**3.4 Bortezomib, a game changer for multiple myeloma and AL amyloidosis**

Monoclonal antibody therapy has become a mainstay of treatment in plasma cell disorders such as multiple myeloma and primary systemic (AL) amyloidosis. Bortezomib (Velcade), a proteasome inhibitor, has shown effectiveness as an initial therapy of multiple myeloma in stem cell transplant (SCT) eligible patients [31, 32]. Bortezomib has been especially effective in younger patients and contributed significantly to improvements in survival seen in the early 2000s [33]. Bortezomib and other proteasome inhibitors are associated with less cardiotoxic risk than chemotherapeutics such as melphalan, cyclophosphamide, and doxorubicin [34]. Modern induction therapy for multiple myeloma now consists a combination of bortezomib and dexamethasone (BD), plus thalidomide or melphalan for both transplanteligible and SCT ineligible patients. A phase IIIB study found no difference in outcomes or survival between BD, BD plus thalidomide, or BD plus melphalan in transplant-ineligible patients [35]. Bortezomib is also effective as a consolidation

**27**

of more effective therapies.

*Amyloidosis: Systems-Based Therapies*

dation therapy [36].

*DOI: http://dx.doi.org/10.5772/intechopen.85201*

**4. Amyloidosis and the nervous system**

action for both CNS and PNS manifestations of the illness.

**4.1 Amyloid beta: Alzheimer's dementia, and cerebral amyloid angiopathy**

There are no current therapies that modify the deposition of A beta amyloid in the CNS. Therefore the focus of treatment has been mainly symptomatic with acetylcholinesterase inhibitors, antidepressants and antipsychotics. However, new research focusing on monoclonal antibodies reducing plaque load prove to have promising results in the mice model [47]. Modest levels of peripherally administration antibodies against the amyloid beta-peptide crossed the blood brain barrier entering the CNS and inducing clearance of preexisting amyloid via activation of microglial cells [48]. Bapineuzumab, Solanezumab, Gantenerumab, Crenezumab, Ponezumab, BAN2401, and Aducaumab are anti-amyloid beta monoclonal antibodies that have progressed to human trials and paved the pathway for the development

The mechanism of Bapineuzumab, one of the first humanized monoclonal IgG1 antibody used in humans, attaches to soluble and fibrillar amyloid beta via the five N-terminal residues inducing Fc receptor-mediated microglial phagocytosis of amyloid beta deposits. In phase 1, 30 patients were divided into low dose (0.5 mg/kg), medium (1.5 mg/kg) and high dose (5 mg/kg), and overall the drug was considered to be safe. 3/10 participants in the high dose category developed MRI findings typical of vasogenic edema that eventually resolved. Amyloid-related imaging abnormalities

and maintenance therapy, prolonging progression-free survival and overall survival in patients with partial or very good partial response following induction/consoli-

AL amyloidosis can present spontaneously or in association with other blood cell disorders such as multiple myeloma and lymphoplasmocytic lymphoma. AL amyloidosis is a well-recognized complication of multiple myeloma in particular, occurring in approximately 10–15% of patients (**Figure 3**) [37]. Not surprisingly, bortezomib therapy is now a recommended treatment for primary AL amyloidosis both in SCT ineligible patients and post SCT patients [38, 39]. Reece et al. showed bortezomib to be a particularly effective and well-tolerated therapy in relapsed AL amyloidosis patients, evidenced by once and twice-weekly treatments both effectively inducing a hematological response in this population [40, 41]. A randomized phase III trial showed more profound and frequent hematological responses to bortezomib versus melphalan plus dexamethasone in patients with newly diagnosed

AL amyloidosis, indicating bortezomib as a promising initial therapy [42].

Neurologic involvement of systemic amyloidosis has been observed in over 20% of cases, and the median duration of neuropathic symptoms prior to diagnosis is 2 years [43]. The pathophysiology of amyloid deposition contributing to the clinical manifestation of neurodegenerative disorders, including Alzheimer's Dementia, Parkinson's Disease, and Huntington's Disease, has been well-documented [44]. Furthermore, cerebral amyloid angiopathy is a well-known cause/risk factor for intracerebral hemorrhage in the elderly [45]. Lastly, systemic amyloidosis (classically, primary amyloidosis) affects not only the central nervous system, but is a well-known cause of peripheral and autonomic neuropathy [46]. Thus, the deposition of abnormally folded proteins has not only been linked to progressive and acute devastating CNS disorders, but also to neurologic sequelae throughout the body. In this section, we describe some of the novel treatments and their mechanisms of

#### *Amyloidosis: Systems-Based Therapies DOI: http://dx.doi.org/10.5772/intechopen.85201*

*Amyloid Diseases*

accepted as transplant candidates.

for AL amyloidosis patients on dialysis, especially those with cardiac involvement. For AA amyloidosis patients on dialysis, Guillaume et al. reported a 15% mortality rate, a better prognosis overall [29]. Treating patients who are on dialysis with HDM/SCT has shown no difference between the hematologic response rate and treatment -associated mortality are similar in dialysis-dependent patients compared

Kidney transplantation is a good option for patients who have a complete hematologic response in AL amyloidosis and do not have significant extrarenal disease. In 2012, Gurusu et al. examined survival rates of 44 patients with amyloidosis who had undergone kidney transplantation and found the same outcomes with patients with other kidney diseases [30]. This indicates that amyloidosis patients should be

with the overall population of patients who undergo this treatment [27].

**3.4 Bortezomib, a game changer for multiple myeloma and AL amyloidosis**

Monoclonal antibody therapy has become a mainstay of treatment in plasma cell disorders such as multiple myeloma and primary systemic (AL) amyloidosis. Bortezomib (Velcade), a proteasome inhibitor, has shown effectiveness as an initial therapy of multiple myeloma in stem cell transplant (SCT) eligible patients [31, 32]. Bortezomib has been especially effective in younger patients and contributed significantly to improvements in survival seen in the early 2000s [33]. Bortezomib and other proteasome inhibitors are associated with less cardiotoxic risk than chemotherapeutics such as melphalan, cyclophosphamide, and doxorubicin [34]. Modern induction therapy for multiple myeloma now consists a combination of bortezomib and dexamethasone (BD), plus thalidomide or melphalan for both transplanteligible and SCT ineligible patients. A phase IIIB study found no difference in outcomes or survival between BD, BD plus thalidomide, or BD plus melphalan in transplant-ineligible patients [35]. Bortezomib is also effective as a consolidation

**26**

**Figure 3.**

*AL amyloidosis organ involvement pattern in patients with multiple myeloma.*

and maintenance therapy, prolonging progression-free survival and overall survival in patients with partial or very good partial response following induction/consolidation therapy [36].

AL amyloidosis can present spontaneously or in association with other blood cell disorders such as multiple myeloma and lymphoplasmocytic lymphoma. AL amyloidosis is a well-recognized complication of multiple myeloma in particular, occurring in approximately 10–15% of patients (**Figure 3**) [37]. Not surprisingly, bortezomib therapy is now a recommended treatment for primary AL amyloidosis both in SCT ineligible patients and post SCT patients [38, 39]. Reece et al. showed bortezomib to be a particularly effective and well-tolerated therapy in relapsed AL amyloidosis patients, evidenced by once and twice-weekly treatments both effectively inducing a hematological response in this population [40, 41]. A randomized phase III trial showed more profound and frequent hematological responses to bortezomib versus melphalan plus dexamethasone in patients with newly diagnosed AL amyloidosis, indicating bortezomib as a promising initial therapy [42].
