treatment. Objective response (63 and 59%, respectively) and median overall survival, OS, (106.5 months for Group A and is estimated at 94 months for Group B, P = 0.327) were similar. There was also no difference regarding OS or cause specific survival (CSS) in each risk group according to IPSSWM. Our observation may be explained by the indolent course of WM in several patients and by the lack of profound cytoreduction in patients with high-risk disease. Possible differences in the 15- or 20-year survival rate between the two groups may be detected with further follow-up of these patients.

Reversibility of renal failure in newly diagnosed patients with multiple myeloma and the role of novel agents.

The purpose of this analysis was to assess the effect of novel agent-based regimens on the improvement of renal impairment (RI) in newly diagnosed patients with multiple myeloma. Ninety-six consecutive patients with RI received conventional chemotherapy (CC)-based regimens (n=32), IMiDs-based regimens (n=47) or bortezomib-based regimens (n=17) as frontline therapy. Improvement of RI was more frequent in patients treated with novel agents (79% in IMiD- and 94% in bortezomib-treated groups versus 59% in CC-treated group; p=0.02). Bortezomib-based regimens and CrCl>30 ml/min at baseline independently correlated with a higher probability of at least renal partial response (PRrenal) and with a shorter time to PRrenal or better. Thus bortezomib-based regimens may be the preferred treatment for newly diagnosed myeloma patients with RI.

Validation of the International Prognostic Scoring System (IPSS) for Waldenstrom's macroglobulinemia (WM) and the importance of serum lactate dehydrogenase (LDH).

The recently proposed, ISSWM staging system for symptomatic patients with WM was based on patients treated with alkylating agents and nucleoside analogs and has not been externally validated nor has been validated for cause-specific survival (CSS). We independently validated ISSWM both for overall survival (OS) and for CSS and assessed whether addition of elevated serum LDH may add to the strength of ISSWM in 335 patients treated upfront mainly with alkylating agents (43%), and rituximab-based therapies (47%). ISSWM could discriminate three groups with significantly different OS and CSS (p<0.01 for both). High serum LDH was predictive of shorter OS and CSS (p<0.01). The combination of high risk according to ISSWM and elevated serum LDH identified a subset of patients for whom innovative treatment approaches are needed.

Prechemotherapy serum levels of CD105, transforming growth factor beta2, and vascular endothelial growth factor are associated with prognosis in patients with advanced epithelial ovarian cancer treated with cytoreductive surgery and platinum-based chemotherapy.

BACKGROUND: Serum CD105 has been associated with angiogenic activity in cancer, and low CD105 expression has been associated with improved prognosis. The present study evaluated the prognostic significance of serum levels of CD105 and related factors in patients with epithelial ovarian cancer (EOC) after cytoreductive surgery and chemotherapy. PATIENTS AND METHODS: Eighty-six patients with stages IIC to IV EOC treated postoperatively with platinum-based chemotherapy were included. The enzyme-linked immunosorbent assay was used to measure prechemotherapy serum levels of CD105, transforming growth factor beta1/2 (TGF-beta1/2), angiopoietin 2, vascular endothelial growth factor, and tumor necrosis factor-alpha. RESULTS: High levels of TGF-beta2 (>8908.86 pg/mL) and CD105 (>4.25 ng/mL) were independently associated with improved overall survival (not reached vs 39 months, P = 0.009 and 75 vs 39 months, P = 0.029, respectively), whereas a high level of TGF-beta2 and a low level of vascular endothelial growth factor (<219.04 pg/mL) were independently associated with improved progression-free survival (49 vs 17 months, P = 0.022 and 57 vs 16 months, P = 0.023, respectively). Among patients with favorable (>4.25 ng/mL) CD105 levels, only patients with low TGF-beta1 levels (<177.1 ng/mL) had superior survival than patients with low CD105 levels. CONCLUSIONS: Our study confirms the prognostic significance of angiogenesis in EOC and supports a biological interaction between CD105 and TGF-beta1. High angiogenic activity may be associated by increased efficacy of postoperative chemotherapy.

Prognostication in young and old patients with Waldenström's macroglobulinemia: importance of the International Prognostic Scoring System and of serum lactate dehydrogenase.

We analyzed 232 patients with previously untreated, symptomatic WM, of whom 10% were < or = 50 years of age and 21% were > 75 years of age. Disease features and response to treatment were similar among age groups. Patients > 75 years of age had significantly shorter survival (OS; 53 months vs. 113 months for those > 50-75 years vs. not reached for patients < or = 50 years of age; P < .001). Despite the fact that 33% of elderly patients died of causes unrelated to WM, disease-specific survival (DSS) was 72 months for patients > 75 years, 120 months for those > 50-75 years and not reached for patients < or = 50 years (P = .001). International Prognostic Scoring System for WM (IPSSWM) could discriminate 3 risk groups with significantly different OS or DSS. The addition of elevated serum lactate dehydrogenase in the IPSS improved the ability of IPSS to identify a group of patients with a significantly worse outcome (median survival, 55 months).

Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide.

PURPOSE: Alkylating agents and the anti-CD20 monoclonal antibody rituximab are among appropriate choices for the primary treatment of symptomatic patients with Waldenström macroglobulinemia (WM), and they induce at least a partial response in 30% to 50% of patients. To improve these results, we designed a phase II study that included previously untreated symptomatic patients with WM who received a combination of dexamethasone, rituximab, and cyclophosphamide (DRC). PATIENTS AND METHODS: Seventy-two patients were treated with dexamethasone 20 mg intravenously followed by rituximab 375 mg/m2 intravenously on day 1 and cyclophosphamide 100 mg/m2 orally bid on days 1 to 5 (total dose, 1,000 mg/m2). This regimen was repeated every 21 days for 6 months. Patients' median age was 69 years and many had features of advanced disease such as anemia (57%), hypoalbuminemia (40%), and elevated serum beta2-microglobulin (43%). RESULTS: On an intent-to-treat basis, 83% of patients (95% CI, 73% to 91%) achieved a response, including 7% complete, 67% partial, and 9% minor responses. The median time to response was 4.1 months. The 2-year progression-free survival rate for all patients was 67%; for patients who responded to DRC, it was 80%. The 2-year disease-specific survival rate was 90%. Treatment with DRC was well tolerated, with 9% of patients experiencing grade 3 or 4 neutropenia and approximately 20% of patients experiencing some form of toxicity related to rituximab. CONCLUSION: Our large, multicenter trial showed that the non-stem-cell toxic DRC regimen is an active, well-tolerated treatment for symptomatic patients with WM.

Reversibility of renal failure in newly diagnosed multiple myeloma patients treated with high dose dexamethasone-containing regimens and the impact of novel agents.

The impact of high dose dexamethasone containing regimens with or without the novel agents thalidomide and bortezomib on the reversal of renal failure (RF) was evaluated in 41 consecutive newly diagnosed patients with multiple myeloma (MM) treated in a single institution. RF was reversed in 73% of all patients within a median of 1.9 months. In patients treated with dexamethasone and novel agents (thalidomide and/or bortezomib) the reversibility rate was 80% within a median of 0.8 months. Severe RF and significant Bence Jones proteinuria were associated with a lower probability of RF reversal. Patients who responded to treatment achieved RF reversal more often than in those who did not (85% versus 56%, p=0.046). In conclusion, RF is reversible in the majority of newly diagnosed MM patients treated with high-dose dexamethasone containing regimens. The addition of novel agents induces a more rapid RF reversal.

Advanced epithelial ovarian cancer in the elderly: chemotherapy tolerance and outcome.

BACKGROUND: The prognostic significance of age in ovarian cancer has not been clarified. We investigated the characteristics of ovarian cancer presenting in ages > 70 years and assessed the prognostic significance of advanced age. PATIENTS AND METHODS: Four hundred and fifty-three patients with stage IIC-IV ovarian cancer (age>70 years n=106 [23%]), treated postoperatively with platinum-based chemotherapy were retrospectively reviewed. RESULTS: Median overall survival (OS) of patients 570 years old (52.3 months, 95% CI: 43.2-61.3) was longer than that of older patients (38.8 months, 95% CI: 29.9-47.7) (p =0.005), but this difference was not significant in a multivariate analysis (p=0.978). Age >70 years was correlated with worse performance status (PS) (p=0.019), higher tumor grade (p=0.033), residual disease >2 cm (p=0.006) and less frequent paclitaxel administration (p<0.001). Toxicity from chemotherapy was similar between the two age groups, but the relative dose intensity of paclitaxel was lower among elderly patients. CONCLUSION: The worse outcome of ovarian cancer in elderly patients may be attributed to other associated adverse prognostic factors, but advanced age was not an independent prognostic factor.