Marcia Mulquin

Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma.

IMPORTANCE Carfilzomib-lenalidomide-dexamethasone therapy yields deep responses in patients with newly diagnosed multiple myeloma (NDMM). It is important to gain an understanding of this combinations tolerability and impact on minimal residual disease (MRD) negativity because this end point has been associated with improved survival. OBJECTIVE To assess the safety and efficacy of carfilzomib-lenalidomide-dexamethasone therapy in NDMM and high-risk smoldering multiple myeloma (SMM). DESIGN, SETTING, AND PARTICIPANTS Clinical and correlative pilot study at the National Institutes of Health Clinical Center. Patients with NDMM or high-risk SMM were enrolled between July 11, 2011, and October 9, 2013. Median follow-up was 17.3 (NDMM) and 15.9 months (SMM). INTERVENTIONS Eight 28-day cycles were composed of carfilzomib 20/36 mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on days 1 through 21; and dexamethasone 20/10 mg (cycles 1-4/5-8) on days 1, 2, 8, 9, 15, 16, 22, and 23. Patients who achieved at least stable disease subsequently received 24 cycles of lenalidomide extended dosing. MAIN OUTCOMES AND MEASURES Primary end points were neuropathy of grade 3 or greater (NDMM) and at least very good partial response rates (SMM). Minimal residual disease was also assessed. RESULTS Of 45 patients with NDMM, none had neuropathy of grade 3 or greater. Of 12 patients with high-risk SMM, the most common of any-grade adverse events were lymphopenia (12 [100%]) and gastrointestinal disorders (11 [92%]). All patients with SMM achieved at least a very good partial response during the study period. Among the 28 patients with NDMM and the 12 with SMM achieving at least a near-complete response, MRD negativity was found in 28 of 28 (100% [95% CI, 88%-100%]), 11 of 12 (92% [95% CI, 62%-100%]) (multiparametric flow cytometry), 14 of 21 (67% [95% CI, 43%-85%]), and 9 of 12 (75% [95% CI, 43%-94%]) (next-generation sequencing), respectively. In patients with NDMM, 12-month progression-free survival for MRD-negative vs MRD-positive status by flow cytometry and next-generation sequencing was 100% vs 79% (95% CI, 47%-94%; P < .001) and 100% vs 95% (95% CI, 75%-99%; P = .02), respectively. CONCLUSIONS AND RELEVANCE Carfilzomib-lenalidomide-dexamethasone therapy is tolerable and demonstrates high rates of MRD negativity in NDMM, translating into longer progression-free survival in patients achieving MRD negativity. Carfilzomib-lenalidomide-dexamethasone therapy also demonstrates efficacy in high-risk SMM.

A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma

Natural killer (NK) cells are involved in immune surveillance of various malignancies, including multiple myeloma (MM).[1][1] IPH2101 is a fully human monoclonal antibody that blocks HLA-C binding KIR2D receptors (KIR2DL/DS-1, -2 -3) expressed on the surface of NK-cells, enhancing their cytotoxicity

Modeling progression risk for smoldering multiple myeloma: results from a prospective clinical study

Abstract The risk of progression to multiple myeloma (MM) from the precursor condition smoldering MM (SMM) varies considerably among individual patients. Reliable markers for progression to MM are vital to advance the understanding of myeloma precursor disease and for the development of intervention trials designed to delay/prevent MM. The Mayo Clinic and Spanish PETHEMA have proposed models to stratify patient risk based on clinical parameters. The aim of our study was to define the degree of concordance between these two models by comparing the distribution of patients with SMM classified as low, medium and high risk for progression. A total of 77 patients with SMM were enrolled in our prospective natural history study. Per study protocol, each patient was assigned risk scores based on both the Mayo and the Spanish models. The Mayo Clinic model identified 38, 35 and four patients as low, medium and high risk, respectively. The Spanish PETHEMA model classified 17, 22 and 38 patients as low, medium and high risk, respectively. There was significant discordance in overall patient risk classification (28.6% concordance) and in classifying patients as low versus high (p < 0.0001), low versus non-low (p = 0.0007) and high versus non-high (p < 0.0001) risk. There is a need for prospectively validated models to characterize individual patient risk of transformation to MM.

Flow cytometric differentiation of abnormal and normal plasma cells in the bone marrow in patients with multiple myeloma and its precursor diseases

Flow cytometric (FC) enumeration of abnormal plasma cells (APCs) for diagnosis and prognostication of plasma cell dyscrasias (PCD) is challenging. We studied antigen expression in normal plasma cells (NPC) (N = 34) and APC in a series of unselected PCD (N = 59). NPC subpopulations often demonstrated CD19(-), CD20(+), CD45(-) or dim and CD56(+), an immunophenotype observed in PCD. However abnormal CD81 was only observed in APCs (APC detection sensitivity 95%; specificity 100%). We evaluated differences in antigen expression patterns among MGUS (N = 14), SMM (N = 35) and MM (N = 10), finding the combination of CD45 and CD56 helpful in differentiating MGUS from SMM and MM (p = 0.0002).

Phase II clinical trial of cediranib in patients with metastatic castration-resistant prostate cancer.

Recent advances in the treatment of metastatic castration‐resistant prostate cancer (CRPC) have resulted in improved outcomes; however, the effects have not proved to be long term, highlighting the need for new therapies, particularly in patients with docetaxel‐refractory metastatic CRPC. Angiogenesis has been shown to play an important role in the development and progression of prostate cancer. Although targeting angiogenesis appears to be a rational and therapeutic approach for metastatic CRPC, identifying the appropriate subgroups that may benefit from anti‐angiogenic therapy remains a challenge. The study demonstrates the potential use of dynamic contrast‐enhanced (DCE)‐MRI variables as pharmacodynamic endpoints in predicting the clinical outcomes associated with anti‐angiogenic agents such as cediranib. Further investigation into the potential predictive value of DCE‐MRI variables as biomarkers for antiangiogenic therapy is warranted.

Flow cytometric sensitivity and characteristics of plasma cells in patients with multiple myeloma or its precursor disease: influence of biopsy site and anticoagulation method.

Abstract Flow cytometry has increasing relevance for prognosis in myeloma and precursor disease (monoclonal gammopathy of unknown significance/smoldering myeloma), yet it has been reported that plasma cell enumeration by flow varies depending on the quality of marrow aspirate and field biopsied in patchy disease. We demonstrated increased sensitivity of flow over immunohistochemistry in abnormal-plasma cell detection in monoclonal gammopathy (n = 59)/smoldering myeloma (n = 87). We prospectively evaluated treatment-na ve smoldering myeloma (n = 9)/myeloma (n = 11) patients for the percentage of abnormal plasma cells/total plasma cell compartment, plasma cell viability/infiltration and flow immunophenotype depending on anticoagulant use, biopsy site and pull sequence in uni-and-bilateral bone marrow biopsies and aspirates. We found no statistical difference regarding the percentage of abnormal plasma cells, their immunophenotype or number/distribution in marrow samples even when obtained by different sequence in aspirates, or anticoagulants (p > 0.05). Our results show that plasma cell enumeration and immunophenotyping by flow cytometry is consistent under different conditions in these populations.

Bone marrow abnormalities and early bone lesions in multiple myeloma and its precursor disease: a prospective study using functional and morphologic imaging

Abstract The incidence and importance of bone marrow involvement and/or early bone lesions in multiple myeloma (MM) precursor diseases is largely unknown. This study prospectively compared the sensitivity of several imaging modalities in monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and MM. Thirty patients (10 each with MGUS, SMM and MM) were evaluated with skeletal survey, [18F]FDG-PET/CT, [18F]NaF-PET/CT and morphologic dynamic contrast enhanced (DCE)-MRI. An additional 16 SMM patients had skeletal surveys and FDG-PET/CT. Among MGUS patients, DCE-MRI found only one focal marrow abnormality; other evaluations were negative. Among 26 SMM patients, five (19%) were re-classified as MM based on lytic bone lesions on CT and six had unifocal or diffuse marrow abnormality. Among MM, marrow abnormalities were observed on FDG-PET/CT in 8/10 patients and on DCE-MRI in nine evaluable patients. Abnormal NaF uptake was observed only in MM patients with lytic lesions on CT, providing no additional clinical information.

Altered cytokine and chemokine profiles in multiple myeloma and its precursor disease

Currently, no reliable biomarkers are available to predict transformation from smoldering myeloma (SMM) to multiple myeloma (MM). Using an ultrasensitive enzyme-linked immunosorbent assay (ELISA) we assessed the levels of a broad range of cytokines and chemokines in the peripheral blood (PB) and bone marrow (BM) supernatant collected from 14 SMM and 38 MM patients and compared to healthy donors. We found significantly increased levels of key cytokines, in particular CXCL8 (IL-8), associated with progressive disease state (controls→SMM→MM). Cytokine profiles were found similar in PB and BM. Five of fourteen SMM patients (36%) progressed to MM. Our findings, although based on a limited number of patients, suggest that serum-based cytokines may have a future role as biomarkers for disease progression and could potentially be assessed as novel targets for treatment.

Phase II trial of bevacizumab and lenalidomide with docetaxel and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC).

207 Background: Angiogenesis may be vital to mCRPC. Previously, we had shown the potent anti-tumor activity of dual antiangiogenic therapy by combining thalidomide (T) and bevacizumab (B) with docetaxel (D) and prednisone (P) in mCRPC (Ning JCO 2010). We hypothesized that combining lenalidomide (L), an analogue of T, with B, D, and P would have a more favorable efficacy/toxicity profile. METHODS All patients (pts) had chemotherapy-naïve mCRPC. 3 pts received R 15 mg daily, 3 pts had 20 mg daily, and the rest had 25 mg daily for 14 days of every 21-day cycle (C). All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. PSA was assayed each C with imaging after C2 and then after every 3C. RESULTS 47 of the planned 51 pts have been enrolled. Median age was 66 (51-82), Gleason score 8 (5-10), on-study PSA 91.6 ng/ml (0.15-3520), pre-study PSA doubling time 1.43 months (0.52-6.73), number of Cs 14 (1-31), and PFS was 19.3 months as of this analysis. Among 45 pts who have completed ≥2 cycles, 39 (86.7%) and 30 (66.7%) had PSA declines of ≥50% and ≥75%, respectively. Of 29 pts with measurable disease there were 2 CR, 21 PR, and 6 SD (79.3% overall RR). 10/47 pts were taken off study for radiographic disease progression and 5/47 for other reasons. Grade ≥3 toxicities included neutropenia (24/47), anemia (9/47), thrombocytopenia (5/47), weight loss (1/47), hypertension (3/47), and febrile neutropenia (4/47). Other toxicities included perianal fistula (3/47), rectal fissure (1/47), myocardial infarction (1/47), and osteonecrosis of the jaw (ONJ) (16/47, 34.0%). At the time of diagnosis of ONJ, 9/16 pts were on bisphosphonates and 3/16 had used bisphosphonates previously. Although the incidence of ONJ was higher than the 18.3% reported by Ning, a recent study of carboplatin plus weekly docetaxel reported an incidence of 29.3%. CONCLUSIONS Dual antiangiogenic therapy with, B and L, plus D and P was associated with high PSA (86.7%) and tumor (79.3%) responses with manageable toxicities. Further studies are underway to explore the high incidence of ONJ.

Enzymatic activities of circulating plasma proteasomes in newly diagnosed multiple myeloma patients treated with carfilzomib, lenalidomide and dexamethasone

Abstract The proteasome inhibitor carfilzomib is highly effective in the treatment of multiple myeloma. It irreversibly binds the chymotrypsin-like active site in the β5 subunit of the 20S proteasome. Despite impressive response rates when carfilzomib is used in combination with immunomodulatory agents in newly diagnosed multiple myeloma patients; no biomarker exists to accurately predict response and clinical outcomes. We prospectively assessed the activity in peripheral blood of the chymotrypsin-like (CHYM), caspase-like (CASP) and trypsin-like (TRYP) proteolytic sites in 45 newly diagnosed multiple myeloma patients treated with eight cycles of carfilzomib, lenalidomide and dexamethasone (CRd) (NCT01402284). Samples were collected per protocol and proteasome activity measured through a fluorogenic assay. Median CHYM levels after one dose of carfilzomib decreased by >70%. CHYM and CASP activity decreased throughout treatment reaching a minimum after eight cycles of treatment. Higher levels of proteasome activity associated with higher disease burden (r > 0.30; p < 0.05) and higher disease stage (0.10 < p <0.20). No association was found with the probability of achieving a complete response, minimal residual disease negativity or time to best response. Further studies evaluating proteasome activity in malignant plasma cells may help elucidate how proteasome activity can be used as a biomarker in multiple myeloma.