Lentzsch, Suzanne

Background:Patients (pts) with multiple myeloma associated with high cytogenetic risk abnormalities have poor outcomes. In CASTOR, D‐Vd prolonged progression‐free survival (PFS) vs bortezomib and dexamethasone (Vd) alone, and exhibited a manageable safety profile in pts with RRMM. We conducted a subgroup analysis of D‐Vd vs Vd in CASTOR, based on cytogenetic risk.Aims:The purpose of this analysis was to determine the efficacy and safety of D‐Vd in CASTOR based on cytogenetic risk status.Methods:Eligible pts received ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of next‐generation sequencing (NGS) and fluorescence in situ hybridization (FISH)/karyotype testing. High‐risk pts had t(4;14), t(14;16), or del17p abnormalities. Standard (std)‐risk pts were confirmed negative for all 3 abnormalities. Minimal residual disease (MRD; 10–5) was assessed via NGS using clonoSEQ® assay V2.0.Results:In CASTOR (D‐Vd, n = 251; Vd, n = 247), high‐risk was confirmed in 26.7% and 25.9% of pts in the D‐Vd and Vd groups, respectively. At a median follow up of 40.0 months (mo), D‐Vd prolonged PFS vs Vd in pts with high‐ (median 13.4 vs 7.2 mo; HR, 0.40 [95% CI, 0.24–0.65]; P = 0.0002) or std‐risk (median 18.4 vs 6.8 mo; HR, 0.28 [95% CI, 0.20–0.37]; P <0.0001). Higher ORR was seen with D‐Vd vs Vd (high risk: 84.8% vs 60.0%; P = 0.0226; std risk: 85.4% vs 65.0%; P <0.0001), including deep responses of ≥CR (high risk: 33.3% vs 8.3%; std risk: 29.9% vs 10.2%) and ≥VGPR (high risk: 65.2% vs 35.0%; P = 0.0049; std risk: 64.3% vs 28.0%; P <0.0001). Higher rates of MRD negativity (high risk: 17.9% vs 0%; P = 0.0003; std risk: 13.3% vs 2.4%; P = 0.0003), and sustained MRD negativity for ≥6 mo (high risk: 16.4% vs 0%; P = 0.0006; std risk: 6.1% vs 1.8%; P = 0.0859) and ≥12 mo (high risk: 7.5% vs 0%; P = 0.0581; std risk: 1.8% vs 0%; P = 0.2477) were seen with D‐Vd vs Vd. D‐Vd significantly prolonged PFS vs Vd in pts with one prior line of therapy only (high risk: median 20.1 vs 8.4 mo; HR, 0.30 [95% CI, 0.14–0.64]; P = 0.0012; std risk: median 32.6 vs 7.9 mo; HR, 0.18 [95% CI, 0.11–0.29]; P <0.0001; Figure). Additionally, D‐Vd significantly prolonged PFS2 (high risk: median 27.9 vs 18.6 mo; HR, 0.59 [95% CI, 0.37–0.94]; P = 0.0258; std risk: median 40.1 vs 21.6 mo; HR, 0.43 [95% CI, 0.32–0.59]; P <0.0001) regardless of cytogenetic risk status.Additional data including safety analyses will be presented.Summary/Conclusion:Adding daratumumab to Vd demonstrates significant efficacy in pts with high‐risk RRMM including PFS2. Among high‐risk RRMM pts, MRD negativity was only achieved with D‐Vd. These findings support use of D‐Vd for high‐risk RRMM. NCT02136134image

8006 Background: In 2 randomized phase 3 trials of RRMM patients (pts), DRd (POLLUX) or DVd (CASTOR) significantly improved PFS and deepened responses compared with Rd or Vd alone, respectively. The novel mechanism of action of daratumumab (D) may improve the poor prognosis associated with high-risk cytogenetic abnormalities in RRMM. Therefore, we examined the efficacy of DRd and DVd among RRMM pts with standard (std) or high cytogenetic risk status. Methods: Bone marrow aspirates were collected at screening and assessed centrally via next generation sequencing (NGS). Pts with high-risk cytogenetics included those who had ≥1 of the following abnormalities: t(4;14), t(14;16), or del17p; std-risk pts were defined as those confirmed negative for these abnormalities. Efficacy analyses included PFS and ORR. Results: Samples from 311/569 pts in POLLUX and 353/498 pts in CASTOR were assessed via NGS. In POLLUX, the median duration of follow-up was 17.3 months. Significantly longer median PFS and numerically higher ORR were observed with DRd vs Rd among high-risk patients, and significant improvements in these outcomes were observed in std-risk patients (Table). In CASTOR, the median duration of follow-up was 13.0 months. Significantly longer median PFS and higher ORR were observed with DVd vs Vd among both high- and std-risk pts (Table). Concordance rates for t(4;14), t(14;16), and del17p were high (88%-98%) between NGS and FISH. Updated data, including subgroup analyses, will be presented. Conclusions: In RRMM pts, the addition of D to standard-of-care regimens improved outcomes regardless of cytogenetic risk status. Targeting CD38 by combining D with Rd or Vd appears to improve the poor outcomes associated with high-risk cytogenetic status. See table. Clinical trial information: NCT02136134 and NCT02076009. [Table: see text]

Key Points Pomalidomide plus low-dose dexamethasone significantly improved PFS vs pomalidomide alone in relapsed and refractory multiple myeloma. Pomalidomide plus low-dose dexamethasone is an important new treatment option for RRMM patients who have received multiple prior therapies.

Purpose The aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) –related bone disease. Methodology An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members. Recommendations Bisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability.

The past decade has witnessed a paradigm shift in the initial treatment of multiple myeloma with the introduction of novel agents such as thalidomide, lenalidomide, and bortezomib, leading to improved outcomes. High-dose therapy and autologous stem cell transplantation remains an important therapeutic option for patients with multiple myeloma eligible for the procedure. Before the advent of the novel agents, patients underwent stem cell collection prior to significant alkylating agent exposure, given its potential deleterious effect on stem cell collection. With increasing use of the novel agents in the upfront setting, several reports have emerged raising concerns about their impact on the ability to collect stem cells. An expert panel of the International Myeloma Working Group (IMWG) was convened to examine the implications of these therapies on stem collection in patients with myeloma and to develop recommendations for addressing these issues. Here we summarize the currently available data and present our perspective on the problem and potential options to overcome this problem. Specifically, we recommend early mobilization of stem cells, preferably within the first 4 cycles of initial therapy, in patients treated with novel agents and encourage participation in clinical trials evaluating novel approaches to stem cell mobilization.

Abstract Purpose: The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway and the heat shock protein family are up-regulated in multiple myeloma and are both regulators of the cyclin D/retinoblastoma pathway, a critical pathway in multiple myeloma. Inhibitors of mTOR and HSP90 protein have showed in vitro and in vivo single-agent activity in multiple myeloma. Our objective was to determine the effects of the mTOR inhibitor rapamycin and the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on multiple myeloma cells. Experimental Design: Multiple myeloma cell lines were incubated with rapamycin (0.1-100 nmol/L) and 17-AAG (100-600 nmol/L) alone and in combination. Results: In this study, we showed that the combination of rapamycin and 17-AAG synergistically inhibited proliferation, induced apoptosis and cell cycle arrest, induced cleavage of poly(ADP-ribose) polymerase and caspase-8/caspase-9, and dysregulated signaling in the phosphatidylinositol 3-kinase/AKT/mTOR and cyclin D1/retinoblastoma pathways. In addition, we showed that both 17-AAG and rapamycin inhibited angiogenesis and osteoclast formation, indicating that these agents target not only multiple myeloma cells but also the bone marrow microenvironment. Conclusions: These studies provide the basis for potential clinical evaluation of this combination for multiple myeloma patients.