New drugs on the horizon. Treatment of myeloma in ...

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icity in vivo animal models. Some are in early (AC1215) and others, like panobinostat, are in late clinical devel- opment as treatments for multiple myeloma.
New drugs on the horizon. Treatment of myeloma in 2020, a perspective

Heinz Ludwig, Wolfgang Hilbe & Niklas Zojer

memo - Magazine of European Medical Oncology An International Journal for Oncology and Haematology Professionals ISSN 1865-5041 memo DOI 10.1007/s12254-014-0194-0

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Author's personal copy original report memo DOI 10.1007/s12254-014-0194-0

New drugs on the horizon. Treatment of myeloma in 2020, a perspective Heinz Ludwig · Wolfgang Hilbe · Niklas Zojer

Received: 23 December 2014 / Accepted: 26 December 2014 © Springer-Verlag Wien 2015

Abstract  This minireview covers novel drugs and treatment concepts being evaluated in early studies for therapy of patients with multiple myeloma (MM). Panobinostat, a histone deacetylase inhibitor, showed limited improvement in progression-free survival, thus raising doubt whether these substances will provide clinical meaningful benefits in MM. Some of the new proteasome inhibitors beyond carfilzomib offer the benefit of oral administration and reduced neurotoxicity. Monoclonal antibodies with antimyeloma or antistroma cell activity raise expectations for improved treatment outcome when combined with conventional chemotherapy. A series of new inhibitors of signal pathways important for proliferation and progression in MM presently are scrutinized for their clinical usefulness. Among these, inhibitors of the mitogen activated protein kinase (MAPK), epidermal growth factor receptor (EGFR), protein kinase B (AKT) and B-cell receptor pathway as well as drugs inhibiting the spindle protein, Bcl-2 and cyclin-dependent kinases show promise for becoming important antimyeloma dugs. Checkpoint inhibitors have shown significant activity in some solid tumors and are now tested in MM as well. Measles viruses bind via CD46 to myeloma cells, self-amplify at sites of tumor growth, and induce cell death in myeloma but not in normal cells, thus offering a completely new treatment strategy. However, before

introduction of these interesting approaches into the clinic, confirmation of their clinical efficacy is needed. Keywords:  Multiple myeloma  · Novel drug  · Monoclonal antibodies · Kinase inhibitors

Introduction Multiple myeloma is a genetically heterogeneous disease with distinct disturbances of the genetic machinery, including mutations, translocations, and hypo- and hyperploidy among others. Despite recent progress in detecting these aberrations, information about the mechanisms triggering transformation from precursor states like monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM) into active myeloma remains unknown, although knowledge of these factors is important for preventing disease progression and for developing targeted therapies. Recently, new conventional drugs like pomalidomide and carfilzomib have been introduced into the clinic, and several followers are in clinical development. Here, we discuss new drugs that lie outside the conventional spectrum and provide a brief outlook on the near future.

Histone deacetylase inhibitors Prof. Dr. H. Ludwig () Wilhelminen Cancer Research Institute, c/o Department of Medicine I, Center for Oncology, Hematology and Outpatient Clinic and Palliative Care, Wilhelminenspital, Montleartstrasse 37, 1160 Vienna, Austria e-mail: [email protected] W. Hilbe · N. Zojer Department of Medicine I, Center for Oncology, Hematology and Outpatient Clinic and Palliative Care, Wilhelminenspital, Vienna, Austria

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Controlling the coiling and uncoiling of DNA around histones is essential for gene expression. Histone acetyl transferases acetylate the lysine residues in core histones, resulting in a less compact and transcriptionally more active chromatin. Conversely, histone deacetylases (HDACs) remove the acetyl groups from the lysine residues leading to the formation of a condensed and transcriptionally silenced chromatin. Inhibition of this process by HDAC inhibitors can result in increased gene

New drugs on the horizon. Treatment of myeloma in 2020, a perspective  

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Author's personal copy original report

expression and in cell cycle arrest, differentiation, and/ or apoptosis. Several structurally diverse HDAC inhibitors have shown potent antitumor efficacy with little toxicity in vivo animal models. Some are in early (AC1215) and others, like panobinostat, are in late clinical development as treatments for multiple myeloma. Panobinostat in combination with bortezomib–dexamethasone increased the rate of near complette response (nCR), and complette response (CR) and the progression-free survival by 3.9 months compared with placebo–bortezomib–dexamethasone alone in patients with relapsed/ refractory myeloma [1].

New proteasome inhibitors Carfilzomib has already been approved in the USA for treatment of patients with relapsed myeloma pretreated with bortezomib and lenalidomide and therefore will not be discussed here. Four other proteasome inhibitors, ixazomib, oprozomib, marizomib, and delanzomib, are currently being evaluated in early clinical trials (Table 1). Ixazomib is an N-kappa dipeptidyl leucin boronic acid and is available as oral formulation. The drug is rapidly absorbed with a median time to peak plasma concentration of an hour and a longer terminal half-life than bortezomib (3.6–11.3 days). Ixazomib has shown significant single-agent activity and is presently tested in combination with various antimyeloma drugs. A recent phase II study showed an overall response rate of 95 % with ixazomib in combination with lenalidomide/dexamethasone after eight cycles. A total of 64 % of the patients achieved a very good partial response (VGPR) or better. The most notable grade 3 toxicity of a single drug trial with ixazomib was diarrhea, which was seen in 23 % of patients and was easily manageable without the need for treatment discontinuation [2]. Marizomib (NPI-0052; salinosporamide A) is a novel marine-derived β-lactone-γ-lactam natural product, which targets β5 and β2 sites of 20 S-proteasome with a rapid onset of inhibition. Combining marizomib with bortezomib induces synergistic antimyeloma activities in vitro and in a human plasmacytoma xenograft mouse model [3].

Oprozomib (ONYX 0912) and delanzomib (CEP187770) are other oral proteasome inhibitors in very early clinical development. One of the sensitive issues of oral proteasome inhibitors is gastrointestinal toxicity, which seems to be more pronounced with marizomib, but new formulations likely will overcome this limitation.

Monoclonal antibodies A large series of monoclonal antibodies targeting different epitopes on myeloma cells or immune and stromal cells are now in development (Table  2). Among those, elotuzumab, a monoclonal antibody targeting SLAMF7, is the most advanced in clinical evaluation [4]. Elotuzumab plus lenalidomide combined led to greater reduction in tumor mass in a mouse xenograft model compared with either one alone [5]. In the clinical setting, a high overall response rate of 92 % was seen with the combination of elotuzumab with lenalidomide/dexamethasone in patients with relapsed refractory myeloma. Present clinical trials exploring the activities of this combination in newly diagnosed and previously treated patients are on the way. Elotuzumab is a humanized antibody and therefore well tolerated with grade 1 and grade 2 infusion reactions seen in approximately 10 % of patients. Other important targets on myeloma cells are CD38 and CD138. Presently, three antibodies (daratumumab, SAR650284, and MOR202) targeting CD38 are under clinical investigation. Daratumumab is a fully human IgG1 antibody that exerts single-agent activity [6, 7]. Several trials exploring daratumumab in combination, mostly with lenalidomide/dexamethasone, but also with bortezomib-based combinations are ongoing. Initial results show significant activity and very good tolerability. SAR650284 is a humanized IgG1 antibody also targeting CD38. It inhibits binding of myeloma cells to bone marrow stromal cells by blocking the CD38–CD31 interaction [8]. Clinical trials with this drug and with another anti-CD38 developed by MorphoSys are ongoing, but information about their clinical activity and toxicity is scarce. Indatuximab ravtansine (BT-062), a chimeric IgG conjugated to cytotoxic maytansin derivate (DM4), should

Table 1  Mechanism of action, dosing, and route of administration of novel proteasome inhibitors Agent

Class

Type of inhibition

Dose

Route of administration

Carfilzomib

Epoxyketone β5

Irreversible

20 mg/m on days 1, 2, 8, 9, 15, and 16 for cycle 1, then 27 mg/m2 on days 1, 2, 8, 9, 15, and 16, q28d for subsequent cycles*

Intravenous

Marizomib (NPI-0052)

β-lactone β5, β2

Irreversible

0.4 mg/m2 over 60 min or 0.5 mg/m2 over 120 min

Intravenous

Ixazomib (MLN9708)

Boronate β5

Reversible

4 mg on days 1, 8, 15, a28d

Oral

Oprozomib (ONX-0912)

Epoxyketone β5

Irreversible

Variable depending on dosing schedule

Oral

Delanzomib (CEP-187770)

Boronate β5

Reversible

Variable depending on dosing schedule

Oral/intravenous

2

* presently higher doses and once weekly schedules of carfilzomib are being evaluted

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Table 2  Monoclonal antibodies in clinical evaluation in multiple myeloma Target

Isotype

Monoclonal antibodies (mAbs) in advanced stages of clinical testing (phase 3) Elotuzumab (HuLu63)

SLAM7F (SLAM family member 7)

Humanized IgG1

Siltuximab (CNTO 328)

IL-6 (Interleukin-6)

Chimeric IgG1

Denosumab

RANKL (receptor activator of nuclear factor kappa B ligand)

Fully human IgG2

mAbs in earlier stages of clinical testing (phase 1 or 2) BT062

CD 138 (cluster of differentiation 138)

Chimeric IgG1 conjugated to DM4

Lorvotuzumab (IMGN901)

CD 56 (cluster of differentiation 56)

Humanized IgG1 conjugated to DM1

Daratumumab

CD 38 (cluster of differentiation 38)

Fully human IgG1

SAR650984

CD 38 (cluster of differentiation 38)

Humanized IgG1

BI-505

ICAM -1(intercellular adhesion molecule-1

Fully human IgG1

AVE1642

IGF-1R (Insulin growth factor 1 receptor)

Humanized IgG1

Figitumumab (CP-751, 871)

IGF-1R (Insulin growth factor 1 receptor)

Fully human IgG2

Bevacizumab (Avastin)

VEGF (vascular endothelial growth factor)

Humanized IgG1

LY2127399

BAFF (b-cell activating factor)

Fully human IgG4

Milatuzumab (hLL1, IMMU-115)

CD 74 (cluster of differentiation 74)

Humanized IgG1

Milatuzumab-DOX (hLL1-DOX, IMMU-110)

CD 74 (cluster of differentiation 74)

Humanized IgG1 conjugated to doxorubicin

Mapatumumab (HGS-ETR1)

TRAIL-R1

Fully human IgG1

Dacetuzumab (SGN-40)

CD 40 (cluster of differentiation 40)

Humanized IgG1

Lucatumumab (HCD122, Chir-12.12)

CD 40 (cluster of differentiation 40)

Fully human IgG1

Samalizumab (ALXN6000)

CD 200 (cluster of differentiation 200)

Humanized IgG2/4

IPH2101 (1-7F9)

KIR2DL1/2/3 (Killer cell immunoglobulin-like receptor 2DL1)

Fully human IgG4

CT-011

PD-1 (programmed cell death-1)

Humanized IgG1

BHQ880

DKK1 (dickkopf protein 1)

Fully human IgG1

MDX-1097

KMA (kappa myeloma antigen)

Chimeric IgG1

emerge as an active drug because it targets CD138, which is abundantly, but not exclusively, expressed on myeloma cells. Clinical results with BT-062 are limited and do not allow robust judgment of its potential, although the antibody has been shown to exert some clinical activity and has a tolerable toxicity profile.

Plitidepsin Plitidepsin is a cyclic depsipeptide that has been isolated from the Mediterranean marine tunicate, Aplidium albicans. This substance leads to mitochondrial cytochrome C release and induces G1 arrest and G2 blockade and apoptosis in tumor cells and interacts with c-Jun N-terminal kinases and p38 mitogen activated protein kinase (MAPK). Furthermore, it downregulates the vascular endothelial growth factor (VEGF) receptor-1 in leukemia cells and inhibits VEGF secretion. A phase 1 study with single-agent plitidepsin showed an overall response rate (including a minor response (MR) rate) of 22 %. Presently, plitidepsin in combination with dexamethasone is being compared in a phase III trial with single-agent dexamethasone therapy [9]. At the time being, results are not available.

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Filanesib Filanesib (ARRY-520) is a kinesin spindle protein inhibitor, which prevents the formation of a bipolar spindle, which is essential for meiosis [10]. Filanesib induces rapid apoptosis leading to cell death. Furthermore, it suppresses myeloid cell leukemia 1 (a member of the Bcl-2 (B cell lymphoma 2) family), which confers resistance to dexamethasone. Plitidepsin is active in myeloma cells; data generated with the use of the RPMI (Roswell Park Memorial Institute)-8226 cell line showed higher antimyeloma activity compared with bortezomib and synergistic activity when both drugs were combined. A phase II study with filanesib with and without dexamethasone showed an overall response rate in the range of 15 %. The median duration of response varied between 5.1 and 8.6 months [11]. Of note, 53 % of the patients were bortezomib and 57 % lenalidomide refractory, and 41 % were refractory to both drugs. Filanesib induces very little nonhematology toxicity, but induces grade 3 and grade 4 hematological toxicities, particularly anemia, neutropenia, and thrombocytopenia.

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Author's personal copy original report Afuresertib Afuresertib is an inhibitor of protein kinase B (AKT), which is believed to play an important role in the development and growth of cancer cells. A phase I dose escalation study showed single-agent activity in 6 of 34 treated patients with multiple myeloma. Three of them achieved partial response [12]. Combination of afuresertib with bortezomib/dexamethasone resulted in an overall response rate of 31 % in the entire group and 61 % in those who tolerated the highest dose, namely 150 mg daily.

Masitinib Masitinib, a tyrosine kinase inhibitor (TKI), interacts with stem cell growth factor receptor (c-kit) platelet derived growth factor receptor (PDGFR), and fibroblast growth factor receptor 3 (FGFR3), which are overexpressed in approximately 70 % of patients with t(4;14) [13]. The drug is already approved for treating mast cell tumors in veterinary medicine and presently is evaluated in a phase 3 trial in patients with and without t(4; 14) translocations. Other multitarget TKIs (PKC412, dovitinib) demonstrated antimyeloma activity in different test models [14–16]. The more specific FGFR3 inhibitors (SU5402 and PD173074) demonstrated activity in FGFR-overexpressing cell lines but not in those that also harbored (neuroblastoma RAS oncogene) mutations [14].

Inhibitors of the RAS-RAF-MEK-ERK pathway This pathway is activated when one of the extracellular mitogens binds to its membrane receptor, thereby activating Kirsten rat sarcoma viral oncogene homolog (KRAS) which itself activates the protein kinase activity of rapidly accelerated fibrosarcoma (RAF) and subse-

quently of map-erk kinase (MEK) and of mitogen activated protein kinase (MAPK), ensuing in activation of gene transcription. When one of the proteins in the pathway is mutated, it can become stuck in the “on” or “off” position, which is a necessary step in the development of many cancers and leading to uncontrolled growth [17]. Sorafenib, a RAF kinase inhibitor showed single-agent activity in 2 of 11 heavily pretreated myeloma patients in one study [18], but no responses were observed in another study [19] with 14 evaluable patients. Approximately 3–5 % of myeloma patients have mutations in the serine/threonine-protein kinase B-Raf (BRAF) a serine/threonine kinase. Inhibitors like vemurafenib are highly active in BRAF-mutated patients, but the duration of response usually is limited, as tumor cells often develop alternative activation pathways such as increased expression of PDGFR or activation of NRAS mutations. Vemurafenib resulted in significant tumor reduction in few patients with BRAF V600E mutations [20]. Trametinib, an MEK inhibitor, has been reported to exert substantial clinical activity in patients with heavily pretreated myeloma (Bart Barlogie, personal communication, November 2014).

Other inhibitors Inhibitors that interfere with B-cell receptor signaling like ibrutinib, an effective Bruton’s tyrosine kinase inhibitor, and idelalisib, an inhibitor of phosphoinositide-3 kinase, show remarkable activity in CLL (chronic lymphocytic leukemia) and some other lymphoid malignancies. Preliminary data show modest single-agent activity of ibrutinib in relapsed/refractory myeloma [21]. Dinaciclib, an inhibitor of cyclin-dependent kinases, demonstrated single-agent activity in advanced myeloma [22], which merrits testing with various combination partners. AB-199 is a Bcl-2 Inhibitor with significant activ-

Fig. 1  Checkpoint inhibitors targeting PD-1, PD-1L, or CTLA4 unleash the antitumor activity of the immune system. (modified according to Ott [29])

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Author's personal copy original report

ing to them while circulating in peripheral blood, but most myeloma patients have no or only low antimeasles antibody titers [28]. These viruses can be engineered to express additional genes, such as the gene for thyroidal sodium iodide symporter (MV-NIS), to allow for CT and singel photon emission computed tomography (SPECT) in vivo imaging of the extend of the disease and of the response to therapy. Preliminary data in two patients with relapsed/refractory multiple myeloma show complete clearance of bone marrow clonal myeloma cells in both patients and of peripheral plasmacytomas in one after exposure to virus material [28].

Conclusion Fig. 2  Schematic model of a measles virus construct binding via measles hemagglutinin glycoprotein to CD46 on myeloma cells before internalization, self-amplification, and myeloma cell destruction

ity in CLL. In vitro data showed induction of apoptosis in primary myeloma cells with t(11;14), only indicating that its activity is restricted to certain myeloma subtype only [23].

Checkpoint inhibitors Checkpoint inhibitors have primarily been tested in solid tumors, but newer studies also include multiple myeloma. These treatments work by targeting molecules that serve as checks and balances in the regulation of immune responses. By blocking inhibitory molecules or, alternatively, activating stimulatory molecules, these treatments are designed to unleash or enhance preexisting anticancer immune responses (Fig. 1). IPH-2101 is a fully human IgG4 anti-killer immunoglobulin—light receptor (KIR) monoclonal antibody (anti KIR antibody) binding to the respective antigens on NK cells and thereby stimulating and enhancing their activity [24, 25]. The antibody was tested in a phase I escalation trial in combination with lenalidomide [26]. Responses were mainly seen in the cohort with high dose levels and were noted in 5 of 15 patients. Several anti-PD-1 antibodies, such as pembrolizumab (MK-3475), pidilizumab (CT011), and nivolumab and the anti-CTLA-4 antibody ipilimumab presently are evaluated in early clinical trials in blood cancers, including multiple myeloma [27].

Oncolytic viruses Measles viruses are single-strand RNA viruses that bind via CD46 to myeloma cells, self-amplify at sites of tumor growth, and induce cell death in myeloma but not in normal cells (Fig.  2). Circulating measles antibodies may, however, hinder viruses to reach their target by bind-

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During recent years, research efforts have concentrated on the development of new conventional myeloma treatments, but now new treatment targets such as specific gene mutations are identified and drugs are developed aiming to inhibit activating cell processes. Another interesting strategy employs the immune system as powerful instrument in defense against the malignant clone. Encouraging results have already been reported for most of these strategies. For the years to come, a plethora of new treatments with better disease control and survival outcome hopefully will transform this previously incurable cancer into a disease that can be eradicated, or at least very well controlled allowing patients to live a normal or close to normal life. Conflict of interest  H. Ludwig received research funding from Takeda and honoraria from Janssen-Cilag, Celgene, Bristol Meyers, and Onyx. N. Zojer participated in advisory boards for Celgene, Novartis, and Takeda and held presentations for Janssen-Cilag, Celgene, and Amgen. W. Hilbe has no possible conflict of interest to declare.

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