Significant improvement in the survival of patients with multiple myeloma presenting with severe renal impairment after the introduction of novel agents

BackgroundRenal impairment (RI) is a common presenting complication of multiple myeloma (MM); the availability of new treatments has improved the outcomes of patients with MM; however, their impact on the survival of patients who present with RI has not been extensively studied.Patients and methodsWe analyzed the characteristics and outcomes of 1773 consecutive unselected patients who were treated for symptomatic myeloma since January 1990.ResultsAlthough there was a significant increase in the proportion of patients of advanced age in the more recent periods, the frequency of RI as well as the proportion of patients who presented with severe RI (eGFR < 30 ml/min/1.73 m²) remained unchanged around 18%. Thus, after adjustment for age, there was a decrease in the risk of severe RI at presentation after 2000. Myeloma response rates (≥PR) to frontline therapy have substantially increased, and this was translated in a significant increase in the median survival. Specifically for patients with severe RI, the median OS has improved from 18 and 19.5 months in the 1990–1994 and 1995–1999 to 29 and 32 months for the periods 2000–2004 and after 2005 (P = 0.005). Severe RI was associated with a high risk of early death (12% versus 7% for patients with moderate RI versus 3% for patients with mild or no RI (P < 0.001), especially among older patients, and has remained unchanged over time.ConclusionsThere has been a major improvement in the survival of patients with severe RI in the past decade, despite the increasing numbers of patients of advanced age. However, the risk of early death remains high in patients with severe RI, especially in the elderly.     

Efficacy, safety and quality-of-life associated with lenalidomide plus dexamethasone for the treatment of relapsed or refractory multiple myeloma: the Spanish experience

Here we report the efficacy, safety and health-related quality-of-life (HRQoL) associated with long-term lenalidomide and dexamethasone (Len + Dex) treatment in patients with relapsed or refractory multiple myeloma (RRMM) enrolled in the Spanish cohort of the MM-018 study. In this open-label, multicenter, single-arm expanded access study, 63 patients received Len + Dex until disease progression. The overall response rate was 78%, with 21% of the patients achieving a complete response. The quality of response improved with continuous treatment. The median duration of response was 18.4 months. Median time-to-progression and progression-free survival was 13.3 months for both; median overall survival was not reached. Len + Dex had a manageable safety profile consistent with previously reported phase III studies. HRQoL assessments (n = 42) at baseline and 6 months using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ MY-20 questionnaires revealed that patients with RRMM treated with long-term lenalidomide reported clinically relevant improvements in certain QoL and symptoms scores regardless of treatment response (ClinicalTrials.gov: NCT00420849).     

The efficacy and safety of lenalidomide plus dexamethasone in relapsed and/or refractory multiple myeloma patients with impaired renal function

BACKGROUND:

In patients with multiple myeloma, renal impairment (RI) at the time of diagnosis is associated with poor survival. To the authors' knowledge, the current retrospective analysis presented is the first to assess the impact of various degrees of renal dysfunction on safety and efficacy outcomes in a large cohort of patients with relapsed and/or refractory multiple myeloma who received treatment with lenalidomide plus dexamethasone.

METHODS:

Three hundred fifty‐three patients from 2 large phase 3 trials were randomized to receive lenalidomide (25 mg) plus dexamethasone (40 mg). For the purpose of this analysis, RI was defined according to the calculated creatinine clearance (CL_Cr) level as follows: mild or no RI (CL_Cr ≥ 60 mL/minute), moderate RI (CL_Cr from ≥ 30 mL/minute to <60 mL/minute), and severe RI (CL_Cr <30 mL/minute).

RESULTS:

The RI subgroups did not differ significantly in terms of the overall response rate (range, 50%‐64%) or response quality (very good partial response or better, 27%‐37%). In all RI subgroups, the time to progression and progression‐free survival did not differ significantly compared with the mild or no RI group. Patients with RI experienced an increased incidence of thrombocytopenia, required more frequent lenalidomide dose reduction or interruption, and had shorter overall survival than patients with mild or no RI (P = .006). Lenalidomide plus dexamethasone led to improvement in renal function in the majority of patients.

CONCLUSIONS:

The results from this study indicated that, with careful monitoring of the CL_Cr level and adverse events as well as appropriate dose adjustments, lenalidomide plus dexamethasone is an effective and well tolerated treatment option for patients with multiple myeloma who have RI. Cancer 2010. © 2010 American Cancer Society.     

Renal Impairment at Diagnosis in Myeloma: Patient Characteristics,Treatment, and Impact on Outcomes. Results From the Australia and New Zealand Myeloma and Related Diseases Registry

BackgroundRenal impairment (RI) is a common complication of multiple myeloma (MM) and remains a poor prognostic factor despite improved survival with newer therapies.Patients and MethodsWe evaluated baseline characteristics, treatment, and outcomes of newly diagnosed MM patients with RI at diagnosis in the Australia and New Zealand Myeloma and Related Diseases Registry over 5 years to April 2018; we compared patients with RI (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m²) with those with eGFR ≥60. In autologous stem cell transplantation (ASCT) analyses, patients aged 70 years and younger and ≥1 year from diagnosis were included.ResultsOverall, 36% of patients with newly diagnosed MM had RI; they were older, had more advanced disease and comorbidities, and worse performance status. Bortezomib-based induction therapy was most commonly used, although administered to fewer RI patients, despite similar response rates. Patients with RI were less likely to receive ASCT; however, recipients had longer progression-free survival (PFS) and overall survival (OS). Patients with RI had shorter OS and PFS after adjusting for age. In ASCT recipients with RI versus no RI, there was no difference in PFS and OS.ConclusionOur findings in “real world” MM patients with RI confirm that patient-, disease-, and treatment-related factors (such as suboptimal bortezomib and ASCT use), and delays in commencing therapy, might contribute to poorer outcomes, and support the use of ASCT in patients with RI.     

Lower dose dexamethasone/thalidomide and zoledronic acid every 3 weeks in previously untreated multiple myeloma

BackgroundPhysicians in Asia have anecdotally reported that Asian patients with multiple myeloma (MM) are frequently intolerant of conventional doses of dexamethasone (Dex) and/or thalidomide (Thal). Since zoledronic acid (Zol) has an anti-MM effect in preclinical studies, we investigated whether the approved 3-times-weekly Zol combined with lower dose Dex/Thal could be an effective and better tolerated regimen in Asian patients.Patients and MethodsIn this first Asian cooperative multicenter phase II study, previously untreated patients with MM (N = 44) received up to 6 cycles of 3-times-weekly low-dose Dex/Thal and 4 mg Zol (the dtZ regimen). Response was graded using Bladé criteria.ResultsThe average doses of Dex and Thal administered were 185.2 mg/month; and 87.5 mg/day, respectively. Thirty-nine (88.6%) patients demonstrated at least a partial response (PR), including 18.2% very good partial response (VGPR), 15.9% near complete response (nCR) and 18.2% complete response (CR). Achievement of CR/nCR was related to significant (P < .05), rapid, and sustained inhibition of osteoclasts (OCs) and OC precursors (pOCs) by Zol. Sepsis was the most frequently reported serious toxicity, contributing to 3 of 4 deaths. Importantly, there was no peripheral neuropathy, osteonecrosis of the jaw, or nephrotoxicity.ConclusionWe conclude that the dtZ regimen is an effective and well-tolerated regimen for Asian patients with newly diagnosed MM. The high rate of VGPR/nCR/CR suggests that Zol could have a clinically relevant anti-MM effect. Since infections are the most frequent adverse event, it is probably wise to further lower the dose of Dex in future studies.     

The International Scoring System (ISS) for multiple myeloma remains a robust prognostic tool independently of patients’ renal function

BackgroundThe International Staging System (ISS) is the most widely used staging system for patients with multiple myeloma (MM). However, serum β2-microglobulin increases in renal impairment (RI) and there have been concerns that ISS-3 stage may include ‘up-staged’ MM patients in whom elevated β2-microglobulin reflects the degree of renal dysfunction rather than tumor load.Patients and methodsIn order to assess the impact of RI on the prognostic value of ISS, we analyzed 1516 patients with symptomatic MM and the degree of RI was classified according to the Kidney Disease Outcomes Quality Initiative-Chronic Kidney Disease (CKD) criteria.ResultsForty-eight percent patients had stages 3–5 CKD while 29% of patients had ISS-1, 38% had ISS-2 and 33% ISS-3. The frequency and severity of RI were more common in ISS-3 patients. RI was associated with inferior survival in univariate but not in multivariate analysis. When analyzed separately, ISS-1 and ISS-2 patients with RI had inferior survival in univariate but not in multivariate analysis. In ISS-3 MM patients, RI had no prognostic impact either in univariate or multivariate analysis. Results were similar, when we analyzed only patients with Bence-Jones >200 mg/day.ConclusionsISS remains unaffected by the degree of RI, even in patients with ISS-3, which includes most patients with renal dysfunction.     

Phase I Trial of Vorinostat Combined With Bortezomib for the Treatment of Relapsing and/or Refractory Multiple Myeloma

BackgroundDevelopment of targeted therapies for MM has improved response rates and increased patient survival, but ultimately the disease becomes refractory and progresses. Vorinostat combined with bortezomib has demonstrated synergistic antiproliferative and proapoptotic activity in preclinical models of MM. The objectives of this study were to determine the maximum tolerated dose for vorinostat with bortezomib in patients with advanced MM and to evaluate the clinical benefit of this new drug combination.Patients and MethodsPatients ≥ 18 years old with relapsed and/or refractory MM were enrolled into escalating dose cohorts of vorinostat and bortezomib combination therapy. Thirty-four patients were enrolled and were evaluable for safety and efficacy analyses.ResultsAll patients reported adverse events, 89% of which were mild to moderate in severity. Thirteen patients experienced 29 serious adverse events, 12 (41%) of which were considered drug-related. The maximum tolerated dose was not reached. Partial responses were observed in 9 (27%) patients. Minimal responses were observed in 2 additional patients (6%), and another 20 patients (59%) experienced disease stabilization.ConclusionVorinostat with bortezomib is generally well-tolerated and has clinical activity in patients with relapsed and/or refractory MM. Response rates were similar in patients previously exposed to bortezomib and patients who were naive to bortezomib therapy.     

雷利度胺为主方案治疗多发性骨髓瘤25例疗效分析

 目的　观察雷利度胺为主方案治疗多发性骨髓瘤（MM）患者的疗效及不良反应。方法　MM患者25例,其中5例为初治患者,13例为含沙利度胺方案治疗后难治、复发患者,7例为治疗后达平台期维持治疗患者。初治MM患者均采用R-PAD方案,难治、复发患者选用R-MD方案,维持治疗MM患者由于出现Ⅱ级伴疼痛以上的周围神经炎（PN）,采用雷利度胺单药治疗。结果　初治组5例,经过2个疗程的治疗均达到完全缓解（CR）（100 %）;难治、复发组13例,CR率为23.08 %（3／13）,非常好的部分缓解（VGPR）率为15.38 %（2／13）,部分缓解（PR）率为38.46 %（5／13）,总反应率（ORR）为76.92 %（10／13）;其余3例无反应患者中,2例疾病稳定（SD）,1例疾病进展（PD）。维持治疗组7例在平均38周的随访期内均维持缓解;改用雷利度胺后,PN获得不同程度的缓解。结论　对于初治MM患者,R-PAD方案缓解率高,起效快;对于难治、复发患者,特别是伴严重PN的MM患者,R-MD是值得选择的方案;雷利度胺还可用于伴PN的MM患者的维持治疗。     

Treatment with mogamulizumab or lenalidomide for relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation: The Nagasaki transplant group experience

Mogamulizumab (Mog) and lenalidomide (Len) are new therapeutic candidates for relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present study, we retrospectively analyzed 12 patients who received Mog or Len monotherapy for relapsed ATL after allo-HSCT. Eight and three patients received Mog and Len, respectively. The remaining patient received Mog for the first relapse and Len for the third relapse. A complete response was achieved by three and two patients who received Mog and Len, respectively, two and one of whom remained alive with a complete response for more than 20 months. In terms of adverse events, the emergence or progression of graft-versus-host disease was observed in three out of four patients treated with Len and in none of the patients treated with Mog. The development or progression of cytomegalovirus reactivation was detected in four out of eight patients treated with Mog and in none of those treated with Len. The present results suggest that Mog and Len would be promising treatment options for relapsed ATL after allo-HSCT and need to be selected based on adverse event profiles.     

Sunitinib and sorafenib in metastatic renal cell carcinoma patients with renal insufficiency

BackgroundAlthough clinical trials with sunitinib and sorafenib in metastatic renal cell carcinoma (mRCC) have included patients with moderate renal insufficiency (RI), the incidence of renal toxicity induced by their administration as well as the safety of these agents in patients with more severe renal insufficiency has not been extensively reported.Patients and methods: Patients with mRCC treated with vascular endothelial growth factor-targeted therapy with either RI at time of treatment initiation or who developed RI during therapy were identified. RI was defined as serum creatinine (Cr) ≥ 1.9 mg/dl or a creatinine clearance (CrCl) < 60 ml/min/1.73 m² for >3 months before treatment. Objective outcomes and toxic effects of treatment were also measured.ResultsA total of 39 patients were identified: 21 patients who initiated therapy with preexisting RI and 18 patients who developed RI during treatment. In patients with RI at the start of therapy, Cr increased in 57%, and 48% of patients required dose reduction. The median time to maximum RI was 6.6 months (range 0.4–19.6 months). In patients who developed RI while receiving therapy, median serum Cr and CrCl at the start of therapy were 1.5 mg/dl (range 1.1–1.8) and 61 ml/min (range 43–105), respectively. Patients experienced a median increase in serum Cr of 0.8 mg/dl (range 0.3–2.8) and a median decrease in CrCl of 25 ml/min (range 8.54–64.76). Overall, 5 patients (24%) achieved a partial response (PR), 13 (62%) had stable disease (SD) and 3 (14%) had progressive disease (PD). Estimated progression-free survival (PFS) was 8.4 months. The most common toxic effects (all grades) were fatigue (81%), hand–foot syndrome (HFS) (52%) and diarrhea (48%). Six patients experienced grade III toxicity (29%), primarily HFS.Conclusions: Sunitinib and sorafenib can be safely given to patients with renal insufficiency, provided adequate monitoring of renal function. For those patients developing an increase in Cr, dose modifications may be required to allow continuation of therapy. The clinical outcome of patients with baseline renal dysfunction and patients who develop renal dysfunction does not appear to be compromised.     

Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study.

PURPOSE: Temozolomide is a well-tolerated oral alkylating agent with activity in the CNS. A multicenter, open-label, phase II study was conducted to assess the safety and efficacy of temozolomide in patients with brain metastases from metastatic melanoma (MM) who did not require immediate radiotherapy. PATIENTS AND METHODS: Eligible patients had histologically confirmed MM to the brain, and no prior radiotherapy or radiosurgery for brain metastases. Previously untreated patients received temozolomide at 200 mg/m(2)/d x 5 days; previously treated patients received 150 mg/m(2)/d x 5 days every 28 days. Treatment continued for 1 year or until disease progression or unacceptable toxicity. RESULTS: Of 151 patients enrolled, 117 had received no prior systemic chemotherapy, and 34 had received prior chemotherapy for MM. Among previously untreated patients, 25% had more than four brain lesions, eight (7%) achieved an objective response (one complete and seven partial), and 34 (29%) had stable disease in brain metastases. Median overall survival was 3.5 months. Among previously treated patients, 21% had more than four brain lesions, one had a partial response, and six (18%) had stable disease in brain metastases. Median overall survival was 2.2 months. Temozolomide was well tolerated, with four (3%) patients discontinuing because of adverse events. Grade 3/4 hematologic toxicities included thrombocytopenia (3%), neutropenia (2%), and leukopenia (1%). Headache (9%) and vomiting (8%) were the most common nonhematologic grade 3/4 adverse events. CONCLUSION: Temozolomide was well tolerated and demonstrated activity in the treatment of brain metastases from MM. Further evaluation of temozolomide combination therapy is warranted.     

Rational combination treatment with histone deacetylase inhibitors and immunomodulatory drugs in multiple myeloma

Immunomodulatory drugs (IMiDs) thalidomide, lenalidomide (Len) and pomalidomide trigger anti-tumor activities in multiple myeloma (MM) by targetting cereblon and thereby impacting IZF1/3, c-Myc and IRF4. Histone deacetylase inhibitors (HDACi) also downregulate c-Myc. We therefore determined whether IMiDs with HDACi trigger significant MM cell growth inhibition by inhibiting or downregulating c-Myc. Combination treatment of Len with non-selective HDACi suberoylanilide hydroxamic acid or class-I HDAC-selective inhibitor MS275 induces synergic cytotoxicity, associated with downregulation of c-Myc. Unexpectedly, we observed that decreased levels of cereblon (CRBN), a primary target protein of IMiDs, was triggered by these agents. Indeed, sequential treatment of MM cells with MS275 followed by Len shows less efficacy than simultaneous treatment with this combination. Importantly ACY1215, an HDAC6 inhibitor with minimal effects on class-I HDACs, together with Len induces synergistic MM cytotoxicity without alteration of CRBN expression. Our results showed that only modest class-I HDAC inhibition is able to induce synergistic MM cytotoxicity in combination with Len. These studies may provide the framework for utilizing HDACi in combination with Len to both avoid CRBN downregulation and enhance anti-MM activities.     

Prognostic risk factor evaluation in patients with relapsed or refractory multiple myeloma receiving lenalidomide treatment: analysis of renal function by eGFR and of additional comorbidities by comorbidity appraisal

IntroductionRenal impairment (RI) is a dreaded complication in multiple myeloma (MM) and has been associated with decreased progression-free survival (PFS) and overall survival (OS).MethodsForty-five consecutive patients with MM received lenalidomide therapy combined with either dexamethasone or standard chemotherapy, with dose modification according to current guidelines. Comorbidity indices (hematopoietic cell transplantation–specific comorbidity index [HCT-CI], Kaplan Feinstein [KF], and the Freiburg comorbidity index [FCI]) were analyzed and renal function was determined by estimated glomerular filtration rate (eGFR) before lenalidomide treatment and 1, 3, and 6 months after treatment.ResultsThe median patient age was 66 years. Pretreatment was substantial with ≥ 2 treatment lines in 71% of patients. Lenalidomide induced median PFS and OS of 13 and 25 months, respectively. The analysis of comorbidity scores identified only the FCI as significant, with different PFS for low-risk vs. high-risk patients of 20 vs. 9 months (p = .0036) and OS of not reached vs. 12.8 months (p < .0001), respectively. Although baseline renal function by serum creatinine evaluation appeared normal (median 1.0 mg/dL), mild RI was readily detectable by eGFR (median 83 mL/min/1.73 m²). When patients without RI were compared with those with mild, moderate, and severe RI, 1- and 2-year PFS rates were similar (hazard ratio [HR] with decreasing eGFR, 1.028; p = .6927). For OS, the HR of 1.192 indicated decreased survival probabilities with deteriorating eGFR (p = .0411), which was perceived by eGFR but not serum creatinine assessment (p = .2253).ConclusionsLenalidomide was well tolerated in intensively pretreated and elderly MM patients, including those with RI. PFS was not significantly different in patients with decreasing eGFRs, albeit RI and other comorbidities remained significant for OS.     

Occurrence of primary cancers in association with multiple myeloma and Kaposi's sarcoma in the United States, 1973-1995

The causes of multiple myeloma (MM) are obscure, but a laboratory association was recently reported between MM and human herpesvirus 8 (HHV-8), the probable etiologic agent of Kaposi's sarcoma (KS). Although there has been some additional laboratory corroboration, most laboratory studies have found no association between MM and HHV-8. We looked for indirect evidence of an HHV-8/MM association by evaluating whether MM is associated with KS in the United States. Cancer incidence and survival data were obtained from the Surveillance, Epidemiology, and End Results (SEER) program for the years 1973-1995. Strength of association was assessed for a number of cancer pairs using standardized incidence ratios (SIRs) (observed/expected double cancers). KS was strongly associated (SIR > 15) with non-Hodgkin's lymphoma and anal cancer, was modestly associated (2.5 < SIR < 5.5) with MM, Hodgkin's disease, and testicular cancer and was not significantly associated with 6 other cancers. Besides being associated with KS, MM was weakly associated (1.7 < SIR < 2.3) with Hodgkin's disease and testicular cancer. The SIRs for 7 other cancers paired with MM were all less than 1.6. Factors that might be responsible for the KS/MM association include MM-related immune dysfunction, HIV and HHV-8, but the role of these factors cannot be directly assessed through the SEER database. Although we cannot rule out the possibility that HHV-8 is linked to a small proportion of MM cases, the modest KS/MM association is evidence that the vast majority of MM cases are not likely to be associated with HHV-8.     

硼替佐米联合地塞米松治疗24例多发性骨髓瘤的疗效分析

背景及目的:硼替佐米(bortezomib)是一种有效、可逆性的蛋白酶体抑制剂,通过诱导骨髓瘤细胞的凋亡,在骨髓瘤患者的治疗中发挥持久的疗效。本研究旨在观察硼替佐米联合地塞米松治疗初治、难治/复发多发性骨髓瘤(multiple myeloma,MM)患者的疗效和毒副作用,及该方案在肾功能不全患者中应用的安全性。方法:24例MM患者接受硼替佐米联合地塞米松方案治疗,每3周为一个疗程。所有患者共接受中位3个疗程(1～8个疗程)的化疗。采用EBMT疗效评价标准评价疗效,按国立癌症研究所的常规毒性判定标准评价不良反应。结果:全组中位随访4个月,总有效率79.2%(19/24)。轻链型患者CR率57.1%(4/7),明显高于非轻链型患者5.9%(1/17),差异有统计学意义(P=0.014)。7例合并肾功能不全的患者与肾功能正常患者的疗效相近,差异无统计学意义(P=0.272)。Ⅲ～Ⅳ级不良反应包括白细胞减少(2/24,8.3%)、血小板减少(8/24,33.3%)、腹泻(2/24,8.3%)和乏力(1/24,4.2%),经对症治疗或推迟化疗后均可恢复。结论:硼替佐米联合地塞米松方案治疗MM患者有明显疗效,在轻链型患者疗效更加显著。副作用可以耐受,在合并肾功能不全的患者可安全应用。     

Bortezomib and Dexamethasone Therapy for Newly Diagnosed Patients With Multiple Myeloma Complicated by Renal Impairment

BackgroundRenal impairment is a common complication of multiple myeloma (MM) and is related to shorter overall survival and increased rates of early death. Bortezomib is a new agent for the treatment of patients with myeloma, with high response rates and controllable side effects. In this study, we will evaluate the efficacy and safety of bortezomib and dexamethasone in patients with newly diagnosed MM complicated by renal impairment.Patients and MethodsThis is a prospective study of the general characteristics, reversibility of renal impairment, response of myeloma, and side effects of 18 consecutive newly diagnosed patients with MM and renal impairment who received ≥ 2 cycles of bortezomib and dexamethasone.ResultsOf 18 patients newly diagnosed with MM, the median age was 60 years, and the median serum creatinine was 5.3 mg/dL. Patients received a median of 4 cycles of bortezomib and dexamethasone. Reversal of renal impairment was documented in 38.9% of the patients, and the median time to reversal was 16 days. Moreover, 33.3% of the patients achieved renal response (a 50% decrease in serum creatinine). The overall response rate of MM was 83.3%, including a 33.3% complete response (CR) rate, a 16.7% near-CR rate, a 16.7% very good partial response (PR) rate, and a 16.7% PR rate. Grade 3/4 adverse events consisted of infection (n = 3), peripheral neuropathy (n = 3), and ileus (n = 1). After a median follow-up of 15.7 months, the median progression-free survival for all patients was 12.6 months.ConclusionBortezomib plus dexamethasone is a safe and effective regimen for newly diagnosed patients with MM complicated by renal impairment.     

Percentage of urinary albumin excretion and serum-free light-chain reduction are important determinants of renal response in myeloma patients with moderate to severe renal impairment

Reversal of renal dysfunction significantly affects the prognosis of multiple myeloma (MM) with renal impairment (RI). There is no reliable test for predicting reversibility of RI in MM patients. We postulated that MM with high albuminuria may reflect glomerular disease that is difficult to reverse. Here, we examined the impact of urinary albumin excretion. We retrospectively analyzed 279 patients admitted to our hospital from April 2000 to December 2013. Clinical variables and laboratory data that may affect myeloma treatment response were extracted. The results were examined for relationship to renal response by univariate and multivariate analysis. RI (estimated glomerular filtration rate ≦50 ml/min per 1.73 m²) was observed in 116 patients (46%) and renal responses of renal complete response, renal partial response, renal minor response and no response were obtained in 46 (40%), 15 (13%), 13 (11%) and 42 (36%) patients, respectively. Although renal recovery was significantly associated with Durie–Salmon 1 or 2 (P=0.02), myeloma response better than very good partial response (P=0.03), involved free light-chain (iFLC) reduction from baseline 80% at day 12 (P=0.005), ≧95% at day 21 (P<0.001) and urinary albumin ≦25% on admission (P<0.001) on univariate analysis, only reduction of iFLC 95% at day 21 (P=0.015) and urinary albumin ≦25% (P=0.007) remained significant for any renal response. Our observation indicates that increased urinary albumin excretion >25% and reduction of iFLC ≦95% on day 21 were associated with favorable renal recovery in MM patients with RI, and were considered as negative predictors for renal response.Renal impairment (RI) is a major cause of morbidity and mortality in patients with multiple myeloma (MM) and approximately 50 and 20% of patients have RI and acute renal failure depending of its definition.^{1, 2, 3, 4} The presence of RI limits the use of antimyeloma agents and eligibility for stem cell transplantation, and, therefore, places these patients at higher risk for disease progression and myeloma-related complications. RI is also associated with an increased risk of early death,^5,6 although the recent introduction of effective novel agents, such as thalidomide, bortezomib and lenalidomide, has led to the improved survival even in patients with RI.^7,8The most common cause of RI in MM is cast nephropathy, which may be seen in up to 30% of patients;⁹ other causes of RI include monoclonal immunoglobulin (Ig) deposition disease and amyloidosis. It should be noted that non-paraprotein-associated renal lesions are also seen in 25% of patients. As most patients with MM are elderly, age-related comorbidities such as hypertension and diabetes may also be associated with the decline of renal function.As the reversibility of renal function may be dependent on the pathogenesis of renal disease,¹⁰ correct renal pathology is necessary for successful treatment. Use of bortezomib-based regimens in combination with or without plasma exchange has been reported to yield high rates of renal recovery in patients with cast nephropathy.^{11, 12, 13, 14} However, reversibility of renal function in cases other than cast nephropathy is largely unknown. Kidney biopsy cannot be performed in all patients with MM and RI because of its various limitations and possible complications. Recently, Nasr et al.⁹ reported the clinicopathologic correlations in MM patients with kidney biopsy; they reported the highest levels of albuminuria in patients with amyloidosis and lowest levels in those with cast nephropathy.Despite the heterogeneity of renal pathology, urine albuminuria is thought to reflect glomerular injury, and patients with cast nephropathy usually show tubulointerstitial injury and lack heavy albuminuria. Therefore, we postulated that renal response may be different according to urinary albumin excretion. In this study, we retrospectively analyzed the clinical variables that may affect renal response in 116 MM patients with RI at our hospital. We also examined the predictive capacity of urinary albumin and serum-free light-chain (FLC) reduction on renal recovery of RI patients with MM.     

Multiple Myeloma in Hispanics: Incidence,Characteristics, Survival,Results of Discovery,and Validation Using Real-World and Connect MM Registry Data

BackgroundMultiple myeloma (MM) in Hispanics has never been studied. We therefore sought to determine the clinical characteristics and overall survival in MM of Hispanics compared to non-Hispanic whites (NHW) and non-Hispanic blacks (NHB).Patients and MethodsA single-center analysis of 939 patients diagnosed with MM from 2000 to 2017 with a large representation of NHB (n = 489), Hispanics (n = 281), and NHW (n = 169) was conducted to evaluate outcomes and disease characteristics. We used the Connect MM Registry, a large US multicenter prospective observational study with newly diagnosed MM patients, as a validation cohort.ResultsHispanics had a higher incidence of MM compared to NHW. The median age at presentation was 5 years younger (median, 65 years) in Hispanics compared to NHW (median, 70 years), and patients were more likely to present with renal dysfunction (estimated glomerular filtration rate < 30 mL/min). Hispanics had a higher proportion of Revised International Staging System (R-ISS) stage I disease compared to NHW and NHB (P = .03), while there was no difference in cytogenetics between Hispanics and NHB/NHW. In the multivariate analysis, only high-risk disease and response to first-line therapy significantly affected survival.ConclusionIn this first and largest analysis of MM in Hispanics, we found that Hispanics present at a younger age, have a higher incidence of renal dysfunction, and have low R-ISS stage disease at presentation. With equal access to therapy, Hispanics have survival similar to NHW/NHB.     

Clinical Study of Thalidomide Combined with Dexamethasone for the Treatment of Elderly Patients with Newly Diagnosed Multiple Myeloma

Objective: To investigate the relationship between the efficacy and safety of different doses of thalidomide(Thal) plus dexamethasone (Dex) as the initial therapy in elderly patients with newly diagnosed multiplemyeloma (MM). Methods: Clinical data of 28 elderly patients with newly diagnosed MM who underwent theTD regimen as the initial therapy were analyzed retrospectively. The patients were divided into two groupsaccording to the maximal sustained dose of Thal: lower dose (group A) and higher dose (group B). The overallresponse rate (ORR), progression free survival (PFS), overall survival (OS), and adverse events (AES) werecompared between the two groups. Results: A total of 28 patients were followed up with a median of 18 months.The ORR was 60.1%. The median response time and PFS were 2.0 and 17.0 months, respectively. The meansustained dose of Thal in group B was significantly higher than group A (292.9 mg v 180.4 mg, P=0.01). Therewas no significantly difference in ORR (57.1% v 64.3%, P=1.00) and PFS (9.63months v 17.66 months, P=0.73)between groups A and B. During the follow up, only five patients died (<40%) and, therefore, median OS valueswere not available. It is estimated, however, that the mean survival time in the two groups was 35.6 and 33.4months (P>0.05), respectively. All of the patients tolerated the treatment well. The incidence of AES in patientswith a grading above 3 in group B was significantly higher than in group A (P=0.033). Conclusions: The TDregimen results in a high response rate and manageable AES as the initial therapy in elderly patients with MM.TD should be considered as the front line regimen for the treatment of elderly patients with MM in areas withfinancial constraints. The clinical response can be achieved at a low dose Thal with minimal toxicity.