Median survival at a median follow-up of 41 months for patients with versus without genomic aberration.  t(11;14)(q13;q32) and MYC translocations did not impact EFS or OS.  All patients received tandem transplantation in IFM99 studies (auto/ auto or auto/ allo).  Numbers reflect survival post single ASCT.# BACKGROUND
Multiple myeloma (MM) is an aggressive malignant neoplasm of plasma cells that accumulates in the bone marrow and contributes to approximately 15 percent of all hematologic malignancies. In Canada, MM makes up 1.2 percent of all new cancer cases and 1.8 percent of all cancer deaths. 1 Seventy-five percent of all myeloma cases are in patients over the age of 60 years, and the incidence increases steadily with age. 2 MM is not considered curable with current approaches; however, 5-year survival rates have increased over the past few decades due to a variety of newer and more effective treatment options. The clinical course of MM is heterogeneous and survival times range widely, depending on critical factors such as the disease stage and the presence of prognostic indicators. 3 Patients are classified initially as having asymptomatic or symptomatic disease; those with symptomatic disease are then classified further according to the stage of their disease. Treatment options are heterogeneous, and may include therapies such as standard or high-dose chemotherapy regimens, alone or in combination with autologous or allogeneic stem cell transplantations.

# GUIDELINE GOALS AND OBJECTIVES
- To outline the diagnostic criteria for multiple myeloma, monoclonal gammopathy, smoldering myeloma, and amyloidosis - To describe current treatment strategies for multiple myeloma, monoclonal gammopathies, smoldering myeloma, and amyloidosis

# GUIDELINE QUESTIONS
- What are the diagnostic and prognostic criteria for multiple myeloma and related disorders?
- What are the most suitable management strategies of multiple myeloma and related disorders?

# DEVELOPMENT PANEL
This guideline was reviewed and endorsed by the Alberta Provincial Hematology Tumour Team. Members of the Alberta Provincial Hematology Tumour Team include hematologists, medical oncologists, radiation oncologists, surgical oncologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Hematology Tumour Team and a Knowledge Management Specialist from the Guideline Resource Unit.

# SEARCH STRATEGY
The MEDLINE (1966 through July 2012), PubMed, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews databases were searched. In addition, the ASCO and ASH Abstracts and Proceedings databases were searched. The search included practice guidelines, systematic reviews, meta-analyses, randomized controlled trials, and clinical trials.

# TARGET POPULATION
The following guidelines apply to adults over the age of 18 years. Different principles may apply to pediatric patients.

# GUIDELINES I. MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS)
Diagnostic Criteria 4 - M-protein in serum < 30 g/L - Bone marrow clonal plasma cells (PC) < 10%
- No CRAB or ROTI (myeloma Related Organ or Tissue Impairment):
- Ca (corrected) >0.25 mmol/L upper limit of normal or >2.75 mmol/L o Renal impairment: Creatinine > 176 mol/L o Anemia: Hemoglobin  2/year)
The incidence of MGUS is 1% for patients over the age of 50 years, and approximately 3% for patients over the age of 70 years. 5
- Actuarial rate of progression to multiple myeloma or other lymphoproliferative disorder: o 17% at 10 years, 34% at 20 years, and 39% at 25 years o Approximately 1.5% per year 4,6 - Three risk factors for progression to multiple myeloma: 7 1) Non-IgG monoclonal protein 2) Serum M-protein > 15 g/L 3) Abnormal free light chain (FLC) ratio (FLC ratio < 0.

# Investigation and Management
Patients with MGUS do not require any treatment unless they have evidence of organ or tissue impairment (i.e. CRAB or ROTI) and thus should be classified as symptomatic myeloma rather than MGUS. Patients with MGUS are at risk to develop lymphoproliferative diseases such as myeloma, amyloidosis or malignant lymphomas. Those with low risk MGUS do not require follow up with hematology. Instead, they can be monitored by their primary care physician with annual CBC, chemistry, creatinine and calcium. All others should have an annual hematology assessment.
At diagnosis the following tests should be completed: For the purpose of predicting progression to symptomatic myeloma, smoldering myeloma can be divided into 3 risk groups:
- CBC - Creatinine - Calcium - Total protein - Albumin 
- High Risk: serum M protein 30 g/L and bone marrow PC  10% - Intermediate Risk: serum M protein < 30 g/L and bone marrow PC  10% - Low Risk: serum M protein 30 g/L and bone marrow PC < 10%
The serum free light chain ratio can be used to further define the risk of progression for those with high or intermediate risk disease 9.

# Overall High Intermediate Low
Median time to progression 5.5 years 2.4 years 9.2 years 19 years
Rate of progression @ 10 years 62% 76% 59% 32% FLC ratio 0.125 -8.0 59% 58% 32% FLC ratio 8.0 84% 69% 33%
In addition, certain features can identify patients at high risk of progression to multiple myeloma. These include:
- Bone marrow plasmacytosis  60%. (median time to progression to symptomatic myeloma of 7 months; 95% progression within 2 years) 10 - T(4;14) or p53 deletion (median time to progression  100. (median time to progression 15 months) 16
Patients with high-risk features are considered as having overt myeloma and should receive front-line myeloma therapy. Otherwise, no treatment is required for smoldering myeloma until progression to multiple myeloma or other lymphoproliferative disorder. Patients should be followed every 3-4 months and monitored for "myeloma-related" symptoms (CRAB) or organ damage.

# III. MULTIPLE MYELOMA
Diagnostic Criteria 4 - M-protein in serum and/or urine as detected by SPEP, UPEP or FLC - Clonal bone marrow plasma cells or plasmacytoma - Presence of organ dysfunction: CRAB  or ROTI - High risk features including bone marrow plasmacytosis  60%, t(4;14) or p53 deletion, two or more focal bone lesions detected by CT, MRI, or PET scan, or ratio of involved/uninvolved free light chains > 100
The Alberta Provincial Hematology Tumour Team as the standard staging system has adopted the International Staging System, rather than Durie-Salmon, for myeloma patients. - MRI may be indicated in special circumstances (i.e., to rule out cord compression, CNS involvement, non-secretory multiple myeloma, smouldering myeloma and solitary bone or soft tissue plasmacytoma) - PET scan is not currently indicated for the diagnosis or follow-up of multiple myeloma patients - Echocardiogram or cardiac MRI is only indicated if there is clinical suspicion of cardiac amyloidosis Myeloma associated AL amyloidosis is reported in 12-30% of multiple myeloma patients. These patients typically fulfill the diagnostic criteria for multiple myeloma and have evidence of amyloid light chain deposition confirmed by Congo red staining. Amyloidosis should be suspected in the presence of nephrotic range proteinuria with predominant albuminuria; non-hypertensive congestive heart failure without coronary artery disease; low voltage, bradycardia or A-V block on EKG, organomegaly, autonomic neuropathy and carpal tunnel syndrome.
The following investigations should be ordered if the diagnosis of myeloma-associated AL amyloidosis is suspected in order to confirm the diagnosis:
- Congo red staining of the bone marrow o Fat pad aspirate, biopsy, or punch biopsy and Congo red staining if bone marrow is negative o Direct biopsy of suspected involved organ if Congo red stain is negative in bone marrow and fat pad. o Congo red positive biopsies should be forwarded for mass spectroscopy analysis and typing.
Patients with biopsy-proven amyloidosis should be classified as "Myeloma with Documented Amyloidosis" if they have  10% plasma cells and/or myeloma-related bone disease. For the management of these patients, please refer to the section on Amyloidosis below.
Prognostic information reflects the treatment received during the era of a specific publication and may not reflect improvements in outcome expected with the introduction of novel agents, triple induction therapy, maintenance, consolidation, etc.  Flow Cytometry: Flow cytometry should be performed on bone marrow biopsies at diagnosis, and on subsequent biopsies in order to confirm complete remission or detect minimal residual disease. The presence or absence of immunophenotyic evidence of clonal plasma cells on bone marrow samples following therapy is a strong predictor of PFS and survival 21..

# Treatment Guidelines for Newly Diagnosed Multiple Myeloma

# Goal of therapy:
The goals of therapy for young patients with multiple myeloma is to achieve the deepest possible response, ideally a complete remission, and to then maintain that response for as long as possible.
For elderly patients, the goal of therapy is to minimize symptoms and maximize response with as little toxicity as possible.
These guidelines identify effective, evidence based treatment regimes (as opposed to single agents) to be utilized. These treatment regimens can include multi-drug and multi-step approaches, radiation therapy, or single agents when appropriate.

# Patients  65 Years Old and Transplant-Eligible:
Whenever possible, patients should be considered for a clinical trial. In the absence of a suitable trial, patients who are 65 years old or younger and are transplant-eligible should receive a course of therapy consisting of:
- Pre-transplant induction with a 3-drug regimen that includes a novel agent - High dose melphalan +/-bortezomib followed by autologous stem cell transplantation - Post transplant consolidation - Maintenance lenalidomide and/or bortezomib until disease progression.

# Induction Regimens:
Induction regimens should contain at least one novel agent (e.g. bortezomib, lenalidomide, thalidomide). There is consensus amongst the myeloma physicians that a triple drug based induction regimen results in superior outcomes with improved rate and depth of responses (higher CR and sCR rates). Four randomized trials comparing doublet versus triplet-based regimen are in favor of triplet-based regimen since the latter results in improved responses as well as progression free survival . The following figure shows the overall, VGPR, and nCR/CR rates for a selection of phase 2 and phase 3 trials incorporating novel agents. A continuous improvement in response is seen with the combination of newer agents. However many of these are small single-center experiences, and evidence that early responses translate into longerterm survival is not yet available.
(References: VAD 26 TD 27 RD 28 PAD 29 VTD 30 CVD 31 RVD 32 CVRD 26.

# Bortezomib-based induction regimens:
Numerous studies have shown that the depth of response achieved following ASCT is predictive of outcome. Patients achieving CR, nCR, and/or VGPR after transplantation have longer remissions and survival times than those with lesser responses. It has been suggested that if induction regimens with higher initial response rates were used prior to transplant, this should produce deeper responses post transplant, resulting in better PFS and OS. Until recently, this potential benefit of more effective induction had not been shown. A large meta-analysis failed to demonstrate any survival advantage for combination chemotherapy (i.e. VAD, VBMCP) compared to melphalan + prednisone. 33 A randomized trial comparing induction with TD versus VAD showed higher response rates to TD induction, but similar response rates (VGPR 42% vs 44%) after transplant.
However, recent studies of bortezomib based regimens suggest the choice of induction regimen may indeed affect outcome post transplant . They showed an improvement in response with higher CR/near CR post transplant, and superior progression free survival for those receiving bortezomib based regimens, with an improvement in overall survival seen in one study. The findings of these three studies are summarized in appendix A, table1.
Bortezomib and dexamethasone based regimens for 3-4 cycles are well tolerated and shown to be more effective than older regimens, improving response rate, PFS, and OS post transplant. Bortezomib and dexamethasone should be included as part of multi-drug regimens as standard induction therapy prior to stem cell transplantation, along with a third agent such as cyclophosphamide (CyBorD 31 and lenalidomide (VRD 37. Patients refractory to initial therapy with VCD (fail to achieve at least PR) should be switched to second line therapy with lenalidomide and dexamethasone or VRD for several cycles prior to stem cell mobilization. Several large randomized trials have compared induction therapy with thalidomide to dexamethasone.  Trial details can be found in The combination of lenalidomide and dexamethasone is a well tolerated and convenient oral regimen resulting in high response rates when followed by ASCT, with 3 year PFS and OS of 64% and 94% respectively 47. Two large randomized trials comparing an induction therapy with a lenalidomide-based regimen have reported high rates of CR/VGPR and high 2-year PFS and OS rates. 48,49. The impact of a lenalidomide-based induction regimen on survival post-ASCT is unclear since transplant is often deferred until relapse in these studies. Patients treated with 4 cycles of lenalidomide followed by ASCT had a 2 year OS of 93%, similar to those treated with Ld until disease progression.
Because prolonged therapy with lenalidomide can impair stem cell mobilization, consider stem cell collection within 4 cycles of induction lenalidomide.
Other Regimens: Single agent dexamethasone is associated with suboptimal response and should not be used as the only therapy for myeloma.
The VAD regimen should not be used due to the toxicity of this regimen (neurotoxicity, cardiac toxicity, myelosuppression) and its inferior outcomes compared to bortezomib containing regimens.
High Risk Myeloma: Patients with high risk cytogenetic aberrations such as del17p or t(4;14) and t(14;16) have a worse outcome with ASCT than patients without these findings. They should be considered for clinical trials with novel frontline agents with or without SCT. However, in the absence of a clinical trial, patients with high risk myeloma should receive similar treatment as other myeloma patients including induction with a bortezomib based regimen and should be considered for initial therapy with a combination of bortezomib, lenalidomide and dexamethasone (VRD), followed by ASCT.

# Stem Cell Transplantation:
Autologous Stem Cell Transplant (ASCT):
Four large randomized trials have demonstrated the superiority of autologous stem cell transplantation to standard dose chemotherapy with significant prolongation of TTP and OS.  Other trials, with several caveats, have failed to demonstrate the same benefit from ASCT.  Details of these trials are outlined in Table 4 of Appendix A.
Patients are considered transplant eligible if they are under the age of 65, meet minimal requirements for underlying organ function and all other transplant eligibility requirements of the Calgary or Edmonton transplant programs. There is no proven benefit to transplant over standard therapy for patients over the age of 65. These patients can be considered for ASCT if they are meet all transplant eligibility criteria, are physiologically very fit, and have no significant comorbid illnesses.
Transplant eligible patients should receive 3-4 cycles of induction therapy before proceeding to ASCT. The achievement of CR is not required to proceed to transplant. Patients who fail to achieve CR after 3-4 cycles of induction, including those with primary refractory disease, can still benefit from high dose therapy and ASCT and should still be referred for transplant evaluation. Patients with renal failure on dialysis are candidates for autologous stem cell transplant and should be referred without significant delays for transplant evaluation. Twenty to twenty-five percent of patients do recover their renal function and become dialysis-independent up to 6 months post-transplant.

# Stem cell collection:
The standard regimen includes cyclophosphamide 2.5 mg/m 2 with G-CSF starting on day 7. The goal is to collect at least 5 x 10 6 CD34 cells/kg for each planned transplant.

# Conditioning regimen:
The standard transplant conditioning regimen is high dose Melphalan 200 mg/m 2 on day -1. The incorporation of bortezomib (1.3mg/m 2 day -5, -2, +1, and +4) with high dose melphalan conditioning has been shown to improve CR rates and should be considered in those without a contraindication to bortezomib .
Tandem Autologous Transplantation: Tandem autologous transplant should not be routinely performed. Four large randomized trials have addressed the role of tandem transplantation in multiple myeloma, and have shown that tandem transplantation improves survival in patients who fail to achieve a VGPR after the first transplant.  Details of these trials are outlined in Table 5 of Appendix A. However, considerable benefit is also seen with continuous post transplant therapy that includes novel agents.
Allogeneic Stem Cell Transplant: Four studies have been conducted to date comparing tandem autologous to tandem autologousallogeneic stem cell transplant. The details of these trials are outlined in Table 6 of Appendix A. In a French study trial (IFM99-03) of high risk patients (del13 and high 2), no difference in outcome was seen between the two approaches. However it should be noted that only patients with high risk disease were enrolled into this study and high dose ATG was used in the conditioning regimen. 65 In a study by Bruno and colleagues, allogeneic transplant was by far superior however in this study the results of the tandem autologous arm were lower than expected and the study had several reporting caveats. 66 Early results from the PETHEMA group suggest superior results with allogeneic transplant; however they only report a trend for better PFS, not OS. 68 The largest study comparing autologous to transplantation was performed by the US Blood and Marrow Clinical Trials Network. 625 patients were biologically assigned to receive either a tandem ASCT with melphalan 200 mg/m 2 (n = 436) or ASCT with melphalan 200 mg/m2 followed by an allogeneic SCT conditioned with fludarabine and 200 cGy of total body irradiation (n = 189). The 3year PFS was 46% for the tandem autologous arm versus 43% for the autologous-allogeneic arm (P =.67). OS at 3 years was also not significantly different between the groups: 80% for the tandem autografts versus 77% for the autologous-allogeneic arm. Assignment to the autologous-allogeneic arm was associated with worsened survival in patients with stage I and II disease, but not in those with stage III disease 68. At this point, allogeneic transplant is not considered a standard part of therapy for newly diagnosed or relapsed myeloma and should be performed only in the setting of a clinical trial.

# Post Transplant Therapy:
Consolidation: All patients should receive 2 cycles of consolidation therapy in addition to maintenance therapy. Both bortezomib 23 and lenalidomide 69 based regimens have been used. Compared to thalidomide and dexamethasone, the combination of bortezomib, thalidomide, and dexamethasone as consolidation after ASCT significantly improved CR (46% vs 60%) and CR/nCR rates (61% vs 73%). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation.
Our recommendation is for 2 cycles of consolidation with VRD in all patients post ASCT. Lenolidomide in place of thalidomide should be used to minimize risk of neuropathy.  69.At a median follow up of 34 months, maintenance resulted in an improved TTP of 46 months versus 27 months for placebos (p<0.001). Overall survival was also improved, with HR for death 0.62 (p<0.03). Lenalidomide maintenance was associated with an increase in second primary malignancies (SPM) (7.8% vs 2.6%). However event free survival analysis including SPM as study related events continued to show improved survival outcomes in favor of the maintenance arm.
The IFM 2005-02 trial 70 randomized 614 patients to maintenance with lenalidomide 10-15mg daily following ASCT. All patients received two cycles of consolidation with lenalidomide 25mg daily for 21 of 28 days prior to starting maintenance. With a median follow up of 45 months, the 4 year PFS was 43% for lenalidomide compared to 22% for placebo (p<0.001). There was no difference in OS (73% vs 75%). There were 23 second primary malignancies in the lenalidomide group and 9 in the placebo group.
A retrospective analysis of 11 clinical trials of lenalidomide-based therapy for relapsed/refractory multiple myeloma including 3846 patients reported an incidence rate of second primary malignancies (SPMs) of 3.62 71. Incidence rate of invasive (hematologic and solid tumor) SPMs was 2.08, consistent with the background incidence of developing cancer. In a separate analysis of pooled data from pivotal phase 3
The phase III HOVON-65/ GMMG-HD4 trial randomized 827 patients to receive VAD induction followed by ASCT and maintenance therapy with thalidomide (arm A) or bortezomib, doxorubicin, and dexamethasone (PAD) followed by ASCT and maintenance with bortezomib every 2 weeks for 2 years (arm B) 22. The strategy of bortezomib-based induction with bortezomib maintenance resulted in superior response rates ( VGPR 76% vs 56%, p<0.001) and PFS (35 vs 28 months, p=0.02). The study was not designed to evaluate the benefit of bortezomib maintenance on its own. However, the number of patients achieving a response upgrade after starting maintenance was similar between the thalidomide and bortezomib maintenance arms suggesting similar effects of these two strategies. An analysis of PFS calculated from the time of last HDM showed a significant difference in favor of the bortezomib arm (31 versus 26 months). This indicates that although post-transplantation bortezomib and thalidomide both achieved similar response upgrades, bortezomib contributed more to improvement of PFS. Importantly in this study, for patients with del17p, PAD followed by bortezomib maintenance significantly improved PFS (mPFS in arm B vs arm A: 26.2 vs 12.0 months; P=.024) and overall survival (3-year OS rate in arm B vs arm A: 69% vs 17% P=.028)
Thalidomide: Thalidomide maintenance has consistently been associated with an improvement in PFS with a variable effect on OS. However it does lead to reduction in quality of life, and is frequently discontinued due to side effects and toxicity. Four large randomized trials have reported an improvement in TTP and OS with the use of thalidomide maintenance, and a summary of these trials is presented in Table 7 of Appendix A.  The four trials used different doses (100-400 mg) of thalidomide as well as different durations of therapy (6-48 months). The median duration of therapy in the IFM99-02 study was approximately 18 months, with a median thalidomide dose of 200 mg. The IFM99-02 trial compared no maintenance (arm A), maintenance pamidronate (arm C) or maintenance thalidomide (3 mg/L or del13). 72 o Maintenance thalidomide improved response rate (higher CR and VGPR rate with thalidomide: 55% arm A, 57% arm B, 67% arm C) o Thalidomide improved 3-year EFS: 36% arm A, 37% arm B and 52% arm C o Thalidomide improved 4-year OS: 77% arm A, 74% arm B, 87% arm C o Pamidronate did not decrease the incidence of bone events o Patients with del13 or those who achieved a VGPR or better did not benefit from thalidomide -Interferon (IFN): Clinical trials of IFN maintenance produce conflicting results. However it has considerable toxicity and very poor tolerance. With the availability of better tolerated, more effective therapies, the use of IFN is not recommended. Please refer to Table 8 in Appendix A for a review of studies that have reported on the use of IFN. 39,56,76,77 Prednisone:
In non-transplant patients, one randomized study by Berenson and the SWOG group showed better EFS (14 vs. 5 months; p=0.03) and OS (37 vs. 26 months; p=0.05) with prednisone 50 mg compared to prednisone 10 mg. 78 Prednisone is not recommended for maintenance following ASCT.
Members of the Alberta Provincial Hematology Tumour Board recommend maintenance therapy with lenalidomide or bortezomib for patients without progressive disease following ASCT. The risk of SPMs must be taken into account before initiating lenalidomide treatment. In the context of the observed progression free survival benefit after ASCT, the benefit/risk profile of lenalidomide/dexamethasone remains positive. Maintenance with bortezomib (with or without lenalidomide) should be considered in patients with del17p.

# Summary of Recommendations:
Regimens containing bortezomib and dexamethasone as well as a third agent (cyclophosphamide, lenalidomide) are the standard induction regimen prior to stem cell transplantation for transplant eligible patients with standard risk or high risk myeloma requiring treatment. VAD or single agent dexamethasone should not be used.
- CYBORD is the recommended regimen for initial therapy of newly diagnosed transplant eligible patients. Patients should receive 4-6 cycles prior to stem cell collection. Cycles are repeated every 28 days. A twice weekly schedule can be used for sicker patients requiring a more rapid initial response to therapy. Whenever possible, patients should be considered for a clinical trial. In the absence of a suitable trial, combinations of melphalan and prednisone with novel agents (thalidomide, lenalidomide, or bortezomib) have been shown to be superior to melphalan and prednisone alone as initial therapy for transplant ineligible patients. The standard therapy for these patients should therefore include a novel agent, alkylator, and steroids. However, in frail patients, and those with significant com-morbidities or advanced age (>75 years), there is an increased risk of toxicities. For these patients, consideration should be given to dose reductions of the initial regimen, and/or the use of two-drug combinations such as RD or VD 79.
Bortezomib The VMP regimen was compared to VMP plus thalidomide followed by maintenance with bortezomib plus thalidomide (VMPT-VT) 82. VMPT followed by VT as maintenance was superior to VMP alone in patients with multiple myeloma who are ineligible for autologous stem-cell transplantation. The 3-year PFS was 56% in patients receiving VMPT-VT and 41% in those receiving VMP (P =.008). Complete response were 38% in the VMPT-VT group and 24% in the VMP group (P <.001). The 3-year overall survival was 89% with VMPT-VT and 87% with VMP (HR, 0.92; 95% CI, 0.53 to 1.60; P =.77). Grade 3 to 4 neutropenia (38% v 28%; P =.02), cardiologic events (10% v 5%; P =.04), and thromboembolic events (5% v 2%; P =.08) were more frequent among patients assigned to the VMPT-VT group than among those assigned to the VMP group; treatment-related deaths were 4% with VMPT-VT and 3% with VMP. The combination of cyclophosphamide, bortezomib and dexamethasone has been shown in a number of phase II trials to be well tolerated, and produces superior response rates 83. It is currently the regimen of choice for first line therapy for non-transplant eligible myeloma patients.
- Cyclophosphamide 300mg/m 2 orally weekly for 4 weeks o Bortezomib 1.5mg/m 2 intravenously or subcutaneously weekly for 4 weeks o Dexamethasone 40mg orally weekly for 4 weeks.
Patients should receive 9-12 cycles followed by maintenance bortezomib (1.3mg/m 2 every 2 weeks for 2 years).

# Lenalidomide-Based Regimens:
Lenalidomide is currently not funded for first-line use in multiple myeloma.
In the MM015 trial, 459 patients were randomly assigned to receive melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance (MPR-R) therapy until a relapse or disease progression or to receive MPR or MP without maintenance therapy 84. The median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio, 0.49; P<0.001) or MP (13 months; hazard ratio, 0.40; P<0.001). Response rates were superior with MPR-R and MPR (77% and 68%, respectively, vs. 50% with MP; P<0.001 and P=0.002, respectively, for the comparison with MP). The progression-free survival benefit associated with MPR-R was noted in patients 65 to 75 years of age but not in those older than 75 years of age (P=0.001 for treatment-by-age interaction). The 3-year rate of second primary tumours was 7% with MPR-R, 7% with MPR, and 3% with MP.
MPR-R regimen: Nine 28-day cycles of - Melphalan 0.18 mg/kg days 1 through 4
- Prednisone 2 mg per kilogram days 1 through 4
- Lenalidomide 10 mg on days 1 through 21 - Followed by lenalidomide maintenance (10 mg on days 1 through 21 of each 28-day cycle) until disease progression or the development of unacceptable adverse effects
The FIRST study compared MPT for 12 cycles (18months) to lenalidomide and dexamethasone for 18 cycles (18months) and len/dex until disease progression in newly diagnosed myeloma patients not eligible for stem cell transplant 85. The continuous Rd strategy was superior to MPT with improved response rate, PFS and duration of response. Overall survival at 4 years was improved with continuous Rd, but this did not reach statistical significance (4-year OS 59% vs 51%, p=0.0168).
Thalidomide-Based Regimens: Table 9 in Appendix A described the results of three randomized trials which reported a higher response rate and EFS with melphalan + prednisone + thalidomide (MPT) when compared to melphalan + prednisone alone.  - The IFM99-06 and IFM 01-01 trials also reported higher OS rates. 86,87 - MPT was also shown in one trial (IFM99-06) to be superior to tandem transplant with reduced intensity melphalan conditioning (100 mg/m 2 x 2). 86 - Increased toxicity (DVT/pulmonary embolism 12% versus 4% with MP) and higher rates of neutropenia have been reported with MPT therapy.  When therapy is started in elderly patients, frail patients, the very eldery (over 75 years of age) and those with significant co-morbidities are at an increased risk of toxicity from combination regimens. As a result of such toxicitiy, therapy is often terminated early resulting in poorer outcomes than if less intense but more tolerable therapy were to be given for a longer period of time. It is suggested that dose reductions be considered for patients with one or more of these risk factors. 79 In addition, initial therapy with a novel agent plus dexamethasone may be better tolerated than triple drug regimens. Whenever possible, patients with relapsed multiple myeloma should be considered for a clinical trial. In the absence of a suitable trial, treatment of relapsed disease should be determined on individual basis depending on timing of relapse, age, prior therapy, bone marrow function, co-morbidities, and patient preference.
Repeat bone-marrow examination with cytogenetic testing should be performed at relapse as high-risk features frequently develop as the disease evolves  and may affect the choice of therapy. A short duration of last response is also a high risk feature, with poor long term prognosis for those with initial remission lasting less than 1 year 93,94.
The choice of the salvage therapy is mostly guided by the preference of the patient and the treating physician. The following guidelines can help guide treatment decisions:

# Autologous Stem Cell Transplant:
A second high dose chemotherapy treatment with autologous stem cell transplantation for those patients who have had a disease free interval of > 2 years following their initial high dose therapy is a reasonable consideration. The median time to progression after a salvage second autologous stem cell transplant is typically 1-2 years . Re-induction may increase the efficacy of the procedure but prospective data does not exist. The transplant related mortality (TRM) varies between 2 and 10% 100. No data currently exists on the role of maintenance or post-ASCT consolidation after a second transplant. When a patient with relapsed myeloma is being considered for a salvage second transplant, the TRM and the activity of novel agents should be clearly discussed and reviewed with the patient.

# Non-transplant based options:
The majority of patients relapsing with myeloma will not be candidates for high dose chemotherapy and autologous stem cell transplant. Standard approaches generally incorporate a novel-agent containing regimen.
Bortezomib: Bortezomib has long been accepted as a standard for the treatment of relapsed disease 101. It is widely available in Canada and approved for use in this setting in Alberta. Based on the design of the initial phase III trials in this setting treatment should be continued to progression or intolerance. Although the initial trials generally examined bortezomib naive patients, it is important to note that the majority of patients will now have been exposed to this agent in the upfront setting. Thus, the decision to pursue retreatment will be influenced on the response during prior exposure to the drug. When at all possible treatment with a triplet based combination should be considered.

# Immunomodulatory drugs:
The bulk of the evidence for the use of thalidomide in the relapse setting is phase II data Minimal phase III data to guide its use in the relapse setting 102,103. There is minimal monotherapy activity and thus is best used in conjunction with other agents in a doublet or triplet combination when other IMIDs are contraindicated (ex VTD or CTD). While neuropathy continues to be the major limiting side-effect its advantage is that there is minimal myelosuppression.
Lenalidomide Initial trials examined its use in combination with dexamethasone showing improved activity compared with dexamethasone alone and should be delivered as continuous therapy 104. Durable responses can be achieved and continuous therapy is generaly well tolerated. Phase II data supports the use of additional agents such as bortezomib (RVD) 105 or alkylator 106 especially if initial responses with steroid based doublet regimens are sub-optimal.
Pomalidomide This third generation immunomodulatory agent is indicated for use in patients with previous exposure to bortezomib and lenalidomide. At present, it is funded through a drug company sponsored compassionate access program. Inclusion in the provincial formulary is pending review. Phase III date supports its use over single agent dexamethasone 107. Similar to other IMIDs pomalidomide should be combined with dexamethasone and continued to progression.
- IMIDs (thalidomide, lenalidomide, pomolidomide) and proteasome inhibitors (bortezomib, carfilzomib), either as single agents or combination with other drugs (dexamethasone, prednisone, melphalan, cyclophosphamide), have been shown to be active in the treatment of relapsed and refractory myeloma. Table 10 in Appendix A summarizes the results of randomized phase III trials in relapsed and refractory myeloma. - When lenalidomide and dexamethasone are used for relapsed or refractory myeloma, treatment should continue until disease progression - Pomolidomide (4mg for 21/28 days every 4 weeks) with dexamethasone 40mg weekly can be considered for myeloma that is refractory to both lenalidomide and bortezomib.

# Assessment of Response to Therapy:
The response criteria and disease progression/relapse criteria of the International Myeloma Working Group, shown in Tables 7 and 8, have been adopted to assess response to therapy, progression, and other survival parameters.
As part of response assessment, all patients should have a repeat bone marrow aspirate at the time of maximum response.  - Not meeting criteria for CR, VGPR, PR or progressive disease - Not recommended for use as an indicator of response; stability of disease is best described by providing the time to progression estimates)   b It is not used in calculation of time to progression or progression-free survival but is listed here as something that can be reported optionally or for use in clinical practice - Development of new soft tissue plasmacytomas or bone lesions - Definite increase in the size of plasmacytomas or bone lesions as defined by a 50% (and at least 1 cm) increase as measured serially by the sum of the products of the cross-diameters of the measurable lesion - Hypercalcemia >2. 65

# Follow-Up After Treatment
Myeloma patients should not be discharged from the Cancer Centre as they are rarely cured of their disease. Patients should be seen at intervals varying from 1 to 3 months depending on their disease status, and whether they are receiving monthly bisphosphonate. Each visit should include:
- A clinical assessment - CBC, creatinine, calcium, albumin, total protein, quantitative immunoglobulins, and measurement of Mprotein (SPEP and UPEP) - FLC studies are also required in patients with non-measurable disease, oligosecretory and light chain disease, and to monitor for light chain escape which can occur in 6% of IgG myeloma and up to 10% of IgA myeloma - Immuno-fixation on SPEP and UPEP and BM biopsy are required to confirm CR - FLC is required to confirm sCR (stringent CR) - A skeletal survey should be obtained once per year
The recommended follow-up plan as outlined by the International Response Criteria 112 includes:
- Patients undergoing therapy should be tracked monthly for the first year of new therapy and every other month thereafter. - Patients with 'measurable disease' need to be followed by both SPEP and UPEP for response assessment and categorization. - Except for assessment of CR, patients with measurable disease restricted to the SPEP will need to be followed only by SPEP; correspondingly, patients with measurable disease restricted to the UPEP will need to be followed only by UPEP. - Patients with measurable disease in either SPEP or UPEP or both will be assessed for response only based on these two tests and not by the FLC assay. FLC response criteria are only applicable to patients without measurable disease in the serum or urine, and to fulfill the requirements of the category of stringent CR. - To be considered CR, both serum and urine immuno-fixation must be carried out and be negative regardless of the size of baseline M-protein in the serum or urine; patients with negative UPEP values pre-treatment still require UPEP testing to confirm CR and exclude light chain or Bence-Jones escape. - A skeletal survey is not required for assessment of response unless clinically indicated (e.g. to investigate new bone pain) - Bone marrow is required for categorization of CR, and for patients with non-secretory disease. Bone marrow aspirate should be performed at the time of maximum response to therapy. Bone marrow flow cytometry should be used to detect minimal residual disease for those otherwise in CR.
The first study to show a benefit for bisphosphonate use in preventing skeletal events in myeloma reported new events in 24% of those treated with pamidronate versus 41% in those receiving placebo (p<0.001) with a trend to improved survival in the treatment arm (28 vs 23 months, p=0.082). 113 The MRC Myeloma IX trial compared zoledronate to oral clodronate in 1960 newly diagnosed myeloma patients with and without bone lesions, and showed a lower incidence of skeletal related events (27% versus 35%, HR=0.74, p=0.0004). 114 This benefit was seen in those with pre-existing bone lesions (35% versus 43% new events, HR=0.77, p=0.0004) and those with no bone lesions at diagnosis (10% versus 17%, HR=0.53, p=0.007). Vertebral fractures were reduced (5 versus 9%, p=0.0008), as were other fractures (5 versus 7%, p=0.04) and new lytic lesions (5% versus 10%, p<0.0001). There was also an improvement in overall survival (median 50 versus 45.5 months, p=0.04) that may be due to slightly better disease control in the treatment arm.
A recent randomized controlled trial compared the effect of two doses of pamidronate (30mg versus 90 mg) on health-related quality of life and skeletal morbidity in patients with newly diagnosed multiple myeloma. 115 There was no difference seen in mean physical function or time to first skeletal-related event.
Eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group. This group suggests that monthly infusion of pamidronate 30 mg as the recommended dose for prevention of bone disease in patients with multiple myeloma.
A Cochrane meta-analysis evaluated the role of bisphosphonates in the treatment of bone disease in multiple myeloma. 116 Twenty trials (n= 6692) were included in this meta-analysis, and the authors concluded that the beneficial effects of bisphosphonates are:
- Reduction of vertebral fractures (RR=0.74)
- Reduction in skeletal related events (RR=0.80)
- Reduction in pain (RR = 0.75)
- No direct effect of bisphosphonates on overall survival (HR=0.95, 95% CI-0.82-1,13, p=0.64). However, a potency effect is seen, with superior overall survival observed with zoledronate compared with etidronate or placebo, but no difference when compared with other agents.
The IFM 99-02 study assessed the role of maintenance pamidronate post-tandem ASCT and found no reduction in the incidence of bone events and no impact on survival compared to no maintenance. 72 The guidelines for the treatment of bone disease in multiple myeloma are summarized in Table 9. - Intravenous bisphosphonates with either pamidronate 30 -90 mg every 4 weeks or zoledronate 4mg iv every 4 weeks for 2 years is recommended.
- Clodronate 1600 mg daily for 2 years is an acceptable alternative if intravenous treatment with pamidronate or zoledronate is not possible. If after 2 years the patient has achieved remission and is in stable plateau phase off treatment, the bisphosphonates can be discontinued. However, If the MM still requires active treatment, the bisphosphonate treatments can be decreased to every 3 months.

# Bisphosphonates and renal function:
All myeloma patients receiving bisphosphonates should have closely monitoring of renal function before administration of each intravenous infusion by measuring urinary albumin, serum electrolytes, and CrCl. Patients with mild to moderate renal impairment (CrCl 30 to 60 mL/min) should receive reduced doses of zoledronic acid and clodronate. No change to zoledronic acid infusion time is recommended. Pamidronate should be administered via 4-hour infusion in patients with mild to moderate renal impairment. Pamidronate and zoledronic acid are not recommended for patients with CrCl  12 mL/min. Bisphosphonate therapy should be discontinued in patients experiencing changes in renal function until CrCl returns to within 10% of baseline values.

# Osteonecrosis of the Jaws (ONJ):
The strongest correlation for the occurrence of ONJ is reported with use of pamidronate and/or zoledronate and less commonly reported with oral clodronate. The incidence varies between 4% and 11.4% with the higher incidence observed with the use of zoledronate and with prolonged duration of therapy. ONJ is often precipitated by a dental intervention that involves manipulation the mandibular and maxillary bones (i.e. root canal, dental extraction). In order to minimize the risk of ONJ, the following prophylactic and therapeutic guidelines should be followed:
- Prior to initiating therapy with bisphosphonates, a comprehensive dental evaluation should be performed and all invasive dental procedures be completed. - Annual dentist visits and maximal preventive care.
- Avoid dental extractions if possible.
- Withhold bisphosphonates for at least one month before dental extraction and do not resume until recovery and healing is complete. The use of prophylactic antibiotic is recommended after dental extraction to promote healing and prevent infection. - Treatment of ONJ should be conservative (oral Peridex swish and spit, antibiotics to treat infection, hold bisphosphonates indefinitely) and avoid extensive surgical manipulations. Non-randomized trials suggest a possible beneficial role for hyperbaric oxygen therapy.

# Percutaneous Vertebral Augmentation or Kyphoplasty:
Percutaneous balloon kyphoplasty involves the inflation of a balloon prior to polymethyl methacrylate (PMMA) injection into a vertebral compression fracture (VCF). This procedure restores vertebral height and reduces kyphotic deformity in addition to reducing the pain level and stabilizing the fractured vertebral body. The first prospective trial evaluating the role of balloon kyphoplasty in multiple myeloma showed that over 80% of the treated patients experienced significant pain control. In addition, there was an overall 30% height restoration with improvement of 60-70% of height restoration when the procedure was performed for fractures less than 6 month old. A consensus statement from the International Myeloma Working Group regarding the role of kyphoplasty in multiple myeloma was recently published. 87 Summary of the indications and contraindications for this procedure are outlined in Table 11. Referrals for kyphoplasty should be made within six months from the occurrence of the compression fracture, as early referrals appear to yield the maximum benefit from this procedure.

# Radiation Therapy
Isolated Plasmacytoma: see section IV Spinal cord compression: Suggest consultation with radiation oncology for dosage and initiation of therapy. The phase 3 clinical trial 156 specifically excluded patients with multiple myeloma therefore caution in extrapolating these results onto the multiple myeloma population is suggested.
Painful lesions: Radiotherapy may be useful to prevent further osteolysis and reduce pain. 157 Low-dose radiation therapy (10-30 Gy) is used for the palliative treatment of uncontrolled pain, impending pathologic fracture, or impending spinal cord compression. Limited involved fields should be used to limit the effect of irradiation on stem cell harvest or its effect on potential future treatments; the radiation doses administered should not preclude stem cell collection in potential candidates for high-dose therapy and hematopoietic SCT.

# Viral Prophylaxis
Autologous stem cell transplant patients: See Alberta Transplant Guidelines Guidelines.
Vaccination: There is little evidence to support a documented response to vaccination in this population, 158 but with little harm documented, it is generally suggested that patients and their immediate family members and care providers receive yearly vaccination for Influenza. It may be suggested that vaccination for streptococcus pneumonia and Haemophilus influenza is recommended but efficacy is not guaranteed.

# Viral prophylaxis:
Herpes zoster is a possible complication related to bortezomib administration. Antiviral prophylaxis, such as acyclovir or valacyclovir, is recommended against zoster reactivation during bortezomib treatment and for 30 to 60 days after its discontinuation. 159 Viral primary prophylaxis is not recommended for other therapies.

# Orthopedic Surgery:
Orthopedic consultation for impending or actual long bone fracture or bone compression/vertebral column instability is suggested. Prophylactic pinning of impending fractures should be discussed on a case by case basis.

# IV. SOLITARY PLASMACYTOMA
The location of the solitary plasmacytoma is crucial to predicting its natural history. The majority of patients with extra-osseous (non-bone-involving) plasmacytoma have localized disease which is potentially curable with irradiation. The majority of patients with solitary plasmacytoma of bone will eventually manifest overt multiple myeloma (> 50% will progress to multiple myeloma).

# Solitary Plasmacytoma of Bone
Patients should undergo all the usual tests for multiple myeloma. CT scan of the plasmacytoma should be obtained prior to radiation therapy. An MRI of the spine and pelvis may show unsuspected and asymptomatic skeletal lesions. This finding would place the patient in the smoldering myeloma category. PET scan could help determine the extent of bone or soft tissue involvement.

# Treatment and Prognosis

# Solitary Plasmacytoma of Bone:
- Treatment consists of radiation in the range of 40 Gy to 50 Gy - Solitary plasmacytomas > 5 cm, the persistence of an M-protein after radiation or evidence or marrow involvement by MRI have a greater incidence of progression - 50% of patients with solitary plasmacytoma are alive at 10 years - 25-40% of patients survive disease-free at 10 years - Overt multiple myeloma occurs in almost 50% of patients with solitary plasmacytoma of bone (progression may occur 15 years later) - Recommend stem cell harvest in transplant eligible patients Patients with solitary plasmacytoma have a higher risk of progression to myeloma if there is occult bone marrow involvement as detected by flow cytometry 118,119 or a monoclonal light chain secretion in the urine.
- Progression in 72% of patients with and 12.5% without marrow disease, with a time to progression of 26 months vs not reached; (P =.003). - Progression in 91% with and 44% without monoclonal urinary light chains, median TTP, 16 vs 82 months; P <.001
- If no marrow involvement and no urinary light chains, 7.7% progression at 3.7 years versus 75% if either is present.

# Extramedullary Plasmacytoma:
- Treatment with localized radiation (40-50 Gy) and is often curative - Plasmacytoma may recur locally or metastasize to regional nodes - Symptomatic multiple myeloma occurs in only 15% of patients
- CBC, serum creatinine, calcium, and serum protein electrophoresis should be done every 3 months for 1 year, then every 6 months for 2 years, then annually. - A 24-hour urine protein electrophoresis and skeletal survey should be done annually, for at least 5 years for extra-osseous plasmacytomas, and for 5 to 10 years for osseous plasmacytomas.

# V. AMYLOIDOSIS
All patients with suspected or biopsy proven amyloidosis should be immediately referred to an amyloid specialist at the Cross Cancer Institute (Edmonton) or Tom Baker Cancer Center (Calgary) for detailed work up and management.

# Classification and Presentation:
Amyloidosis is a disease of protein misfolding giving rise to stable protein fibril deposits that accumulate in organs eventually causing them to malfunction and fail. Multiple subtypes exist each defined by the specific protein serving as the basis for the toxic fibril. The three most common amyloid subtypes are listed below with further details regarding other variants described in table 12 120.
AL Type: Most common subtype seen. Fibril subtype is clonal light chain. Often associated with a plasma cell dyscrasia but may also be seen other B-cell based lymphoproliferative disorders. Often presents with widespread organ involvement.
ATTR Type: Most commonly manifesting as Senile Systemic Amyloidosis with no mutations noted in the transthyretin (TTR) gene. Also manifests as Familial Amyloid Polyneuropathy (FAP) and associated with a number of mutations in the TTR gene (REF). Almost exclusivelypresents with cardiac and nervous system involvement.
AA Type: Fibril giving rise to the amyloid deposits is abnormal Serum Amyloid A (SAA) protein. This is an acute phase reactant and thus the disease is associated with systemic inflammation (autoimmune disorders, chronic infection, hereditary fever syndromes etc.). Almost exclusively presents with renal involvement.
Only AL amyloid falls under the category of plasma cell dyscrasia. Amyloidosis is a symptomatic plasma cell dyscrasia, fulfilling the criteria for ROTI, and requires therapy in the vast majority of cases. AL amyloid is the only subtype of amyloidosis that benefits from chemotherapy, highlighting the importance of confirming the diagnosis. As it is due to an underlying clonal population of cells (most often of plasma cell origin but is also associated with indolent B-cell based lymphorpoliferative disorders) it is considered a malignancy.
Table 12. Amyloid subtype characteristics and manifestations

# Diagnostic Pathway for AL Amyloidosis
Consider AL amyloidosis in the differential if there is evidence of a clone by serology (SPEP, UPEP or sFLC assay) or tissue biopsy (bone marrow, or lymph node) an evidence of organ involvement such as:
- proteinuria/Albuminuria (especially in context of nephrotic range proteinuria)
- non-ischemic cardiomyopathy with ventricular hypertrophy - unexplained diastolic dysfunction - unexplained raised HS-Troponin T, troponin I, BNP or NT-proBNP - unexplained persistent elevation of Alkaline phosphatase +/-hepatomegaly
- Peripheral neuropathy - Autonomic neuropathy
Confirmation by tissue biopsy is required to confirm the diagnosis and must be obtained before initiating therapy. Since MGUS is not uncommon, especially in patients with advanced age, the presence of a monoclonal protein in a patient with positive Congo red staining on a tissue biopsy is not adequate to make a diagnosis of AL amyloidosis. False positive diagnoses have been reported in between 7-25% of cases if only serologic methods are used to base the diagnosis of AL amyloid. In addition, some patients with AL amyloidosis will not have an abnormal SPEP or free light chain assay. Immunohistochemical staining is frequently unreliable and not able to accurately determine the type of amyloid present.
While obtaining a sample from the target tissue in question is the gold standard the diagnosis can sometimes be confirmed on more easily accessible surrogate tissue (bone marrow biopsy, fat pad biopsy or punch biopsy with sufficient subcutaneous adipose tissue).
All cases should be referred for hematopathology review. Subtyping should be done using immunohistochemistry with review by a pathologist with sufficient experience in confirming the diagnosis. Laser microdissection with mass spectrometry (LMD/MS) is now the gold standard for typing amyloid, enabling precise identification of type in over 98% of cases 121.

# Initial Tests:
All patients should have a complete plasma cell dyscrasia baseline workup if the underlying clone is thought to be secondary to clonal plasma cells (see section III above). If the underlying clonal disorder is thought to be lymphoma then appropriate disease specific testing should be undertaken as per current guidelines. Patients should also have baseline assessments of all potentially affected organs as outlined in table 13: In presence of of radiographic findings PFTs should be performed at baselin and in followup examining for alterations in diffusion capacity.
No specific imaging test. May note hepatomegaly with non specific infiltrative changes on US, CT or MRI.
Total liver span >15 cm in the absence of heart failure, or alkaline phosphatase level >1.5 times upper lim it of norm al
No specific lab test. If symptoms suggest, and in absence of other tissue proof of amyloid, biopsy is highly recommended.
Based on symptoms and/or biopsy proof

# Soft tissue
No specific lab test. If symptoms suggest, and in absence of other tissue, proof of amyloid biopsy is highly recommended.
Based on symptoms and/or biopsy proof

# Staging and Prognosis:
Outcome in AL amyloid is primarily determined by the presence and degree of cardiac involvement. Even with modern novel agent containing regiments the early death rate remains as high as 20% within the first 6 weeks. The Mayo staging system, defined by elevations in Troponin T and NT-proBNP, is the most widely used staging system 122. Even amongst Mayo stage III patients, further stratification can be performed using an NT-proBNP of > 8500 ng/L and a systolic blood pressure of < 100mmHg to identify ultra-high-risk patients requiring aggressive supportive care and urgent initiation of therapy under the auspices of a dedicated specialists 123.

# Treatment of AL Amyloidosis
Most hematological responses will result in clinical improvement of some degree even up to 12 months after the hematological responses have been recorded. The goal of the therapy is to halt the production of the amyloid protein (hematological remission, response criteria below). It should be noted that the treatment of an amyloidosis patient is multidisciplinary and requires the active involvement of a nephrologist and cardiologist. A comprehensive list of the current therapeutic options in this disease is described in table 11, appendix A.

# Combination Chemotherapy:
Bortezomib Based Regimens: While effective, high-dose chemotherapy is feasible in a minority of patients. Low-dose combination chemotherapy is the general approach pursued for the majority of patients.
Proteosome inhibitor-based regimens have evolved to be treatment of choice in AL amyloidosis. Prospective studies have shown deep and rapid response rates with the ability to treat those with advanced cardiac disease. Various groups have investigated triplet combinations using bortezomib with the classic steroid/alkylator backbone.  In those surviving long enough to benefit from therapy CR rates of up to 65% are reported, especially when used in the upfront setting. A recent multi-institutional study focusing on the use of this combination in Mayo stage III patients demonstrated an unprecedented 1-year OS of over 50% in this poor-risk group of patients. 128 Two recent case-control studies examining a bortezomib-alkylator-steroid combination compared with two standard regimens (melphalan and dexamethasone and CTD) have corroborated these findings, suggesting that bortezomib may be an important agent especially in the frontline setting. 126,127 In the absence of grade 2 neuropathy or grade 1 neuropathy with pain, a bortezomib based regimen should be considered first line of therapy:
- The standard initial therapy for amyloidosis is CyBorD (bortezomib 1.5 mg/m 2 weekly, cyclophosphamide 300 mg/m 2 orally weekly, and dexamethasone 40 mg weekly) 129.
IMIDs: Immunomodulatory drugs such as thalidomide, lenalidomide and pomalidomide have emerged as important agents. Initial studies with thalidomide and dexamethasone demonstrateclonal responses of 48% (CR in 19%) and organ responses of 26%. However, 60% experienced 3 grade toxicity. 130 The use of cyclophosphamide, thalidomide and dexamethasone (CTD) may result in more rapid responses (CR in 21% and PR in 53%) and organ responses in 33% but toxicity remains high. 131 Treatment with lenalidomide and dexamethasone has shown responses rates of up to 67% (CR = 29%). 132 Recently pomalidomide has also shown activity in this disease with haematologic responses of 48% and median OS and PFS of 28 and 14 months respectively. 133 Continuous therapy may be a key component to durable responses when IMiDs are used 134.
Alkylating Agents: Alkylating agents such as melphalan and cyclophosphamide, in conjunction with a steroid, have been used for over 40 years 135. While complete response (CR) rates of around 20-30% are achievable 136 responses are slow. Thus, unless a novel agent based strategy is contraindicated a double therapy with an alkylator and steroid is not recommended as a frontline option. If required the recommended standard regimen is melphalan 10 mg/m 2 days 1 to 4 plus high-dose oral dexamethasone (40 mg per day on days 1 to 4) for up to 18 treatment courses if no severe adverse effects have occurred.

# Autologous Stem Cell Transplant:
Prior to the era of rigorous patient selection this modality of therapy resulted in unacceptable levels of transplant related morbidity (TRM). 137 However, using modern patient selection criteria with a focus on cardiac involvement, the TRM now approaches that expected in myeloma  A recent publication demonstrates the durability of responses achieved with ASCT and highlights the improvements seen in TRM with modern patient selection criteria. The median overall survival (OS) was 6.3 years. Of the 34% achieving CR the median OS was 13.2 years. The TRM was 11.4% however in those treated in the modern era it was as low as 5.6%138.Two recent series have corroborated these findings 139,140. Long-term outcomes may be similar irrespective of whether the transplant is done as first line therapy or at relapse 139.
An NT-proBNP>5000 pg/ml and troponin T >0.06ng/L are important predictors of outcome post-ASCT.
With serum levels below these thresholds the TRM may be as low as of 1%. 141 When stem cell transplantation is performed, the following guidelines should be followed:
- Patients should be 50 mL/min 2) intermediate risk patients are <71 years old and have 12 organs involved, one of which must include cardiac or renal with creatinine clearance <51 mL/min 3) poor risk patients have either three organs involved or advanced cardiac involvement - Stem cell mobilization with G-CSF alone (5-6 g/kg q12 hours for 5 days) - Debulking with VAD or other regimens pre-transplant is unnecessary and not recommended - Conditioning with dose melphalan (140-200 mg/m 2 adjusted according to number of organ involved and the degree of heart failure

# Supportive Treatment
Supportive care is a fundamental part of an integrated treatment approach to AL amyloidosis patients and requires the coordinated expertise of several specialists. Table 14 summarizes the recommended supportive measures. - Neuropathic pain is difficult to control - Gabapentin starting with 300 mg daily and with daily increments up to 1800 mg

# Response Criteria and Disease Monitoring
Outcomes are assessed using both haematologic and organ response criteria. In addition to the traditional clonal assessments by serum and urine protein electrophoresis and immunofixation, the serum free light chain assay is also monitored. The difference between serum free light chains (dFLC) has become the predominant tool for clonal response assessment. The Consensus criteria for organ and haematologic response are described below 142. Attaining a dFLC-VGPR or better has emerged as being integral to longterm survival with this disease. Even in the setting of a PR ongoing excess of amyloidogenic free light chains will lead to further organ deterioration, making at least a dFLC-VGPR the ultimate goal of therapy.

# Hematologic (Immunochemical) Response:
- Complete response: Serum and urine negative for a monoclonal protein by means of immuno-fixation, normal kappa:lambda free light-chain ratio, and normal absolute value of the involved serum free light-chain (in patients without renal insufficiency) - Partial response: Serum M component >0.5 g/dL and 50% reduction; light chain in the urine with a visible peak >100 mg/day and 50% reduction; or free light chain >10 mg/dL and 50% reduction - Progression after complete response: Any detectable monoclonal protein or abnormal free light-chain ratio (light chain must double) - Progression after partial response or stable response: 50% increase in serum M protein to >0.5 g/dL or 50% increase in urinary M protein to >200 mg/day with a visible peak Organ Response:
- Heart: Mean interventricular septal thickness decreased by 2 mm, 20% improvement in ejection fraction, improvement by two New York Heart Association classes without an increase in diuretic use, and no increase in wall thickness - Kidney: 50% decrease (a decrease of at least 0.5 g/day) in 24-hr urinary protein (must be >0.5g/day before treatment), creatinine and creatinine clearance must not worsen by 25% over baseline level - Liver: 50% decrease in abnormal alkaline phosphatase value, at least 2 cm decrease in liver size on radiographic imaging - Nerve: Improvement in nerve conduction velocity on electromyogram (rare)

# IMPLEMENTATION STRATEGY
- Present and review the guideline during local and provincial tumour team meetings and weekly rounds.
- Post the guideline on the Alberta Health Services website.

# EVALUATION STRATEGY
A formal review for new and updated evidence will be conducted in May 2018, however if new evidence is brought forward before that time, the guideline will be changed accordingly.

# DECLARATION OF CONFLICT OF INTEREST
None of the authors of this guideline had any conflict of interest related to evidence or recommendations in this guideline.

# APPENDIX A: EVIDENCE TABLES FOR TREATMENT REGIMENS IN MULTIPLE MYELOMA
. Otherwise, dose 2, 3, and 4 can be given without additional monitoring.
- Subcutaneous bortezomib (given at the same dose and concentration as iv bortezomib) is an acceptable alternative for patients who develop peripheral neuraopathy or other intolerance, or who have significant neuropathy prior to the start of therapy.
A minimum of 72 hours should separate the doses of bortezomib. 5. Approximately 30% patients achieve a PR after 4 cycles; therefore do not discontinue treatment if only stable disease is seen after 4 cycles.    3. On the following days, platelet counts should be  30 and ANC > 1.0. For patients with recurrent dose delays secondary to cytopenias, dose reductions of melphalan are required.