Bortezomib-induced Peripheral Neuropathy Research Articles

Acupuncture for Neuropathic Pain Due to Bortezomib in a Patient with Multiple Myeloma

Multiple myeloma (MM) is characterised by an increase in plasma cells, particularly in the bone marrow but also in other organs and systems, and with the abnormal production of immunoglobulin. Bortezomib, a current treatment option, inhibits angiogenesis by proteasome inhibition and is known to be effective in the treatment of MM. Peripheral neuropathy (PN) is a common dose-related side effect of bortezomib in patients with MM. We describe a case of PN due to bortezomib treatment which responded dramatically to acupuncture treatment, enabling his bortezomib treatment to continue. The patient was a 74-year-old man with pain, numbness, tingling and weakness in his hands and feet after 22 days of bortezomib treatment given by the haematology clinic. His neuropathic pain score was 8/10. There were no autonomic symptoms. Electroneurophysiological testing confirmed sensorimotor PN. Acupuncture treatment was planned as his neuropathic pain continued. Acupuncture was administered bilaterally to ST36, SP6 and LI4 15 times (every other day in the first five sessions and then twice a week). The numbness, tingling and pain symptoms substantially decreased after the first two treatments. After the 15th session acupuncture treatment was continued once a month. At the end of the sixth month the neuropathic pain assessment score was 0/10. There was no side effect of acupuncture treatment. Acupuncture seems promising as a complementary medical treatment for neuropathic pain from bortezomib-induced PN. Clinical studies involving more cases and electrophysiological studies are necessary to investigate the effectiveness of acupuncture.

(337) Bortezomib-induced neuropathic pain is blocked and reversed by blocking the S1P/S1PR1 axis

Bortezomib-induced peripheral neuropathy (BIPN) is a major dose-limiting factor for bortezomib, which is used to treat multiple myeloma. BIPN, often accompanied by chronic neuropathic pain, can last for months to years after treatment cessation, decreasing the patient’s quality of life; there are currently no effective treatments. Our lab has recently shown that the spingosine-1-phosphate (S1P) to S1PR1 pathway is important in the initiation and maintenance of BIPN, through peripheral and central mechanisms.

Assessment of bortezomib induced peripheral neuropathy in multiple myeloma by the reduced Total Neuropathy Score

We evaluated bortezomib induced peripheral neuropathy (BIPN) characteristics in an attempt to better clarify the type, grade, duration and reversibility of neuropathy as well as investigate possible peripheral neuropathy (PN) risk factors and detect the best way to manage it. We calculated the grading of neuropathy using the Total Neuropathy Score reduced version (TNSr) in a series of 51 patients with relapsed/refractory multiple myeloma treated with bortezomib. Seventy percent developed clinical PN. BIPN, although manageable, is frequently underestimated in patients treated with bortezomib intravenously. Continuous follow-up and management of PN are needed to avoid quality of life impairment.

TNF-α-mediated JNK activation in the dorsal root ganglion neurons contributes to Bortezomib-induced peripheral neuropathy

Bortezomib (BTZ) is a frequently used chemotherapeutic drug for the treatment of refractory multiple myeloma and hematological neoplasms. The mechanism by which the administration of BTZ leads to painful peripheral neuropathy remains unclear. In the present study, we first determined that the administration of BTZ upregulated the expression of TNF-α and phosphorylated JNK1/2 in the dorsal root ganglion (DRG) of rat. Furthermore, the TNF-α synthesis inhibitor thalidomide significantly blocked the activation of both isoforms JNK1 and JNK2 in the DRG and attenuated mechanical allodynia following BTZ treatment. Knockout of the expression of TNF-α receptor TNFR1 (TNFR1 KO mice) or TNFR2 (TNFR2 KO mice) inhibited JNK1 and JNK2 activation and decreased mechanical allodynia induced by BTZ. These results suggest that upregulated TNF-α expression may activate JNK signaling via TNFR1 or TNFR2 to mediate mechanical allodynia following BTZ treatment.

The positive effects of one-hour intravenous administration of bortezomib on peripheral neuropathy in multiple myeloma patients.

Bortezomib-induced peripheral neuropathy (BiPN) in multiple myeloma (MM) patients is a common and serious side effect. Currently, it has been reported that subcutaneous (SC) administration of bortezomib decreases the incidence of BiPN as compared to standard intravenous (IV) bolus injection without any differences in efficacy. However, there are reports of severe injection site reaction following SC administration of bortezomib. The aim of this study was to evaluate the response rate and incidence of BiPN following one-hour IV infusion of bortezomib. The data was retrospectively collected from MM patients who had been treated with IV administration of bortezomib for one hour. Twenty-three patients were evaluated (median age 72 years, 13 males). The median number of treatment cycles was 5 (range 2–10). The cumulative bortezomib dose was 26.0 mg/m2 (14.3–66.3) and percent of actual per expected cumulative dose was 90% (50–100). The overall response (complete response plus partial response) rate was 65%. The incidence of BiPN was 57% (n = 13) and incidence of severe neuropathy was 4% (n = 1). One-hour IV infusion of bortezomib was an effective regimen for MM with reduced incidence of severe BiPN. This route of administration of bortezomib could be an alternative mode of delivery for patients with severe injection site reactions following SC administration.

Gabapentin Inhibits Bortezomib-Induced Mechanical Allodynia Through Supraspinal Action in Mice

Bortezomib, an inhibitor of proteasome holoenzyme, is used to treat relapsed and refractory multiple myeloma. Peripheral neuropathy is a treatment-limiting adverse effect of bortezomib and is very difficult to control. In this study, we examined the efficacy of gabapentin in inhibiting bortezomib-induced peripheral neuropathy. Single intravenous injections of bortezomib (0.03 – 0.3 mg/kg) dose-dependently induced mechanical allodynia with a peak effect 12 days after injection. Bortezomib (0.3 mg/kg) also caused mechanical hyperalgesia, but neither affected thermal nociception nor induced cold allodynia. Bortezomib increased the response of the saphenous nerve to weak punctate stimulation but not response to cool stimulation of the skin. When administered 12 days after bortezomib injection, oral and intracisternal gabapentin markedly inhibited mechanical allodynia. Intrathecal, but not intraplantar, gabapentin had a tendency to reduce mechanical allodynia. The antiallodynic activity of orally administered gabapentin was suppressed by noradrenaline, but not serotonin, depletion in the spinal cord. Bortezomib did not affect the expression levels of the calcium channel α2δ-1 subunit, a high-affinity binding site of gabapentin, in the plantar skin, spinal cord, medulla oblongata, and pons. These results suggest that gabapentin inhibits bortezomib-induced mechanical allodynia, most likely through the activation of the descending noradrenergic system.

Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity mechanisms in bortezomib-induced peripheral neuropathy

Bortezomib (BTZ) is the first proteasome inhibitor entered in clinical practice. Peripheral neuropathy is likely to be a class side effect of these drugs, although its severity is largely variable, and it deserves to be further investigated, since the mechanisms of BTZ-induced peripheral neurotoxicity (BiPN) are still unknown. In our study, we investigated in vivo and in vitro possible pathogenic events relevant to BiPN using a well-established rat model, with particular reference to the extent of proteasome inhibition and the effects on α-tubulin polymerization in sciatic nerves and dorsal root ganglia specimens obtained from animals treated with chronic regimens at a dose of 0.2 mg/kg intravenously. The same assessments were also performed after a single injection. Moreover, these studies were replicated in vitro using embryonic DRG neurons exposed to 100 nM BTZ and adult DRG neurons exposed to 10–50 nM BTZ for 24 h and 48 h. A significant increase in the polymerized fraction of α-tubulin and prolonged proteasome inhibition were observed after the chronic BTZ treatment in vivo. Recovery to physiological levels was observed after a 4-week follow-up post-treatment period. Proteasome inhibition and increased α-tubulin polymerization were also observed following BTZ treatment of both embryonic and adult DRG neurons in vitro. Our in vivo results suggest that proteasome inhibition and alteration of tubulin dynamics contribute to BiPN. The in vitro systems here described reliably replicate the in vivo results, and might therefore be used for further mechanistic studies on the effects of proteasome inhibitors on neurons.

Reduced-Dosage Of Three Drugs Combination Of Cyclophosphamide, Bortezomib and Dexamethasone (reduced-CyBorD) Is Suitable For Elderly Frail Patients With Multiple Myeloma

BackgroundThe three drugs combination of cyclophosphamide, bortezomib and dexamethasone (CyBorD) is highly active regimen for the treatment of the patients with multiple myeloma (MM). However, twice-weekly schedule of bortezomib and high dose dexamethasone has been shown to cause significant toxicities, including peripheral neuropathy (PN) and thrombotic events. Once-weekly bortezomib induction therapy with reduced dosage of dexamethasone (modified-CyBorD) has shown less toxicity with high response rate equal to original regimen (Reeder, CB et al. Leukemia 2009). However, it was found more than half of the patients still developed bortezomib induced PN (BiPN) in this modification. Thus it was still concerned adverse event for the transplant ineligible patients, especially frail elderly patients because it often caused interruption or withdrawal of the treatments, resulting in fewer efficacies. Under these circumstances, we have studied the reduced-dosage of CyBorD regimen (reduced-CyBorD) in the treatment of transplant ineligible patients with MM to assess response and toxicity. MethodsThe protocol consisted of bortezomib given intravenously at a dose of 1.3 mg/m2 once a week on days 1, 8, 15, cyclophosphamide orally at a dose of 50 mg daily on days 1-21, and dexamethasone orally or intravenously at a dose of 20 mg daily on days 1,2,8,9,15,16 in 4-week cycles. Total of 32 patients, including 20 newly diagnosed and 12 refractory, were treated with reduced-CyBorD and evaluated its efficacy and safety. ResultsThe median age was 72 years (range from 62 to 88). 14 patients were more than 75 year-old (44 %). 15 patients were female. According ISS, 4 patients were classified in stage I, 10 were in II, and 18 were in III. The overall response (ORR) was 90.6 % with 43.8 % of CR/nCR (6 CR, 8 nCR, 7 VGPR and 8 PR). Hematological adverse events were anemia (18.8%; G1/2 n=7), neutropenia (37.5%; G1/2 n=10, G3/4 n=2), lymphocytopenia (43.8%; G1/2 n=10, G3/4 n=4), thrombocytopenia (12.5%; G1/2 n=1, G3/4 n=3). Non-hematological adverse events were pneumonia (12.5%; G2 n=2, G3 n=2), VZV infection (15.6%; G1/2 n=5), cerebral infarction (3.1%; G2 n=1). Importantly, only 6 patients (18.8%) developed grade 1 PN, and no patient reduced or discontinued bortezomib due to PN. The overall survival (OS) at 1, 2, and 3 years were 81, 63.1, and 45.9 %, respectively. In this study, neither inferior response nor poor survivals were significantly observed between over 75 year-old patients group (n=14) and under 75 year-old group (n=18) (ORR; 100 vs 83.4 %, CR/nCR; 42.9 vs 44.4 %, 1-year PFS 54.6 vs 50 %, and 3-year OS 29.8 vs 55 %). ConclusionsReduced-CyBorD with three times once-weekly bortezomib retained high efficacy seen in standard and modified CyBorD previously reported (ORR; 90.6 vs 88 and 93 %, CR/nCR; 43.8 vs 39 and 43 %). These results showed that our regimen has less toxicity, especially BiPN (18.8 %) compared with those previous regimens (64 % and 57 %), resulting in no discontinuation nor reduction of bortezomib. Furthermore, over 75 year-old patients group did not showed inferior outcomes in comparison with under 75 year-old patients group. Our results suggested that reduced-CyBorD might be suitable for the transplant ineligible patients, especially elderly frail patients (over 75 year-old) with MM. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Phytohemagglutinin-induced IL2 mRNA in whole blood can predict bortezomib-induced peripheral neuropathy for multiple myeloma patients

The proteasome inhibitor bortezomib has revolutionized the treatment of multiple myeloma. However, bortezomib-induced peripheral neuropathy (BiPN) is a serious complication that compromises clinical outcome. If patients with a risk of developing BiPN could be predicted, physicians might prefer weekly, reduced-dose, or subcutaneous approaches. To seek biomarkers for BiPN, we conducted a multicenter prospective study using a simple and unique system. Multiple myeloma patients received twice-weekly or weekly 1.3 mg/m2 bortezomib intravenously, and a 2-ml sample of whole blood was obtained before treatment and 2–3 days and 1–3 weeks after the first dose. Induction of gene expression was then quantified by real-time PCR. Of a total of 64 enrolled patients, 53 patient samples qualified for mRNA analysis. The BiPN grade was associated with phytohemagglutinin-induced IL2, IFNG and TNFSF2, as well as with lipopolysaccharide-induced IL6 levels. More importantly, of the 19 patients showing a ⩾3-fold increase in phytohemagglutinin-induced IL2, 14 did not suffer from BiPN (73.7% prediction), whereas of the 34 patients with a <3-fold increase, 23 experienced BiPN (67.6% prediction). Therefore, we concluded that pretreatment of phytohemagglutinin-induced IL2 mRNA levels in whole blood serve as a promising biomarker for predicting BiPN, and this finding warrants validation in a larger study.

Proteasome inhibition induces DNA damage and reorganizes nuclear architecture and protein synthesis machinery in sensory ganglion neurons.

Bortezomib is a reversible proteasome inhibitor used as an anticancer drug. However, its clinical use is limited since it causes peripheral neurotoxicity. We have used Sprague-Dawley rats as an animal model to investigate the cellular mechanisms affected by both short-term and chronic bortezomib treatments in sensory ganglia neurons. Proteasome inhibition induces dose-dependent alterations in the architecture, positioning, shape and polarity of the neuronal nucleus. It also produces DNA damage without affecting neuronal survival, and severe disruption of the protein synthesis machinery at the central cytoplasm accompanied by decreased expression of the brain-derived neurotrophic factor. As a compensatory or adaptive survival response against proteotoxic stress caused by bortezomib treatment, sensory neurons preserve basal levels of transcriptional activity, up-regulate the expression of proteasome subunit genes, and generate a new cytoplasmic perinuclear domain for protein synthesis. We propose that proteasome activity is crucial for controlling nuclear architecture, DNA repair and the organization of the protein synthesis machinery in sensory neurons. These neurons are primary targets of bortezomib neurotoxicity, for which reason their dysfunction may contribute to the pathogenesis of the bortezomib-induced peripheral neuropathy in treated patients.

Bortezomib alters microtubule polymerization and axonal transport in rat dorsal root ganglion neurons

Bortezomib is part of a newer class of chemotherapeutic agents whose mechanism of action is inhibition of the proteasome-ubiquitination system. Primarily used in multiple myeloma, bortezomib causes a sensory-predominant axonal peripheral neuropathy in approximately 30% of patients. There are no established useful preventative agents for bortezomib-induced peripheral neuropathy (BIPN), and the molecular mechanisms of BIPN are unknown. We have developed an in vitro model of BIPN using rat dorsal root ganglia neuronal cultures. At clinically-relevant dosages, bortezomib produces a sensory axonopathy as evidenced by whole explant outgrowth and cell survival assays. This sensory axonopathy is associated with alterations in tubulin and results in accumulation of somatic tubulin without changes in microtubule ultrastructure. Furthermore, we observed an increased proportion of polymerized tubulin, but not total or acetylated tubulin, in bortezomib-treated DRG neurons. Similar findings are observed with lactacystin, an unrelated proteasome-inhibitor, which argues for a class effect of proteasome inhibition on dorsal root ganglion neurons. Finally, there is a change in axonal transport of mitochondria induced by bortezomib in a time-dependent fashion. In summary, we have developed an in vitro model of BIPN that recapitulates the clinical sensory axonopathy; this model demonstrates that bortezomib induces an alteration in microtubules and axonal transport. This robust model will be used in future mechanistic studies of BIPN and its prevention.

Efficacy comparison between standard and reduced doses of bortezomib combined with adriamycin and dexamethasone in the treatment of patients with multiple myeloma

To compare the efficacy and safety of standard or reduced doses of bortezomib combined with adriamycin and dexamethasone (PAD) in patients with multiple myeloma (MM). Eighty-two newly diagnosed or refractory/relapsed patients received bortezomib [either 1.2-1.3 mg/m(2) (standard dose) or 1.0-1.1 mg/m(2) (reduced dose) on day 1, 4, 8 and 11], and adriamycin (10 mg/m(2)) plus dexamethasone (40 mg/m(2)) on day 1-4 at 3-week intervals for 1 to 6 courses. The International Myeloma Working Group Criteria were used to evaluate the response. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (Version 3.0). Two courses of standard dose of PAD resulted in a similar response rate of partial and very good partial complete remissions (PR) compared with reduced dose (80.0% vs 80.8%, P=0.728). Grade III- Ⅳ neutropenia and thrombocytopenia were higher with standard dose than that with reduced doses of PAD (21.1% vs11.1%, P=0.270; 10.5% vs 6.3%, P=0.619, respectively). Grade III-Ⅳ bortezomib-induced peripheral neuropathy, herpes zoster, fatigue or abdominal distention were significantly higher with standard dose than that with reduced dose of PAD (15.8% vs 1.6%, P=0.037; 26.3% vs 6.3%, P=0.028; 36.8% vs 14.3%, P=0.046; 15.8% vs 1.6%, P=0.037, respectively). Reduced dose of PAD appears to result in a similar overall response rate, but a better tolerance and safety compared with standard dose.

A case of peripheral nerve microvasculitis associated with multiple myeloma and bortezomib treatment

Bortezomib-induced peripheral neuropathy typically presents as a painful, length-dependent sensory predominant neuropathy. A case report, including nerve pathology, is presented of a man with multiple myeloma who developed a severe motor predominant polyradiculoneuropathy in the setting of bortezomib treatment. We also review the Mayo Clinic Hematology Dysproteinemia database for patients treated with bortezomib. A 53-year-old man with Stage III multiple myeloma developed a severe motor predominant polyradiculoneuropathy following bortezomib treatment with electrophysiological features of multiple conduction blocks and pathological evidence of peripheral nerve microvasculitis. Our institutional experience is that 36.5% of dysproteinemia patients treated with bortezomib develop treatment-emergent peripheral neuropathy, and the most common pattern is a painful sensory predominant peripheral neuropathy. A motor predominant polyradiculoneuropathy is a rare presentation of bortezomib-associated peripheral neuropathy in multiple myeloma patients which may progress despite treatment withdrawal and may be due to microvasculitis.

Itraconazole may increase the risk of early-onset bortezomib-induced peripheral neuropathy

Bortezomib (BOR) is an effective drug for the treatment of multiple myeloma and BOR-induced peripheral neuropathy (BIPN) is a major adverse event. BIPN tends to occur after two or three cycles of treatment (late-onset BIPN), but may occur during the first treatment cycle (early-onset BIPN). BIPN severity was retrospectively assessed and graded in 48 patients with relapsed or refractory multiple myeloma treated with BOR for the first time between June 2007 and February 2011 at Keio University Hospital. PN grade 2 or higher occurring within the first cycle of BOR was defined as early-onset severe BIPN. Early-onset severe BIPN occurred in 13 patients. Concomitant use of itraconazole [ITCZ: odds ratio (OR) 29.14 (3.02-281.56), p = 0.004] and a proton pump inhibitor [OR 9.00 (1.05-77.1), p = 0.04] were identified by univariate analysis, as risk factors for developing early-onset severe BIPN. Based on multivariate analysis, concomitant use of ITCZ was the only significant risk factor for developing early-onset severe BIPN [OR 19.00 (1.89-190.96), p = 0.01]. Concomitant use of ITCZ with BOR significantly increased the incidence of early-onset severe BIPN in our study population, suggesting that administration of ITCZ in patients receiving BOR should be avoided.

A Pilot Study of Acupuncture in Treating Bortezomib-Induced Peripheral Neuropathy (BIPN) in Multiple Myeloma (MM) Patients.

AbstractAbstract 3168 Background:Peripheral neuropathy (PN) is the dose-limiting toxicity of bortezomib in MM patients, affecting >30% patients, including painful PN. Treatment is mostly supportive with narcotics, antidepressants, and anticonvulsants. Acupuncture has been reported to be effective in treating neuropathic pain in diabetic and cancer patients. Methods:We initiated a pilot study to assess the feasibility, safety and efficacy of acupuncture in reducing the severity of BIPN in MM patients. Patients had acupuncture twice weekly for 2 weeks, weekly for 4 weeks, and then biweekly for 4 weeks. All patients continued their prescribed PN medications. Clinical Total Neuropathy Score (TNSc), Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire and Neuropathy Pain Scale (NPS) were used to assess patients at study entry and week 1, 2, 3, 4, 5, 6, 8, 10 during and after 4 weeks of completion of therapy. Serum was obtained from the patients at baseline, right after first acupuncture and before acupuncture session on week 2, 4, 8, and at follow up visit on week 14. Serum samples were used to measure cytokines concentrations. Before and after acupuncture treatments, a complete neurological examination was performed. Nerve conduction studies at baseline and end of study were conducted. Treatment included insertion of disposable sterile acupuncture needles, which retained for 25 minutes, at the following points: bilateral ear points: shen men, point zero, two auricular points where electro-dermal signal was detected, and bilateral body acupuncture points: LI4, SJ5, LI11, ST40, and Ba Feng in upper and lower extremities. Results:From May 17, 2011 to February 28, 2012, 27 MM patients were enrolled in the study. Thirteen patients were women; median age was 63 years (range: 49–77); nine were black, one Asian, 17 Caucasian, and eight had diabetes. All patients had grade 2–4 sensorimotor PN: grade 2 (n=12), grade 3 (n=14), and grade 4 (n=1); 8 had painful PN. All patients had persistant PN despite discontinuation of bortezomib for a median of 19 months (range: 1–83). Eight patients were enrolled within 6 months of stopping bortezomib, all of them had grade 3–4 painful PN. Median time from diagnosis of MM to study entry was 30 months (range: 5–178). Nineteen patients were in remission and eight had progressive disease. MM therapy at study entry and through the follow up period included: revlimid (n=12), carflizomib (n=2). Therapy of PN included narcotics (n=13), gabapentin (12), amitriptyline (n=3), pregabalin (n=2), and duloxetine (n=2). Two patients withdrew after first acupuncture treatment. Twenty-five patients were evaluable for response after completion of 3 weeks (n=2), 6 weeks (n=2), 9 weeks (n=1) and 10 weeks of acupuncture (n=20). There were no adverse events associated with the acupuncture treatment. All but five patients maintained the same dose of pain medications throughout the study. Fourteen patients (56%) reported improved daily functions (e.g. walking and coordination). Ten patients (40%) reported > 50% decrease in average NPS during treatment (week 1–10). Seven patients reported 50% reduction in FACT/GOG-Ntx total scores. The decrease in NPS and FACT/GOG-Ntx, was statistically significant between baseline assessments through week 14; p-values are 0.001 and <0.0001, respectively. On the other hand, TNSc scores, an objective clinical assessment, did not significantly change. Of fifteen patients who had nerve conduction studies, five showed >10% increase in motor nerve amplitude but there was no correlation observed between symptoms/function improvements and nerve conduction studies. At week 8, one of the measured cytokines: Brain-Derived Neurotrophic Factor (BDNF) significantly increased from baseline (p=0.043). This increase was no longer significant at week 14 follow up. Conclusions:Acupuncture is safe and effective in treating persistent moderate to severe BIPN, with improvements of patient reported outcomes, pain and function. The increased BDNF during acupuncture treatment suggests that acupuncture may work through promoting survival and growth of neurons, a lengthy process that may explain the lag of significant objective clinical improvement in the short follow up of our patients. The mechanism of acupuncture working through BDNF to treat PN warrants further evaluation. Disclosures:No relevant conflicts of interest to declare.

Reduced-Dosage of Three Drugs Combination of Cyclophosphamide, Bortezomib and Dexamethasone (reduced-CyBorD) Retains High Response Rate with Less Toxicities in Elderly Patients with Multiple Myeloma

AbstractAbstract 1865 Background:The three drugs combination of cyclophosphamide, bortezomib and dexamethasone (CyBorD) has been proven to be a powerful regimen for the treatment of the patients with multiple myeloma (MM). However, twice-weekly schedule of bortezomib and high dose dexamethasone has been shown to cause significant toxicities, including severe peripheral neuropathy (PN). Recently, once-weekly bortezomib induction therapy with CyBorD (modified-CyBorD) has shown less toxicity with high response rate equal to original regimen (Reeder, CB et al. Leukemia 2009). However, more than half of the patients developed bortezomib induced PN (BiPN) in modified-CyBorD. Thus it was still concerned adverse event for the transplant ineligible patients, especially frail elderly patients because it often caused interruption or withdrawal of the treatments, resulting in fewer efficacies. Under these circumstances, we introduced the reduced-dosage of CyBorD regimen (reduced-CyBorD) in the transplant ineligible patients with multiple myeloma for continuation of the treatment. Methods:The protocol consisted of bortezomib given intravenously at a dose of 1.3 mg/m2once a week on days 1, 8, 15, cyclophosphamide orally at a dose of 50 mg daily on days 1–21, and dexamethasone orally or intravenously at a dose of 20 mg daily on days 1,2,8,9,15,16 in 4-week cycles. Total of 20 patients, including 12 newly diagnosed and 8 refractory, were treated with reduced-CyBorD and evaluated its efficacy and safety. Results:The median age was 72 years (range from 62 to 81). 14 patients were more than 70 year-old (70%). A half of the patients were female. According ISS, 3 patients were classified in stage I, 6 were in II, and 11 were in III. The overall response was 86.6 % with 26.7 % CR/nCR (1 CR, 3 nCR, 5 VGPR and 4 PR). Hematological adverse events were neutropenia (35%; G1/2 n=7), lymphocytopenia (35%; G1/2 n=1, G3/4, n=1), thrombocytopenia (10%; G1/2 n=2). Non-hematological adverse events were pneumonia (20%; G2 n=2, G3 n=2), VZV infection (15%; G2 n=3), cerebral infarction (5%; G2 n=1). Importantly, only three patients (15%) developed grade 1 PN, and no patient reduced or discontinued bortezomib due to PN. Conclusions:Reduced-CyBorD with three times once-weekly bortezomib retained high efficacy seen in standard and modified CyBorD (4 times bortezomib administration). Furthermore, it was found that this regimen obviously revealed less toxicity, especially BiPN compared with those previous regimens (See Table). Our results suggested that reduced-CyBorD might be safe and effective approach to the transplant ineligible patients, especially elderly frail patients with MM. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Discovery of Unique Biomarkers That Predict Bortezomib-Induced Peripheral Neuropathy: The Results of a Multicenter Prospective Clinical Study of Multiple Myeloma in Japan

AbstractAbstract 1816 Introduction:The first-in-class proteasome inhibitor bortezomib (Bzb) has revolutionized the treatment of multiple myeloma (MM). However, Bzb often induces peripheral neuropathy (PN), which negatively affects clinical outcomes by necessitating the reduction or discontinuation Bzb treatment. If patients who are likely develop Bzb-induced PN (BiPN) could be predicted, physicians might have an additional opportunity to modify the dose regimen or reduce the Bzb dose in Bzb-based combination regimens, administer Bzb subcutaneously, or use different drugs. Methods:We conducted a multicenter prospective study to seek biomarkers that predict BiPN. Patients with previously treated or untreated symptomatic MM received twice-weekly or weekly doses of 1.3 mg/m2 Bzb with or without dexamethasone. All patients had measurable M-protein levels. All patients provided written informed consent. Review boards at each site approved the study, which was conducted in accordance with the Declaration of Helsinki. A 2 ml sample of heparinized whole blood was obtained before treatment, as well as 2–3 days and 1–2 weeks after the first dose of i.v. administration of Bzb in the 1st cycle. Triplicate aliquots of 0.06 ml of whole blood were mixed with phytohemaglutinin (PHA), heat-aggregated IgG (HAG), lipopolysaccharide (LPS), zymosan A (ZA), or solvent phosphate buffered saline (PBS), and incubated for 4 hours at 37°C. After incubation, samples were stored at −80°C. The levels of the target mRNAs (IL2, gamma IFN, GMCSF, alpha TNF, CCL4, IL6, CXCL10, and control ACTB) were quantified from each aliquot by a previously described method (J Immunol Methods 363: 95, 2010). The analysis of mRNA and collection of clinical data were performed separately at different centers. PN was graded according to the NCI-CTCAE. Results:Between March 2010 and March 2012, a total of 64 patients (33 male and 31 female) were enrolled from 6 centers. The median age of all patients was 62 years. The original protocol stipulated that only relapsed or refractory patients were eligible, but in October 2011, the protocol was amended to include newly diagnosed patients due to changes in the Japanese National Health Insurance policy. Consequently, 42 patients were previously treated and 22 patients were untreated. After excluding 1 patient each for loss of consciousness or early death due to progressive disease, 62 patients were eligible for toxicity analysis. Of the 59 patients without PN before enrollment, 18 (1 of 18), 9 (8 of 9), and 4 (3 of 4) developed Grade (G)1, G2, and G3 BiPN (with pain), respectively. After treatment with Bzb, the symptoms of 2 patients who had G1 PN prior to treatment worsened to G2 PN. No change was observed in 1 patient with G2 PN. The median follow-up time of estimable patients was 165.5 (range, 31 to 666) days. A total of 2,444 (64 [patients] × 5 [stimulants] × 3 [triplicate] × 3 [time points] with some sampling failure subtracted) mRNA/cDNA samples were prepared, and 19,552 (2,444 [cDNA] × 8 [mRNAs]) PCRs were performed. In total, 53 patient blood samples qualified for mRNA analysis. In the 32 sample dataset (4 stimulants × 8 mRNAs) obtained before Bzb treatment, the BiPN grade correlated with the PHA-induced IL2, gamma IFN, and alpha TNF, and LPS-induced IL6 levels. More importantly, out of 29 patients with a more than 3-fold increase in PHA-induced IL2, 14 patients were BiPN non-inducers (73.7% prediction of non-inducer), whereas out of 34 patients with a less than 3-fold increase in PHA-induced IL2, 23 were BiPN inducers (67.6% prediction of inducers). The mRNA data from blood samples obtained after Bzb treatment did not show any substantial correlation to BiPN. Conclusion:A PHA-induced increase in IL2 in peripheral whole blood obtained before Bzb administration is a promising biomarker for predicting patients who are BiPN inducers and non-inducers. [Display omitted] Disclosures:Mitsuhashi:the company who owns the technology of mRNA analysis used in this study: Employment. Abe:Janssen Pharmaceutical K.K.: Honoraria, Research Funding. Nakagawa:Janssen Pharmaceutical K.K.: Honoraria. Nakamura:Janssen Pharmaceutical K.K.: Honoraria. Iida:Janssen Pharmaceutical K.K.: Honoraria. Kizaki:Janssen Pharmaceutical K.K.: Honoraria.

Erectile Dysfunction Associated With Bortezomib Treatment in a Patient With Multiple Myeloma and Amyloidosis

Case Report Peripheral neuropathy (PN) is the dose-limiting toxicity of bortezomib, a reversible selective proteasome inhibitor approved for the treatment of MM. The incidence of new or worsening bortezomibinduced PN in untreated and relapsed or refractory MM is 44% and 36%, respectively, with Grade 3–4 neuropathy occurring in up to 15% of patients. Bortezomib-induced PN (BiPN) is most commonly sensory and although less frequent, motor PN has been eported, including life-threatening motor neurotoxicity. Still less ommon is autonomic neuropathy, including cutaneous hyperemia, ostural hypotension, paralytic ileus, abdominal distention, and uriary retention. We herein present the first detailed report of a patient with MM who developed erectile dysfunction (ED) after bortezomib treatment. A 60-year-old man without significant past medical history was found during a routine dental workup to have prolonged bleeding, with laboratory tests revealing iron deficiency with mild anemia and a protein gap. Work-up revealed asymptomatic IgG MM. Though a fat pad aspiration was positive for amyloidosis, biopsies taken during esophagogastroduodenoscopy and colonoscopy were Congo Red negative. Despite resolution of iron deficiency with iron

Improvement of Painful Bortezomib-Induced Peripheral Neuropathy Following Acupuncture Treatment in a Case Series of Multiple Myeloma Patients

Abstract Background: Bortezomib-induced peripheral neuropathy (BIPN) is a common and severe dose-limiting side effect in multiple myeloma (MM) patients. Treatment with narcotics, antidepressants, and anticonvulsants are of limited value in reducing symptoms, and they have the potential for significant side effects. Acupuncture has been reported to be effective in treating neuropathic pain. There has been limited reporting on the effect of acupuncture in treating BIPN. Objective: The aim of this study was to report on the effect of acupuncture in treating BIPN. Design and Patients: This study was a retrospective case series of five MM patients experiencing painful BIPN. Intervention: The patients were treated with the same acupuncture protocol on a weekly basis, adjusted to twice a week or once every 2 weeks based on response. Treatment included insertion of disposable sterile acupuncture needles, which were retained for 25 minutes, at the following bilateral ear points: shen men, point zero, and two auric...

Immune modulation therapy in the management of bortezomib-induced peripheral neuropathy

Peripheral neuropathy (PN) is one of the most common side effects of bortezomib therapy. The majority of bortezomib-related PN is a sensory neuropathy of mild to moderate degree, and is reversible after dose reduction or discontinuation. However, occasionally bortezomib-induced neuropathy can be severe and affects motor and/or autonomic nerves, and may be mediated by immune process. The role of immune modulation therapy in the management of bortezomib-induced PN was not well established. Here, we reported a case of bortezomib-induced severe PN that responded well to plasma exchange and steroid treatment.