Analysis of the Efficacy of Thalidomide Plus Dexamethasone-Based Regimens in Patients With Relapsed/Refractory Multiple Myeloma Who Received Prior Chemotherapy,Including Bortezomib and Lenalidomide: KMM-166 Study

BackgroundFor patients with multiple myeloma (MM) that relapsed after treatment with bortezomib- and lenalidomide-based regimens, there were no other treatment options in Korea until 2016. We aimed to determine the efficacy of thalidomide plus dexamethasone-based regimens in patients with relapsed/refractory MM (RRMM).Patients and MethodsWe conducted a multicenter retrospective analysis in Korea for patients with RRMM treated with thalidomide-based regimens who previously received bortezomib and immunomodulatory agents (IMiDs), including thalidomide and lenalidomide.ResultsIn 47 patients with RRMM, the median age was 64 years and the median number of previous treatment lines, including bortezomib and IMiDs, was 3. Primary resistance to bortezomib and lenalidomide was observed in 12 (26%) and 8 (17%) patients, respectively. The most common regimen was a combination of thalidomide, cyclophosphamide, and dexamethasone. The overall response rate was 38%; 2 patients (4%) experienced a complete response, and 2 patients (4%) experienced a very good partial response. The overall response rate of patients previously exposed to thalidomide was 53%. The median progression-free survival was 5.9 months, and overall survival was 9.2 months. Patients with disease that responded to the thalidomide-based regimen had better progression-free survival compared to those who did not (median, 8.8 vs. 2.5 months; P = .008). The most common adverse events were anemia (51%) for hematologic toxicities and peripheral neuropathy (30%) for nonhematologic toxicities.ConclusionThalidomide-based regimens are potential salvage treatment options for patients with RRMM, even those with disease with prior resistance to IMiDs.     

Lenalidomide and its role in the management of multiple myeloma

Treatment of multiple myeloma has changed in recent years. Advances in the understanding of the pathogenesis of the disease and the mechanism of drug resistance have led to the development of novel effective biological treatment agents such as thalidomide and bortezomib. Lenalidomide is an oral analogue of thalidomide that lacks the neurotoxic side effects associated with the parent drug, and has shown significant antimyeloma activity. Lenalidomide has now been approved by the US FDA and the European Medicines Agency for use in combination with dexamethasone in patients with at least one prior therapy. Several trials are testing lenalidomide-based regimens in both newly diagnosed and relapsed patients. This review summarizes the profile of lenalidomide and its current role in the treatment of multiple myeloma.     

Lenalidomide and its role in the management of multiple myeloma

Treatment of multiple myeloma has changed in recent years. Advances in the understanding of the pathogenesis of the disease and the mechanism of drug resistance have led to the development of novel effective biological treatment agents such as thalidomide and bortezomib. Lenalidomide is an oral analogue of thalidomide that lacks the neurotoxic side effects associated with the parent drug, and has shown significant antimyeloma activity. Lenalidomide has now been approved by the US FDA and the European Medicines Agency for use in combination with dexamethasone in patients with at least one prior therapy. Several trials are testing lenalidomide-based regimens in both newly diagnosed and relapsed patients. This review summarizes the profile of lenalidomide and its current role in the treatment of multiple myeloma.     

Phase II trial of syncopated thalidomide, lenalidomide, and weekly dexamethasone in patients with newly diagnosed multiple myeloma

IntroductionOver the past decade, the novel agents thalidomide, lenalidomide, and bortezomib have emerged as effective treatment in patients with multiple myeloma (MM). Initially used in the relapse setting, these agents have been incorporated into frontline treatment algorithms. They have been combined in doublets with corticosteroids, in triplets with alkylators, or with each other. Because thalidomide and lenalidomide have different clinical activity and toxicity profiles, we designed a trial to evaluate a syncopated schedule of thalidomide and lenalidomide with weekly dexamethasone in patients with newly diagnosed MM to determine response and toxicity.Patients and MethodsTwenty-two patients with newly diagnosed MM were treated with syncopated thalidomide (200 mg on days 1-7 and 15-21), lenalidomide (25 mg on days 8-14 and 22-28 for the first cycle and 50 mg on the same schedule for subsequent cycles) with weekly dexamethasone (40 mg). Each cycle lasted 28 days. MM parameters were assessed at the end of each cycle. It was intended that the patients proceed to stem cell mobilization and autologous transplantation after 4 cycles of therapy.ResultsThe median number of cycles administered was 3.5. The overall response was 68%. The regimen was well tolerated by the majority of the patients; only patient discontinued treatment because of toxicity.ConclusionWe conclude that a syncopated schedule of thalidomide and lenalidomide with weekly dexamethasone was tolerated well, with no unexpected toxicities. However the response rate, even using lenalidomide at 50 mg, was not superior to standard dosing of thalidomide or lenalidomide plus dexamethasone.     

Analysis of Efficacy and Prognostic Factors of Lenalidomide Treatment as Part of a Dutch Compassionate Use Program

Background and Methods:To obtain efficacy and safety data on lenalidomide treatment outside of clinical trials, we analyzed the clinical data of 114 patients with refractory or relapsed multiple myeloma treated with lenalidomide on a compassionate use basis. The recommended treatment consisted of lenalidomide 25 mg given on days 1-21 of a 28-day cycle, in combination with dexamethasone. A median of 3 previous lines of therapy were given, including thalidomide in 91%. Most patients were treated until progression or intolerable toxicity.Results:The median number of cycles was 7 (range, 1-21+ cycles) with a maximum response after a median of 3 cycles (range, 1-10 cycles). The overall response rate was 69%, including complete response in 6%, very good partial response in 19%, and partial response in 44%. The response rate was not influenced by previous thalidomide and/or bortezomib treatment. The median time to progression (TTP) was 9 months and the median overall survival (OS) was 22 months. A significantly longer TTP was observed in patients who previously underwent allogeneic stem cell transplantation (12.5 months vs. 8 months; P = .036). Overall survival was significantly affected by performance status (P < .0001). Lenalidomide toxicity was predominantly hematologic (37%; Common Toxicity Criteria ≥ 3) and the incidence of venous thrombotic events was low (5%) using the recommended prophylaxis.Conclusion:This analysis confirms that, outside clinical prospective trials, treatment with lenalidomide is highly effective and feasible in heavily pretreated patients with multiple myeloma.     

Carfilzomib,lenalidomide and dexamethasone in patients with heavily pretreated multiple myeloma: A phase 1 study in Japan

This is the first study in which the carfilzomib, lenalidomide and dexamethasone (KRd) regimen was evaluated in heavily pretreated multiple myeloma. This study is a multicenter, open‐label phase 1 study of KRd in Japanese patients with relapsed or refractory multiple myeloma (RRMM) patients. The objectives were to evaluate the safety, tolerability, efficacy and pharmacokinetics of the regimen. Carfilzomib was administrated intravenously over 10 min on days 1, 2, 8, 9, 15 and 16 of a 28‐day cycle. In cycle 1, the dosage for days 1 and 2 was 20 mg/m², followed by 27 mg/m². Lenalidomide and dexamethasone were administered at 25 mg (days 1–21) and 40 mg (days 1, 8, 15 and 22), respectively. Twenty‐six patients were enrolled. Patients had received a median of four prior regimens and 88.5% and 61.5% received previous bortezomib and lenalidomide, respectively. High‐risk cytogenetics were seen in 53.8% of patients. The overall response rate was 88.5%. A higher rate of hyperglycemia was observed than in a previous carfilzomib monotherapy study, but this was attributed to dexamethasone. Carfilzomib pharmacokinetics were not affected by lenalidomide and dexamethasone. The KRd regimen was well tolerated and showed efficacy in Japanese RRMM patients.     

High Frequencies of Response After Limited Primary Therapy for Multiple Myeloma

BackgroundRecent bortezomib combinations have induced remission in approximately 90% of patients newly diagnosed, with moderate frequency of adverse effects.PatientsIn an attempt to reduce adverse effects, and to prepare qualified patients for early intensification, we assessed the antimyeloma effect and toxicity of 3 different bortezomib combinations in small numbers of patients.MethodsWith reduced doses and short durations of exposure, we combined bortezomib with (a) cyclophosphamide/dexamethasone, (b) lenalidomide/dexamethasone/liposomal doxorubicin, and (c) cyclophosphamide/dexamethasone/lenalidomide.ResultsResponse rates were high, with rare episodes of severe drug-related toxicity.ConclusionsFurther study of similar combinations of effective drugs given in limited doses and for short durations would be useful.     

Treatment Outcomes in Patients With Newly Diagnosed Multiple Myeloma Who Are Ineligible for Stem-Cell Transplantation: Systematic Review and Network Meta-analysis

Many new regimens have been applied to newly diagnosed transplant-ineligible multiple myeloma, but no head-to-head research has been performed to compare the efficacy of these treatments. Currently lenalidomide plus dexamethasone (Rd) is one of the standard treatments. Our aim was to make a comparison of these treatments to Rd by a network meta-analysis. We performed a systematic review and network meta-analysis. We searched PubMed, Embase, and the Cochrane Library for articles published from January 1, 1988, to April 26, 2018, as well as research presented at 5 international conferences (American Society of Clinical Oncology, American Society of Hematology, European Hematology Association, European Society of Medical Oncology, and International Myeloma Working Group) between January 2015 and December 2018. Our interest outcomes were hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS). Bayesian fixed-effects mixed-treatment comparisons were used for this study. A total of 23 articles describing 10,401 participants were included for this network meta-analysis. Lenalidomide and dexamethasone plus daratumumab (HR, 0.57; 95% credible interval [CrI], 0.43-0.73), daratumumab plus bortezomib, melphalan, and prednisone (HR, 0.59; 95% CrI, 0.36-0.91), and the combination of bortezomib with lenalidomide and dexamethasone (RVd) (HR, 0.72, 95% CrI, 0.56-0.90) all showed significant effect compared to Rd for PFS. RVd demonstrated significant benefit compared to Rd (HR, 0.72; 95% CrI, 0.53-0.96) for OS. Our study results suggested that lenalidomide and dexamethasone plus daratumumab; daratumumab plus bortezomib, melphalan, and prednisone; and RVd showed better efficacy than Rd in PFS; and RVd showed better efficacy than Rd in OS in patients with newly diagnosed transplant-ineligible multiple myeloma in the absence of head-to-head research.     

Randomized Clinical Trial Representativeness and Outcomes in Real-World Patients: Comparison of 6 Hallmark Randomized Clinical Trials of Relapsed/Refractory Multiple Myeloma

BackgroundConcern has been increasing in oncology regarding randomized clinical trial (RCT) eligibility limiting the generalizability of the findings to real-world populations. Using a large US electronic health record database, we investigated the real-world generalizability of the findings from recent RCTs for relapsed and/or refractory multiple myeloma (RRMM).Patients and MethodsPatients with RRMM initiating second-to fourth-line therapy with the control arm of the following RCTs were retrospectively identified and categorized as “RCT eligible” or “RCT ineligible” according to the eligibility criteria: (1) Rd (lenalidomide, dexamethasone)—ASPIRE, TOURMALINE-MM1, POLLUX, and ELOQUENT-2; and (2) Vd (bortezomib, dexamethasone)—CASTOR and ENDEAVOR. Predictors of RCT ineligibility and overall survival were analyzed using logistic regression and Cox regression analysis.ResultsVariations in the individual trial ineligibility rates were noted, with up to 72.3% (range, 47.9%-72.3%) of patients not meeting the eligibility criteria for 1 of the 6 hallmark RCTs (n = 788 for Rd; n = 477 for Vd). Other malignancies, cardiovascular disease, acute infection, and renal dysfunction were the common reasons for ineligibility. Advanced age, Charlson comorbidity score of ≥ 2, later therapy lines (3-4), and refractory status to the previous line were independently predictive of RCT ineligibility. RCT-ineligible versus RCT-eligible patients had a significantly greater mortality risk (hazard ratio, Rd, 1.46; Vd, 1.51).ConclusionMost real-world patients with RRMM were ineligible for the hallmark RCTs. The eligibility rates varied across the RCTs, underlining the flawed nature of cross-study comparisons without RCT validation. Overall survival was significantly affected by the inability to meet the criteria, highlighting the limited generalizability of the RCT results. Greater efforts are required to broaden the eligibility criteria to reflect real-world clinical characteristics and narrow the gap between RCT efficacy and the observed effectiveness in real-world patients with RRMM.     

Second primary malignancies in multiple myeloma: an overview and IMWG consensus

BackgroundTherapeutic advancements following the introduction of autologous stem cell transplantation and ‘novel’ agents have significantly improved clinical outcomes for patients with multiple myeloma (MM). Increased life expectancy, however, has led to renewed concerns about the long-term risk of second primary malignancies (SPMs). This review outlines the most up-to-date knowledge of possible host-, disease-, and treatment-related risk factors for the development of SPMs in patients with MM, and provides practical recommendations to assist physicians.DesignA Panel of International Myeloma Working Group members reviewed the most relevant data published in the literature as full papers, or presented at meetings of the American Society of Clinical Oncology, American Society of Hematology, European Hematology Association, or International Myeloma Workshops, up to June 2016. Here, we present the recommendations of the Panel, based on this literature review.ResultsOverall, the risk of SPMs in MM is low, multifactorial, and partially related to the length of patients’ survival and MM intrinsic susceptibility. Studies suggest a significantly increased incidence of SPMs when lenalidomide is administered either following, or concurrently with, oral melphalan. Increased SPM incidence has also been reported with lenalidomide maintenance following high-dose melphalan, albeit to a lesser degree. In both cases, the risk of death from MM was significantly higher than the risk of death from SPMs, with lenalidomide possibly providing a survival benefit. No increase in SPM incidence was reported with lenalidomide plus dexamethasone (without melphalan), or with bortezomib plus oral melphalan, dexamethasone, or thalidomide.ConclusionIn general, the risk of SPMs should not alter the current therapeutic decision-making process in MM. However, regimens such as lenalidomide plus dexamethasone should be preferred to prolonged exposure to lenalidomide plus oral melphalan. SPM risk should be carefully discussed with the patient in the context of benefits and risks of different treatment options.     

The emerging role of novel therapies for the treatment of relapsed myeloma

Despite advances in the first-line treatment of multiple myeloma, almost all patients eventually relapse, become chemoresistant, and die of the disease. Improved understanding of potential myeloma targets and molecular mechanisms of drug resistance, along with the development and clinical investigation of targeted antitumor agents, have led to new strategies for the treatment of relapsed myeloma. The proteasome inhibitor bortezomib, the immunomodulatory agent thalidomide, and the thalidomide derivative lenalidomide, are all recently approved treatment options for myeloma. Single-agent bortezomib has been shown to provide significantly greater efficacy than high-dose dexamethasone, and bortezomib has also been investigated in combination with other agents commonly used to treat myeloma, including thalidomide and lenalidomide, with high overall and complete response rates. The safety profile of bortezomib has been well characterized, and side effects have been shown to be generally predictable and manageable, including in high-risk and elderly patients and those with renal impairment. Thalidomide has been extensively studied alone and in combination in patients with relapsed myeloma, demonstrating substantial efficacy, and is therefore widely used in this setting. The toxicity profile is dose- and duration-linked, with lower doses appearing to be better tolerated. Lenalidomide plus dexamethasone has been shown to have significantly greater activity than dexamethasone alone in the relapsed setting, with impressive duration of disease control. Other combinations are also under investigation, with promising early results. Some aspects of the toxicity profile appear significantly reduced relative to thalidomide, although myelosuppression is increased. Other novel therapies at earlier stages of development are being studied and may provide further options in the treatment of relapsed myeloma. This review focuses on results from key phase II and III trials of bortezomib, thalidomide, and lenalidomide alone or in combination, and their emerging role in improving outcomes.     

Management of disease- and treatment-related complications in patients with multiple myeloma

Treatment of myeloma has dramatically changed after introduction of novel agents, such as thalidomide, lenalidomide and bortezomib, with a significant improvement in response rate and survival of patients with myeloma. For newly diagnosed patients not eligible for transplant, the standards of care are now considered melphalan and prednisone (MP) plus thalidomide and MP plus bortezomib. Ongoing randomized trials are evaluating lenalidomide plus MP and lenalidomide plus dexamethasone. For newly diagnosed patients eligible for transplant, new induction regimens included the combination of high-dose dexamethasone plus thalidomide, high-dose dexamethasone plus lenalidomide (RD) and high-dose dexamethasone plus bortezomib (VD). The combinations RD, VD and bortezomib plus pegylated-liposomal-doxorubicin have received the US Food and Drug Administration approval for the treatment of relapsed myeloma. Different efficacious regimens are therefore now available for patients with myeloma. Disease control leads to improvement of all myeloma-related complications (anemia, bone disease, immune dysfunction and renal impairment), but physicians should take into account the choice of the therapeutic strategy, the expected toxicity profile of each of these regimens, together with the patient’s biologic age and comorbidities. Supportive care is an essential part of myeloma therapy, both for the treatment of myeloma-related complications, together with anti-myeloma treatment, and for the management of treatment-emergent adverse events. This chapter will provide an overview of frequency and management of main complications related to the disease itself and to the use of new drugs in newly diagnosed and relapsed patients with myeloma.     

Carfilzomib-Dexamethasone Versus Bortezomib-Dexamethasone in Relapsed or Refractory Multiple Myeloma: Updated Overall Survival,Safety, and Subgroups

IntroductionThe phase III RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma (ENDEAVOR) trial showed significantly improved progression-free survival and overall survival (OS) with carfilzomib (56 mg/m²) and dexamethasone (Kd56) versus bortezomib and Kd56 (Vd) in patients with relapsed or refractory multiple myeloma (RRMM). We report updated OS and safety data after 6 months of additional follow-up.Patients and MethodsPatients with RRMM (1-3 previous lines of therapy) were randomized 1:1 to Kd56 or Vd. Median OS was estimated using the Kaplan–Meier method; OS was compared between treatment groups using Cox proportional hazards models.ResultsAs of July 19, 2017, median follow-up was 44.3 months for Kd56 and 43.7 months for Vd. Median OS was 47.8 months (Kd56) versus 38.8 months (Vd; hazard ratio, 0.76; 95% confidence interval, 0.633-0.915). OS was longer with Kd56 versus Vd within age and cytogenetic subgroups, and according to number of previous lines of therapy, previous bortezomib exposure, previous lenalidomide exposure, and lenalidomide-refractory status. Exposure-adjusted incidences per 100 patient-years of adverse events (AEs) were 1352.07 for Kd56 and 1754.86 for Vd; for Grade ≥3 AEs, these values were 162.31 and 175.90.ConclusionWith median follow-up of approximately 44 months, clinically meaningful improvements in OS were observed with Kd56 versus Vd, including in all subgroups examined. The Kd56 safety profile was consistent with previous analyses.     

EMA Review of Daratumumab (Darzalex) for the Treatment of Adult Patients Newly Diagnosed with Multiple Myeloma

The use of daratumumab in combination with established regimens for the treatment of newly diagnosed multiple myeloma has recently been authorized by the European Medicines Agency based on results from three separate phase III randomized, active controlled, open‐label studies that have confirmed enhanced efficacy and tolerability in both transplant‐ineligible (MMY3008 and MMY3007) and transplant‐eligible (MMY3006) patients, without compromising transplant ability. Trial MMY3008 showed an improvement in progression‐free survival (PFS) when daratumumab was added to lenalidomide and dexamethasone compared with lenalidomide and dexamethasone; the median PFS had not been reached in the daratumumab arm and was 31.9 months in the control arm (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.43–0.73; p < .0001). Trial MMY3007 showed an improvement in PFS when daratumumab was added to bortezomib, melphalan, and prednisone compared with bortezomib, melphalan, and prednisone; PFS had not been reached in the daratumumab arm and was 18.1 months in the control arm (HR, 0.5; 95% CI, 0.38–0.65; p < .0001). In trial MMY3006, daratumumab added to bortezomib, thalidomide, and dexamethasone was compared with bortezomib, thalidomide, and dexamethasone as induction and consolidation treatment prior to autologous stem cell transplant. The stringent complete response rate at day 100 after transplant in the daratumumab group was 29% compared with 20% in the control group (odds ratio, 1.60; 1.21–2.12 95% CI; p = .0010). Overall adverse events were manageable, with an increased rate of neutropenia and infections in the daratumumab arms. Regulatory assessment of efficacy and safety results from trials MMY3006, MMY3007, and MMY3008 confirmed a positive benefit‐risk ratio leading to an approval of the extensions of indication.Implications for PracticeA set of extensions of indication was recently approved for daratumumab (Darzalex) in the setting of newly diagnosed multiple myeloma in combination with established regimens. Results of the MMY3006, MMY3007, and MMY3008 trials have shown enhanced efficacy and a favorable side effect profile of several daratumumab‐based combinations in patients both ineligible and eligible for transplant, without compromising transplant ability. The combinations of daratumumab with either lenalidomide and low‐dose dexamethasone or bortezomib, melphalan, and prednisone were approved for transplant‐ineligible patients. The combination of daratumumab with bortezomib, thalidomide, and dexamethasone was approved for transplant‐eligible patients. These combinations are expected to improve the survival outlook for patients with multiple myeloma, without an unacceptable risk of increase in adverse events, and updated information on progression‐free survival and overall survival is expected from the above trials.     

A Phase II Study of Venetoclax in Combination With Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma

BackgroundVenetoclax is a selective BCL-2 inhibitor with clinical activity in relapsed/refractory multiple myeloma (RRMM). Combinations of venetoclax with agents that have complementary mechanisms of action may improve venetoclax efficacy in RRMM. This study evaluated venetoclax with pomalidomide and dexamethasone (VenPd) in RRMM.Patients and MethodsThis phase II open label study (NCT03567616) evaluated VenPd in patients with RRMM who had received ≥ 1 prior therapy and were refractory to lenalidomide. Venetoclax was administered orally daily for days 1 to 28, pomalidomide was administered orally daily for days 1 to 21, and dexamethasone was administered weekly for each 28-day cycle. The primary objective was to characterize the safety and tolerability of VenPd. The secondary objectives were to evaluate the efficacy and pharmacokinetics. The study was terminated early due to partial clinical hold and decision to pursue biomarker driven strategy.ResultsEight patients were enrolled. Patients had a median age of 67.5 years. All patients received 400 mg venetoclax; 4 patients experienced dose-limiting toxicities and the dose was not escalated. All patients had a grade ≥ 3 adverse event, and the most common was neutropenia (n = 6); cytopenias were the most prevalent adverse events. Five patients (63%) had a confirmed response, and the median duration of response was 12.9 months. The median progression-free survival was 10.5 months.ConclusionsGiven the limited enrollment, no clear safety or efficacy conclusions about VenPd can be drawn. Preliminary safety data, particularly the occurrence of cytopenias, can be used to guide dosing strategies for future combinations of venetoclax with immunomodulatory agents.     

A phase 2, open-label,multicenter study of ixazomib plus lenalidomide and dexamethasone in adult Japanese patients with relapsed and/or refractory multiple myeloma

Background

TOURMALINE-MM1 was a global study that demonstrated a significant improvement in progression-free survival with ixazomib plus lenalidomide and dexamethasone compared with placebo plus lenalidomide and dexamethasone, in patients with relapsed and/or refractory multiple myeloma. The current study was conducted to evaluate further the efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients.

Methods

This phase 2, open-label, single-arm, multicenter study enrolled patients aged ≥ 20 years with relapsed and/or refractory multiple myeloma at 16 sites in Japan. Patients refractory to lenalidomide or proteasome inhibitor-based therapy at any line were excluded. The primary endpoint was the rate of very good partial response or better in the response-evaluable analysis set. Secondary endpoints were progression-free survival, overall response rate, duration of response, time to progression, overall survival and safety.

Results

In total, 34 patients were enrolled. The rate of very good partial response or better was 50.0% (95% confidence interval 31.9–68.1) and the overall response rate was 84.4% (95% confidence interval 67.2–94.7). Median progression-free survival was 22.0 months (95% confidence interval 17.3–not evaluable) and median overall survival was not estimable. The safety profile of ixazomib plus lenalidomide and dexamethasone in this study was similar to that in the TOURMALINE-MM1 study.

Conclusions

The efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients with relapsed and/or refractory multiple myeloma are comparable with reported TOURMALINE-MM1 study results.

Clinicaltrials.gov identifier

NCT02917941; date of registration September 28, 2016.

     

Daratumumab,Bortezomib, and Dexamethasone versus Bortezomib and Dexamethasone in Chinese Patients With Relapsed or Refractory Multiple Myeloma: Updated Analysis of LEPUS

BackgroundIn the phase 3 LEPUS study, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Here, we report updated efficacy and safety results from LEPUS.Patients and MethodsChinese patients with ≥ 1 prior line of therapy were randomized 2:1 to bortezomib (1.3 mg/m²) and dexamethasone (20 mg) for eight cycles ± daratumumab (16 mg/kg) until disease progression. The primary endpoint was progression-free survival (PFS).ResultsIn total, 211 patients were randomized to D-Vd (n = 141) or Vd (n = 70). At a 25.1-month median follow-up, D-Vd prolonged PFS versus Vd (median, 14.8 vs. 6.3 months; hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.24-0.51; P < .00001). PFS benefit of D-Vd versus Vd was maintained across prespecified subgroups, including patients with prior bortezomib (HR, 0.36; 95% CI, 0.25-0.53), patients who were refractory to last prior line of therapy (HR, 0.42; 95% CI, 0.27-0.65), and patients with high-risk cytogenetics (HR, 0.41; 95% CI, 0.23-0.71). Overall response rate (84.7% vs.66.7%; P = .00314) and rates of very good partial response or better (71.5% vs. 34.9%; P < .00001) and complete response or better (40.1% vs 14.3%; P = .00016) were higher with D-Vd versus Vd. No new safety concerns were identified.ConclusionsIn this updated analysis, D-Vd maintained significant efficacy benefits versus Vd alone and demonstrated a consistent safety profile, further supporting the use of D-Vd as a standard of care in Chinese patients with RRMM.     

Longitudinal Real-World Neuropathy and Patient-Reported Outcomes With Bortezomib and Lenalidomide in Newly Diagnosed Multiple Myeloma

BackgroundPeripheral neuropathy is a common treatment-emergent side effect during the treatment of newly diagnosed multiple myeloma. Although bortezomib is most commonly implicated, real-world data suggest that lenalidomide and dexamethasone (VRd) and autologous stem cell transplantation (ASCT) may also contribute to neuropathy and health-related quality of life (HRQoL).MethodsThe Multiple Myeloma Research Foundation (MMRF) CoMMpass Registry was queried for all patients who received frontline VRd or bortezomib, cyclophosphamide and dexamethasone (VCd). Incidence of neuropathy and patient-reported HRQoL outcomes over the first 12 months after diagnosis were compared between patients receiving VRd or VCd with or without early ASCT before 6 months.ResultsThere were 368 and 191 patients treated with VRd and VCd, respectively. VRd with early ASCT was associated with worse grade 1 neuropathy compared to VRd without early ASCT, as well as compared to VCd with early ASCT. There were no differences in neuropathy between VRd and VCd without early ASCT, and no differences in grade ≥2 neuropathy. There were significant improvements in HRQoL between baseline and 12 months in both VRd and VCd cohorts, regardless of early ASCT. Development of neuropathy was not associated with decrements in progression-free survival or overall survival.ConclusionsIn this longitudinal database analysis, there were no differences in grade ≥2 neuropathy between VRd and VCd frontline induction, and overall HRQoL significantly improved across all cohorts. However, differences in grade 1 neuropathy between VRd and VCd induction suggest that lenalidomide and high-dose melphalan may augment the risk of neuropathy in newly diagnosed multiple myeloma.     

New Agents in Multiple Myeloma: An Examination of Safety Profiles

Numerous treatments are available for relapsed and/or refractory multiple myeloma (MM), with safety profiles varying across drug classes and across agents within the same class. Thus, it is important to understand the toxicities of each antimyeloma agent when making treatment decisions. Neutropenia is commonly associated with lenalidomide and pomalidomide, and may be common with histone deacetylase (HDAC) inhibitors, but is relatively unusual with thalidomide, bortezomib, and carfilzomib. Infection was common in trials of lenalidomide and pomalidomide, and upper respiratory tract infection and pneumonia have been seen with carfilzomib. Cardiac toxicity was observed with thalidomide and may occur with proteasome inhibition. Thromboembolic complications occur with thalidomide and its derivatives, but are less common with bortezomib. Peripheral neuropathy (PN), an important complication of MM, may be exacerbated by bortezomib and thalidomide, and was also observed with lenalidomide. In contrast, PN is rarely observed with carfilzomib and pomalidomide. Renal impairment reduces the clearance of lenalidomide but does not seem to affect substantially the pharmacokinetics of pomalidomide, carfilzomib, or bortezomib. Several therapies have recently been approved, such as the oral proteasome inhibitor ixazomib, the HDAC inhibitor panobinostat, and the monoclonal antibodies elotuzumab and daratumumab. Others are still in clinical development, including the HDAC inhibitors romidepsin and vorinostat, with safety data continuing to emerge. Therapy decisions should consider safety profiles in association with pre-existing comorbidities and toxicities from previous therapeutic regimens. Optimal treatment selection and the management of toxicities will result in fewer patients requiring dose reductions and treatment discontinuations, ultimately leading to improved outcomes.     

Daratumumab,Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Chinese Patients with Relapsed or Refractory Multiple Myeloma: Phase 3 LEPUS (MMY3009) Study

BackgroundDaratumumab plus bortezomib/dexamethasone (D-Vd) significantly improved outcomes versus Vd in patients with relapsed or refractory multiple myeloma (RRMM) in the phase 3 CASTOR study. We report the results of a prespecified interim analysis of the phase 3 LEPUS study of D-Vd versus Vd in Chinese patients with RRMM.Patients and MethodsChinese patients with ≥ 1 prior line of therapy were randomized 2:1 to receive 8 cycles (21 days/cycle) of bortezomib (1.3 mg/m² subcutaneously) and dexamethasone (20 mg orally/intravenously) ± daratumumab (16 mg/kg intravenously). The primary endpoint was progression-free survival (PFS).ResultsA total of 211 patients were randomized (D-Vd, 141; Vd, 70). After an 8.2-month median follow-up, D-Vd significantly prolonged PFS versus Vd (median, not reached vs. 6.3 months; hazard ratio, 0.28; 95% confidence interval, 0.17-0.47; P < .00001) and significantly improved the rates of overall response (83% vs. 65%; P = .00527), ≥ very good partial response (65% vs. 33%; P = .00002), ≥ complete response (33% vs. 11%; P = .00079), and minimal residual disease negativity (10^–5 sensitivity; 22% vs. 3%; P = .0002). The PFS benefit of D-Vd versus Vd was maintained across prespecified subgroups, including patients with prior bortezomib treatment and with high-risk cytogenetics. Thrombocytopenia (D-Vd, 51%; Vd, 37%), lymphopenia (44%; 29%), and lung infection (30%; 22%) were the 3 most common grade 3/4 treatment-emergent adverse events. Although patients in both treatment groups experienced higher rates of grade 3/4 lymphopenia and infections versus patients in CASTOR, the safety profile was generally consistent with that of CASTOR.ConclusionThese data support the use of D-Vd in Chinese patients with RRMM.