Enhancing the therapeutic index of radiation in multiple myeloma

Drug Discovery Today: Disease Mechanisms

DRUG DISCOVERY

TODAY

Vol. 3, No. 4 2006

Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA

DISEASE Hematological disorders MECHANISMS

Enhancing the therapeutic index of radiation in multiple myeloma Apollina Goel1, Angela Dispenzieri2, Thomas E. Witzig2, Stephen J. Russell1,* 1 2

Molecular Medicine Program, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905, USA Division of Hematology and Internal Medicine, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905, USA

Multiple myeloma is a systemic malignancy that remains incurable with current therapy. Myeloma is highly radiosensitive, and radiation-based therapies have the potential to provide significant clinical benefit.

Section Editor: John Tisdale – National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, USA

Effective deployment of radiotherapy as a systemic modality in myeloma depends on maximizing its therapeutic index by efficiently and accurately delivering the radiation to sites of myeloma cell growth and increasing the radiosensitivity of myeloma cells relative to normal tissues. In this review, we discuss various strategies that are currently under investigation to enhance clinical benefit of radiotherapy in multiple myeloma.

normal tissues. Alternatively, radiation-modifying drugs can be used to target specific intracellular pathways (e.g. NF-kB, Ras signaling) that are aberrantly expressed in myeloma cells and/or to disrupt myeloma-bone marrow stromal cell interactions that support myeloma cell survival and radiation resistance. Interventions that combine targeted radiotherapy with radiosensitizing molecular target based drugs (chemoradiotherapy) are envisaged in the future. In this review, we discuss the development of novel radionuclide-based therapeutic regimens that may impact survival and quality of life in patients with multiple myeloma.

Introduction Multiple myeloma is a plasma cell neoplasm that is characterized by skeletal destruction, renal failure, anemia and hypercalcemia [1]. This malignancy has a median survival approximately 4 years and is responsible for more than 10,000 deaths each year in USA [2]. The majority of patients have chemosensitive disease but eventually become refractory [1]. High dose (myeloablative) melphalan therapy followed by autologous stem cell transplantation increases the number of complete remissions but does not greatly prolong survival [3,4]. Radioisotopes with medium energy beta emissions and half-life of a few days can be conjugated to myeloma-targeting ligands and delivered systemically to sites of myeloma growth, thereby reducing collateral toxicity to *Corresponding author: S.J. Russell ([email protected]) 1740-6765/$ ß 2006 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.ddmec.2006.11.012

Myeloma cells and the bone marrow microenvironment Multiple myeloma is sustained by several constitutively active autocrine and paracrine survival pathways in its microenvironment [5,6]. Several growth factors supporting myeloma cells have been identified such as interleukin (IL)-6, insulin-like growth factor (IGF)-1, vascular endothelial growth factor (VEGF), IL-1b, stromal cell-derived factor (SDF)-1a, tumor necrosis factor (TNF)-a, B-cell activating factor belonging to the TNF family (BAFF), a proliferationinducing ligand (APRIL), macrophage inflammatory protein (MIP-1a), Wnt and Notch family members. These growth factors, in combination with direct interactions between myeloma cells and bone marrow stromal cells or the extracellular matrix, activate a variety of myeloma cell signaling 515

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Figure 1. Signaling cascades that mediate growth, survival and migration in multiple myeloma are indicated. The adhesion of myeloma cells to the microenvironment favors production of cytokines (IL-6, IGF-1, VEGF, TNF-a, Fas-L), which activate receptors available in the myeloma cells. This interaction triggers downstream pathways like Ras/extracellular signal-regulated kinase (ERK), PI3K (phosphatidylinositol 30 -kinase)/Akt and NF-kB supporting tumor proliferation and apoptosis inhibition. Red arrows in the figure indicate signaling pathways that may be activated following ionizing radiation (IR) exposure to myeloma cells. IR results in phosphorylation of receptor tyrosine kinases (RTKs), which serve as docking sites for signaling entities of additional downstream signal transduction pathways such as the Ras/ERK, PI3K/Akt, pathways downstream of death receptors (Fas), procaspases and DNA damage signals, including the c-Jun N-terminal kinase (JNK). Activation of NF-kB is a well-conserved response in cells exposed to IR where IkB is phosphorylated the IKK complex, the phosphorylated IkB is additionally ubiquinated and degraded, resulting in NF-kB translocation into the nucleus to activate target genes exhibiting antiapoptotic functions. DNA damage caused by IR activates phosphatidylinositol (PI)-related kinases such as ataxiatelangiectasia mutated (ATM), ATM-related (ATR) protein and DNA-dependent protein kinase (DNA-PK) resulting in the downstream events of cell cycle arrest and induction of DNA repair genes. Radiation can induce cell cycle arrest or delay in G1, S and G2 by modulating checkpoint kinases (CHK) and cyclin kinase inhibitor (CKI) proteins. The molecular chaperone Hsp90 is involved in mediating cellular response to radiation by modulating client proteins like Cdks, Raf-1 and Akt. In addition, IR causes lipid peroxidation, ceramide generation and protein oxidation in the membrane, cytoplasm and nucleus. Abbreviations: Apaf-1, apoptotic protease activating factor-1; FADD, fas-associated death domain protein; HB-EGF, Heparin-binding epidermal growth factor-like growth factor; RIP, receptor interacting protein; TRADD, TNF receptor-1 (TNFR-1)-associated death domain protein.

pathways including phosphatidylinositol-3 kinase (PI3K)/ Akt, I kappa B kinase (IKK)/nuclear factor kappa-B (NF-kB), Ras/Raf/mitogen-activated protein kinase (MAPK) kinase (MEK)/extracellular signal-related kinase (ERK), and Janus kinase (JAK) 2/signal transducers and activators of transcription (STAT) 3 (Fig. 1). The PI3K/Akt signaling pathway is activated by cytokines IL-6 and IGF-1 [7], or as a consequence of N- and K-RAS mutations [8], or as a result of PTEN (phosphatase and tensin homologue deleted on chromosome 10 gene) mutations [9]. Constitutive activation of PI3K leads to activation of downstream kinase Akt/PKB (protein kinase B) resulting in phosphorylation of various proteins such as (i) NF-kB; (ii) Bad; caspase 9 and oncoprotein Mdm2, which mediates p53 degradation promoting antiapoptosis; (iii) fork-related transcription factor 1 (FKHRL-1), which inhibits transcription of genes coding for Fas-ligand, the pro-apoptotic protein Bim and the cyclin-dependent kinase inhibitor 516

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p27Kip1; and (iv) glycogen synthase kinase-3 (GSK-3), which is inhibited thereby stabilizing cell cycle regulators including cyclin D1, cyclin E and c-Myc. Furthermore, mammalian target of rapamycin (mTOR), the downstream ‘rate limiting’ regulatory protein of the PI3K/Akt pathway, activates two downstream pathways: the 40S ribosomal protein S6 kinase (p70S6K) and the 4E-binding protein 1 (4E-BP1), regulating G1/S checkpoint and translation of mRNA transcripts, thereby promoting cell growth and proliferation. Thus, both the bone marrow microenvironment and oncogenic mutations activate a complex signaling network that favors myeloma cell survival and promotes tumor expansion. Increasingly, it is recognized that the effects of many antimyeloma modalities are due in part to an indirect action of attenuating bone marrow support to the myeloma cells. Also, compared with other lymphoid cells and hematopoietic progenitors, myeloma cells are rather radioresistant [10,11]. As

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plasmacytomas show high clinical radioresponsiveness to radiotherapy, disruption of microenvironmental interactions may be a key factor contributing to the reported in vivo radiosensitivity of this malignancy.

Radiotherapy of multiple myeloma In vivo, myeloma cells are highly radiosensitive, and radiotherapy has been used for more than 50 years as definitive treatment for potential cure of patients with solitary plasmacytoma [12]. With radiotherapy doses of 40 Gy or more, there have been reports of local control rates of 88–100% for solitary plasmacytoma of bone and 80–100% for extramedullary plasmacytoma [13]. Radiotherapy also provides effective palliation of pain, neurologic compromise or structural instability from focal disease in multiple myeloma. Lower doses of 10–20 Gy will afford effective palliation in the vast majority of patients while allowing for retreatment at the same site in those few in whom it is required [14]. However, efforts to employ radiation as a systemic modality for definitive therapy of multiple myeloma have been problematic. Total body irradiation (TBI) has been used in combination with or in place of melphalan as myeloablative conditioning therapy before infusion of autologous stem cells. However, efficacy is no better than with melphalan conditioning and toxicity is greater [3,15]. Double hemibody radiotherapy, in which the upper half and then the lower half of the body are sequentially irradiated, is associated with unacceptable toxicity [16,17]. Targeted radionuclide therapy provides an appealing alternative to TBI or double hemibody radiotherapy, offering the prospect of selective delivery of ionizing radiation to sites of myeloma cell growth. Three common patterns of disease are recognized in multiple myeloma; diffuse, nodular and mixed [18,19]. ‘Diffuse’ describes a pattern of relatively homogeneous bone marrow infiltration by myeloma plasma cells, whereas ‘nodular’ describes an alternative disease distribution in which there are multiple discrete, well-vascularized tumors (myelomas), typically located in the axial skeleton and typically strongly stimulating osteoclastic bone resorption. The mixed pattern of diffuse and nodular disease is seen most frequently in patients with advanced (stage III) disease. In addition to these well-recognized disease patterns, there is evidence for a third disease compartment comprising the treatment-resistant myeloma stem cells from which the disease ultimately relapses. There is some evidence to suggest that these cells may be CD20 positive [20] and may therefore take sanctuary in peripheral lymphoid organs including the liver, spleen and lymph nodes. Radioactive materials decay to release alpha particles, beta particles or gamma rays. Alpha particles are essentially helium nuclei, whereas beta particles are fast moving electrons or positrons. In myeloma, targeted delivery of radionuclides emitting short-range beta particles (e.g., iodine-131

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or samarium-153) may allow the delivery of effective doses of radiation to neoplastic plasma cells in bone marrow or in tumor nodules while sparing other organs. Through their g emissions these radionuclides are also amenable to noninvasive photon-based imaging studies to reveal the biodistribution of the isotope in the body, facilitating complex dosimetry calculations [21]. Short-lived alpha-emitting radionuclides such as bismuth-212 transfer their energy over a much shorter path length compared to beta particles and have been used for the treatment of myeloma [22]. In a comparative study using myeloma cell lines, 213[Bi]-B-B4 has shown markedly greater efficacy than 131[I]-B-B4, suggesting that a-RIT might be more suitable for treating singlecell tumor models such as multiple myeloma [23] than b-RIT. Depending on the dose administered, radiation can be used with or without stem cell support. The key to effective utilization of radioisotopes for myeloma therapy is to deliver them accurately and efficiently to all sites of disease in the body, thereby reducing collateral toxicity to normal tissues. This can be achieved by conjugating the radioisotope to a targeting ligand such that it localizes directly to bone or to the surface of the myeloma cells or genetically modifying the myeloma cells to facilitate radioisotope trapping (Table 1). Preliminary clinical studies in myeloma patients have tested bone-seeking compounds conjugated with radionuclides holmium-166 [24,25] or samarium-153 [26,27]. 153-Sm-EDTMP is a beta-emitting radionuclide complex that binds rapidly and irreversibly to the surfaces of cortical and trabecular bone throughout the skeleton and is licensed for palliation of bone pain caused by metastatic cancer. This agent localizes particularly well to newly formed bone at the periphery of osteoblastic bone metastases [21]. The primary dose limiting toxicity is myelosuppression, which is mild and reversible at lower doses (1–3 mCi/kg) but mandates the use of autologous stem cell rescue at higher doses [26,28–31]. High dose (30 mCi/kg) 153-Sm-EDTMP has been administered to myeloma patients undergoing high dose melphalan therapy with stem cell rescue [27]. Using this approach, the radiation absorbed dose delivered to the bone marrow has been considerably higher than can be delivered using TBI, but the marrow absorbed dose is heterogeneous and the isotope does not necessarily co-localize with neoplastic plasma cells [32]. The major theoretical limitation of 153-Sm-EDTMP is that it cannot deliver lethal radiation to nodular myeloma deposits because these are devoid of bone trabeculae and typically do not provoke an osteoblastic reaction at their periphery. Indium-111 diethylenetriaminepentaacetate adenosylcobalamin (In-111DAC) is a Vitamin B12 labeled radionuclide conjugate that has shown preferential uptake in malignant tissue compared to normal tissue through imaging transcobalamin II receptors in sarcoma xenografts in nude mice [33]. Preclinical studies in murine myeloma models have shown that In-111DAC is an excellent imaging agent (Greipp PT www.drugdiscoverytoday.com

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Table 1. Various agents that can be used for targeted radiotherapy for multiple myeloma Agent

Radiation source

Radiation target

Clinical status

Refs

153-Sm-EDTMP

153[Sm]

Hydroxyapatite (bone)

Phase I/II

[63]

166-Ho-DOTMP

166[Ho]

Hydroxyapatite (bone)

Phase I/II

[24]

Potential radiation source

213[Bi]-MAb B-B4

213[Bi]

CD138

Phase I/II

[22]

Anti-CD20 Aba

–

CD20

Phase I/II

[35]

90[Y], 131[I]

Anti-CD40 Ab

–

CD40

Phase I/II

[37,38]

90[Y], 131[I]

Anti-HM1.24 Ab

–

HM1.24

Phase I

[40]

Anti-CD71 Ab

–

CD71

Preclinical

[76]

90[Y], 131[I]

Anti-CD38 Ab

–

CD38

Preclinical

[39]

90[Y], 131[I]

Preclinical

[77]

90[Y], 131[I] 131[I]

Anti-integrin Ab c

–

b

VLA-4

d

e

f

BLyS

–

BAFF-R /TACI /BCMA

Preclinical

[41]

MV-NIS

131[I]

CD46

Preclinical

[43]

Vitamin B12

111[In]

TCII-Rg

Preclinical

[34]

90[Y], 111[In] 131[I], 213 [Bi]

a

Ab: antibody. VLA-4: very late antigen-4. c BlyS: B-lymphocyte stimulator. d BAFF-R: receptor for B-cell activating factor belonging to the tumor necrosis factor [TNF] family. e TACI: Transmembrane activator and calcium modulating cyclophilin ligand interactant. f BCMA: B-cell maturation antigen. g TCII-R: transcobalamin II receptors. b

et al., unpublished) and could be utilized to complete routine studies in staging myeloma patients and assessing tumor burden. An extreme elevation in the Vitamin B12 transport protein has been noted in multiple myeloma patients [34] and appears to correspond to the increased metabolic demand for the vitamin on the murine imaging studies. In the near future, therapeutic studies at Mayo Clinic may entail In-111DAC with melphalan and/or bortezomib. Alternatively, adenosylcobalamin labeled with Y-90 or Bi-213 are being developed to assess if greater radiation deposition within myeloma cells can be achieved to improve therapeutic efficacy. Radiation can be targeted directly to myeloma cells using radiolabeled antibodies or protein ligands recognizing myeloma cell surface markers such as syndecan-1 (CD138), CD38, CD40, BLys receptor(s), HM1.24 or CD71 (Table 1). The monoclonal antibody B-B4, which targets CD138 has been coupled with 213[Bi] and used for radioimmunotherapy of myeloma cell lines [22]. Circulating clonotypic B-cells from myeloma patients have been shown to express moderate levels of CD20, providing a basis for trials of CD20-directed serotherapy with Rituximab [35]. A clinical trial of CD20-directed radioimmunotherapy using ibritumomab tiuxetan (zevalin) incorporated in a melphalan-based stem cell transplant conditioning regimen to eliminate myeloma progenitor cells is currently underway at Mayo Clinic [36]. CD40, a member of the TNF receptor superfamily, is highly expressed on myeloma cells where binding by its natural ligand (CD40L) leads to growth induction. Anti-CD40 mAb CHIR-12.12 and SGN-40 have shown cytotoxicity in human myeloma [37,38]. Anti-CD38 mAb (IB4) 518

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coupled to a type 1 ribosome-inactivating protein saporin-S6 has shown activity against myeloma [39] and humanized mAb against HM1.24 caused antibody-dependent cellular cytotoxicity myeloma cells [40]. B-lymphocyte stimulator (BLyS), a TNF family member that is critical for maintenance of normal B-cell development and homeostasis, is overexpressed in a variety of B-cell malignancies including multiple myeloma [41]. Studies have shown that BLyS may serve as a targeting molecule for selective delivery of radionuclides to malignant B-cells [42]. As an alternative approach to the use of chemical carriers or protein ligands conjugated to radionuclides, we have used an engineered version of the Edmonston vaccine strain of measles virus (MV-NIS) to deliver a gene that increases the avidity of multiple myeloma cells for radioactive iodine. The MV-NIS virus selectively binds, infects and kills myeloma cells via the cell surface marker CD46, which is expressed in greater abundance on their surface compared to other bone marrow-resident cells. The virus has been engineered to incorporate a gene coding for the human thyroidal iodide symporter (NIS) such that infected cells express the NIS protein, resulting in the selective trapping of radioiodine by infected myeloma cells at sites of active virus propagation [43,44]. The MV-NIS virus will soon be tested administered intravenously to patients with relapsed/refractory multiple myeloma at Mayo Clinic in a Phase I dose escalation study.

Cellular targets of radiation The cellular response to damage inflicted by ionizing radiation has been extensively characterized [45,46]. Sensing of DNA damage in the form of single- and double-strand breaks

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Drug Discovery Today: Disease Mechanisms | Hematological disorders

leads to cell cycle arrest and the activation of DNA repair mechanisms. In parallel with this cellular first-aid response, there is simultaneous activation of pro-apoptotic and antiapoptotic signaling cascades whose relative intensities are the key determinants of whether the cell will live or die (Fig. 1). Radiation activates the PI3K/Akt pathway, and several enzymes (ATM, ATR, DNA-PK) involved in sensing DNA damage are members of the PI3K-related protein kinase (PIKK) family. NF-kB can be secondarily activated by PI3K [47], Akt [48] and MAPK cascades [49]. Tumor suppressor protein p53, known as ‘guardian of the genome’, is a critical regulator of the cellular response to radiation and induces apoptosis, cell cycle arrest and premature senescence of cells. Thus, p53 mutations or deletions are a common occurrence in various cancers. Surprisingly, in myeloma patients, p53 is rarely mutated or deleted at diagnosis, but these changes may be associated with disease progression [5]. To attain a maximum therapeutic benefit of radiotherapy in myeloma, it is essential to first delineate key molecules or signal transduction pathways that are constitutively active in myeloma cells or modulated after radiotherapy and decrease the likelihood of apoptosis. In myeloma, radio-resistance is increased by RAS-activating mutations and by IL-6-driven Ras pathway activation [50]. Also, the ubiquitin proteasome pathway is of major relevance to the survival of irradiated myeloma cells because proteasomes themselves are redox-sensitive targets of radiation and several proteins modulating the cellular response to radiation undergo radiation-induced post-translational modifications that depend on the ubiquitin proteasome pathway [51].

Radiosensitizers in multiple myeloma Radiosensitizers can be defined as agents that, when given before or during radiation exposure, lead to potentiation of

radiation injury or modification of the cellular response to radiation injury [52]. Radiosensitization strategies that increase the frequency of DNA strand breaks include the modification of DNA with halogenated pyrimidine analogues, enhancement of free radical generation (through water radiolysis) either by enhancing tumor oxygenation, using of small molecules that mimic the effect of oxygen, or suppressing the levels of free radical scavengers such as glutathione. Drugs that modify the cellular response to radiation damage can be divided broadly into three categories, depending whether they interfere with the DNA repair process, accentuate pro-apoptotic signaling or interfere with antiapoptotic survival signaling. DNA repair is inhibited by fluoropyrimidines such as 5-fluorouracil, gemcitabine and capecitabine that selectively perturb tumor nucleoside metabolism [53]. Increased apoptotic signaling can be achieved through the use of TNF-a, although this multifunctional cytokine can act as a survival factor for myeloma cells [54]. Several drugs that interfere with antiapoptotic survival signaling pathways have been tested as radiosensitizers with encouraging results. These include tyrosine kinase inhibitors, farnesyltransferase inhibitors and, more recently, cyclooxygenase 2 inhibitors [55,56]. Also, it has recently become clear that the NF-kB signaling pathway can be important for survival signaling and is therefore a potentially appealing target for the development of new radiosensitizers [57–59]. The combination of radiation with chemotherapy has not yet been effectively exploited in myeloma therapy, although there are several approaches that are currently under investigation (Table 2). The combination of melphalan and 153Sm-EDTMP has been found to be safe and effective when used in myeloablative preclinical myeloma models [60,61] and in clinical studies [62,63]. PS-341 is a synthetic dipeptide boronate compound that inhibits 26S proteasome activity and

Table 2. Various agents that have been combined with radiotherapy in multiple myeloma Agent(s)

Drug target

Radiation source

Radiation target

Clinical status

Refs

Melphalan

DNA

153-Sm-EDTMP

Hydroxyapatite (bone)

Phase I

[63]

Vincristine, melphalan, cyclophosphamide, prednisone

DNA

Sequential hemibody radiation therapy

Nonspecific

Phase I/II

[78]

Zoledronic acid

Osteoclasts

153-Sm-EDTMP

Hydroxyapatite (bone)

Pilot

[72]

Melphalan, prednisone

DNA

Total bone marrow irradiation

Nonspecific

Phase I

[79]

PS-341

26S proteasome

153-Sm-EDTMP

Hydroxyapatite (bone)

Phase I/II

[69]

Paclitaxel, doxorubicin

Tubulins hetero-dimers, DNA

213[Bi]-B-B4

Myeloma cells

Preclinical

[75]

PS-341

26S proteasome

External beam

Nonspecific

Preclinical

[11]

Anti-CD40 mAb 5C11

CD40

External beam

Nonspecific

Preclinical

[80]

Epigallocatechin-gallate

Antioxidant

External beam

Nonspecific

Preclinical

[73]

Resveratrol (trans-3,40 ,5trihydroxystilbene)

Antioxidant

External beam

Nonspecific

Preclinical

[74]

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has shown remarkable activity in patients with multiple myeloma [64]. PS-341 blocks proteasomal degradation of multiple cellular proteins involved in the regulation of cell cycle progression, DNA damage repair, apoptosis and survival [65]. Although the various mechanisms by which PS-341 mediates its antimyeloma effects are the subject of continuing study, it is clear that the drug is a potent inhibitor of the NF-kB signaling pathway, which is constitutively active in myeloma cells [66]. For this reason, there has been considerable interest in the possible use of PS-341 to the cells sensitize to the effects of DNA damaging agents including ionizing radiation [67]. Several studies have pointed to the feasibility of using PS-341 as a radiosensitizer in nonplasma cell malignancies [57,59,68]. In addition, we recently demonstrated that PS-341 is a potent radiosensitizer for myeloma plasma cells and that this activity strongly correlates with its inhibition of NF-kB survival signaling [11]. Using a syngeneic, orthotopic 5TGM1 murine myeloma model, we subsequently observed a synergistic antimyeloma activity of PS-341 used in combination low dose (nonmyeloablative) 153-Sm-EDTMP [69]. Bisphosphonates are routinely used for the prevention of skeletal destruction in myeloma, [70] and zoledronic acid was recently shown to have synergistic toxicity to myeloma cells when combined with external beam irradiation on myeloma cell lines [71], and on this premise, a small pilot trial using the combination has been performed combining it with 153-SmEDTMP in myeloma patients [72]. Epigallocatechin gallate, a potent antioxidant present in tea, and resveratrol (trans3,40 ,5-trihydroxystilbene), a natural compound present in various plant species and relatively found in abundance in wine, have also been shown to enhance radiation-induced apoptosis of myeloma cell lines when combined with external beam irradiation [73,74]. Doxorubicin, a DNA intercalator, and Paclitaxel, an inhibitor of microtubule polymerization, have been combined with 213-bismuth aradioimmunotherapy resulting in synergistic cytotoxicity to myeloma cell lines, although the mechanism of synergy was not elucidated in these studies [75]. Several additional drugs that modulate intracellular signal transduction pathways, apoptosis, cell cycle checkpoints and antiangiogenic agents may warrant investigation as radiation sensitizers in myeloma.

Summary With the treatments used currently, multiple myeloma remains incurable and causes more than 10,000 deaths each year in the USA [2]. High dose melphalan therapy, followed by autologous stem cell transplantation, increases the number of complete remissions but does not greatly prolong the median survival, which currently stands at approximately 4 years [1]. Because the majority of myeloma patients are not candidates for stem cell transplantation, and those who do 520

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receive high dose therapy will eventually relapse, efforts toward the development of a nonmyeloablative radionuclide-based regimen are of immense clinical importance. The therapeutic index of a targeted radionuclide is determined by two factors: biodistribution of the radionuclide and radiosensitivity of the tumor cells relative to exposed normal tissues. To achieve high therapeutic ratios, all tumor cells in the body should be exposed to a supralethal dose of radiation, whereas normal tissue exposures should be limited to much lower nondestructive doses. Because myeloma cells reside primarily in the bone marrow, the primary toxicity of bone-seeking or myeloma cell targeted radionuclides is to bone marrow. Thus, there is a strong rationale to develop approaches to selectively increase the sensitivity of myeloma cells to ionizing radiation without affecting the radiosensitivity of normal bone marrow progenitors. This field of endeavor is still in its infancy, but great advances are expected in the coming years based on the use of highly specific radiolabeled targeting ligands administered in combination with novel radiosensitizing drugs.

Acknowledgements Grant support: This study has been supported by JARI Research Foundation and grant from the National Institutes of Health (NIH; CA100634-02).

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