MULTIPLE MYELOMA MEDICAL SCIENTIFIC ADVISORY GROUP (MSAG) PANEL MEMBERS.

MEDICAL SCIENTIFIC ADVISORY GROUP (MSAG) TO THE MYELOMA FOUNDATION OF AUSTRALIA (MFA) Clinical Practice Guideline Coordinated on behalf of the MSAG, Dr Hang Quach and Professor Miles Prince MEDICAL SCIENTIFIC ADVISORY GROUP (MSAG) PANEL MEMBERS. Bradley Augustson WA Ross Brown - NSW Laurence Catley - QLD John Gibson - NSW Joy Ho - NSW Simon Harrison - VIC Noemi Horvath - SA Wilfrid Jaksic - SA Doug Joshua - NSW Peter Mollee - QLD H Miles Prince - VIC Hang Quach - VIC Andrew Roberts - VIC Brian Rosengarten - MFA Andrew Spencer - VIC Jeff Szer - VIC Daniel Sze - NSW Bik To - SA Dipti Talaulikar - ACT Andrew Zannettino - SA 1

TABLE OF CONTENTS Table of Contents 2 1 INTRODUCTION: 3 2 DIAGNOSTIC CRITERIA AND STAGING SYSTEM: 4 2.1 THE ROLE OF PROGNOSTIC MARKERS: 5 2.2 INITIAL DIAGNOSTIC WORK-UP 6 3 MANAGEMENT OF AN OVERVIEW 11 3.1. THE DECISION TO COMMENCE MYELOMA THERAPY: 11 3.2. UPFRONT TREATMENT OF - AN OVERVIEW: 12 3.2.1 Patients eligible for AuSCT: 12 3.2.2 Tandem vs. single AuSCT: 13 3.2.3 Induction therapy prior to AuSCT: 14 3.2.4 Stem cell mobilisation 16 3.2.5 Monitoring post AuSCT 17 3.2.6 Allogeneic Stem Cell Transplant 17 3.2.7 Patients not eligible for AuSCT: 18 3.2.8 Patients with high risk MM. 20 3.3 CONSOLIDATION/MAINTENANCE THERAPY 21 3.4 TREATMENT OF RELAPSED 23 3.5 LENALIDOMIDE-INDUCED SECONDARY MALIGNANCIES: IS THIS A CONCERN? 25 4 CONCLUDING REMARK 26 5 REFERENCE 27 MEDICAL SCIENTIFIC ADVISORY GROUP (MSAG) PANEL MEMBERS. Bradley Augustson WA Ross Brown - NSW Laurence Catley - QLD John Gibson - NSW Joy Ho - NSW Simon Harrison - VIC Noemi Horvath - SA Wilfrid Jaksic - SA Doug Joshua - NSW Peter Mollee - QLD H Miles Prince - VIC Hang Quach - VIC Andrew Roberts - VIC Brian Rosengarten - MFA Andrew Spencer - VIC Jeff Szer - VIC Daniel Sze - NSW Bik To - SA Dipti Talaulikar - ACT Andrew Zannettino - SA 2

1. INTRODUCTION Multiple myeloma (MM) is a plasma cell malignancy characterised by an abnormal serum and /or urine immunoglobulin intact paraprotein or free immunoglobulin light chain as a result of clonal expansion of plasma cells. It is often accompanied by complications of enhanced bone loss associated with diffuse osteopenia or focal lytic lesions, renal failure, hypercalcaemia, immune suppression and anaemia. Approximately 1200 new cases are diagnosed in Australia each year [1]; it is a disease of the elderly with median age at diagnosis of 65-70 years [2], however, younger patients with MM are also seen. Although MM remains an incurable disease, survival outcomes transplant (AuSCT) in the late 1990s, then novel therapeutic agents including thalidomide, its immunomodulator Treatment options for MM are now diverse. Apart from basic treatment principles, there is no strict consensus for standard of care for both upfront or relapsed/refractory disease. Local treatment guidelines vary, based on both the local availability of novel therapeutic agents, and familiarity of the treating physician to these agents. The following Group (MSAG) to the Myeloma Foundation Australia (MFA), which consists of a panel of haematologists across Australia. Levels of evidence and grades of recommendations in this guideline are as follows: Table 1 Level of evidence and grades of recommendations. LEVELS OF EVIDENCE 1A Evidence from meta-analysis of randomised control trials 1B Evidence from at least one randomised controlled trial. 2A Evidence from at least one well-designed non-randomised trial, including phase II trials and case-control studies 2B Evidence from at least one other type of well-designed, quasi-experimental study such as observational studies. 3 Evidence from well-designed non-experimental descriptive studies. 4 Evidence obtained from expert committee reports or opinions and/or of respected authorities. GRADES OF RECOMMENDATIONS A Recommendation based on at least randomised controlled trial of good quality addressing specific recommendation (evidence level 1A and 1B) B Recommendation based on well-conducted studies but no randomised controlled trial on topic of recommendation. (Evidence level 2A, 2B, and 3) C Recommendation based on expert opinions or reports (Evidence level 4) 3

2 DIAGNOSTIC CRITERIA AND STAGING SYSTEM: with an increased number of bone marrow plasma cells. The diagnostic criteria established by the International Myeloma Working Group [4] is now used in preference to the earlier Durie & Salmon diagnostic criteria for MM. Three categories in the International Myeloma working Group diagnostic criteria [table 2] include: 1. Monoclonal Table 2. Diagnostic criteria according to the International Myeloma Working Group 2003[4] MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS) ASYMPTOMATIC MYELOMA SYMPTOMATIC MYELOMA - Serum paraprotein <30g/l - Bone marrow clonal plasma cells <10% in the aspirate, and low level of plasma cell - No myeloma related organ or tissue - No evidence of other B-cell lymphoproliferative disease (LPD) or light chain associated amyloidosis or other light chain, heavy chain or immunoglobulin - Serum paraprotein marrow clonal plasma - No myelomarelated organ or tissue impairment or - Paraprotein in serum - Bone marrow clonal plasma cells or biopsy - Any myeloma-related organ or tissue Table 3. Related Organ Tissue Injury (ROTI) MYELOMA RELATED EFFECTS - Increased calcium level. Corrected serum Calcium 0.25mmol/l above the upper limit of normal or 2.75mmol/l - Renal insufficiency. Creatinine 173mmol/l. - Anaemia Hb <100g/L or 20g/L below the lower limit of normal. - Bone lesions Lytic lesions, or osteoporosis with compression fractures on MRI or CT - Other Symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (2 episodes in 12 months). 4

2.1 THE ROLE OF PROGNOSTIC MARKERS: The natural history of MM can vary markedly between patients; survival can range from several months, to many years. Prognostic factors at diagnosis serve as a basis on which comparison of treatment outcomes can be made in high-risk patients[5]. Currently, the most widely adopted prognostic model is the international prognostic index (IPI) [6]. This model is based on serum levels of ß 2 microglobulin (ß 2 M) and albumin, and separates MM patients into three prognostic groups predict outcome. Table 5 outlines the prognostic factors used at the Mayo clinic to classify patients as having high risk with HDT and AuSCT compared to other patients with MM [7-9]. Table 4. International Prognostic index [6] STAGE CRITERIA MEDIAN SURVIVAL (MONTHS) I Serum ß 2 M <3.5mg/l and serum Albumin 35g/l 62 II Neither I nor III 45 III Serum βß 2 M5.5mg/l 29 Table 5. Criteria for high-risk myeloma: HIGH RISK ABNORMALITIES Conventional Cytogenetics. - Deletion of chromosome 13* - Hypodiploidy - Del 17p Fluorescent in situ hybridisation (FISH) - t(4;14) - t(14;16) - Del17p - 1q21 amplification p53 on immunohistochemistry (IHC) Plasma cell labelling index 3% High lactate dehydrogenase (LDH) Amplification of 1q21 The following tests for high-risk disease are routinely available and are recommended. Conventional Cytogenetics **. Fluorescent in situ hybridisation (FISH) ** - t(4;14) - t(14;16) - t(14;20) - Del 17p - 1q21 amplification. LDH p53 on IHC Plasma cell labelling index (by flow cytometry)*** patients with 15% plasma cells in the aspirate as the yield of metaphases is low with a lesser plasma cell burden 5

2.2 INITIAL DIAGNOSTIC WORK-UP The initial diagnostic work-up process (Figure 1) aim to establish the diagnosis, the stage of disease, and prognostic The following recommendations are grade C and based on level 4-evidence unless otherwise stated. Figure 1: Initial diagnostic work up. ALL PATIENTS SUSPECTED OF HAVING MULTIPLE MYELOMA 1. Haematology: Biochemistry: - U&E, Ca++, PO 4 /Mg ++, urate - ß 2 Microglobulin, LDH, C-reactive protein (CRP) 2 Bone marrow aspirate and trephine. Flow cytometry: Imaging: SELECTED CASES: MGUS and asymptomatic myeloma. Follow up as per figure 2. Symptomatic myeloma (ie. with related organ tissue injury) ADDITIONAL INVESTIGATION UPON REQUIREMENT OF TREATMENT: SELECTED PATIENTS: - Viral serology: Hep B, Hep - HLA typing for siblings/ extended family if aged <65 years - Sestamibi scan 4 (Grade B, level 3 evidence) - PET scan 4 (Grade B, level 3 evidence) - Gated blood pool scan or echocardiogram in patients with cardiac history and considered for anthracycline - Echocardiogram or cardiac MRI if amyloid is suspected 1.The extent of initial diagnostic work up for patients with MGUS is more limited compared to patients suspected of having multiple myeloma, and is dependent on the level of paraprotein and individual risk assessment for progression towards multiple myeloma. Please refer to the recent international myeloma working group (IMWG) consensus [10] 2. The serum immunoglobulin-free light chain (SFLC) assay is recommended by the IMWG as part of screening in combination with SPE and IF, which altogether yields high course of management. Cytogenetics is often only possible in patients with 15% plasma cells in the aspirate as the yield of metaphases is low with a lesser plasma cell burden. 4. Sestamibi or PET can be useful additional diagnostic tools for detection of otherwise occult myelomatous sites in early stage MM. Overall sensitivity for MIBI is ~92% and 6

Figure 2: Management of MGUS and Asymptomatic Myeloma. MGUS Asymptomatic Myeloma 3 to 12 monthly monitoring depending on individual risk of progression to symptomatic MM 1 (grade B recommendation, level 3 evidence) - Clinical assessment. - Serum ± urinary protein electrophoresis (immunofixation not required) - FBE, U&E, Ca 2+ - Targeted radiographic imaging if indicated. Evidence of related organ tissue injury (table 2). Rapidly rising paraprotein or heavy bone marrow plasma cell infiltration. 2 NO evidence of related organ tissue injury (table 2) See management of symptomatic myeloma. (Figure 3) 1 For MGUS: SPEP can be repeated annually. aspirate and trephine is considered if paraprotein is rising to assess for evidence of MM. If these results are satisfactory, patients can be followed at 6 monthly intervals for 1 year, then yearly provided the treating physician is contacted upon any clinical changes [15]. 2 It would be reasonable to commence treatment in patients with a rapidly rising paraprotein or a heavy tempo of progression. 7

Figure 3: Management of Newly Diagnosed Symptomatic Myeloma. Newly Diagnosed Symptomatic Myeloma Eligible for available clinical trial? NO YES Entry into Clinical Trial Induction+ AuSCT: (Grade A, level 1B evidence for patients age 65; grade B, level 2A evidence for patients aged 65) -3-6 cycles of induction therapy (see table 6A) -Response assessment post each cycle. - Supportive measures (see table 8) YES Stem cell collection sufficient for planned therapy Adequate response? (ideally PR or better) post 3 cycles/months. NO Response post ~3 cycles AuSCT: MEL 200* conditioning. (Grade B recommendation, level 2A evidence) * Lower dose MEL conditioning can be considered in patients aged 70, or younger patients with impaired renal function and comorbidities. Response YES Achieved VGPR? NO Consider maintenance with thalidomide ± alternate days prednisolone (Grade A recommendation, level 1B evidence) Second AuSCT (Grade C recommendation) RIC AlloSCT in highly selected cases (see allogeneic stem cell section) (Grade C recommendation) YES Transplant candidate. 1 NO Salvage induction therapy incorporating novel agents (see table 6A). Relapsed/ Progressive disease Salvage therapy: See relapsed myeloma - Induction therapy: MPT, MVP, MPR-3 (table 6B) (Grade A, level 1B evidence) Other: table 6A. 2 - Supportive measures (see table 8) 1 2 Patients who are not immediate transplant candidates but in whom AuSCT may still be a viable option at relapse should avoid the alkylating agent melphalan so as not to compromise potential stem cell harvest. Induction regimens without melphalan are outlined in table 6A.

Figure 4 Management of relapsed Myeloma. Salvage therapy incorporating novel therapeutic agents (see table 9): (grade B recommendation, level 2A evidence) - Thalidomide based regimen. - Bortezomib - Lenalidomide based regimen. - Combination novel agent-chemotherapy Relapsed Myeloma Eligible for available clinical trial? NO - For patients still transplant eligible, and with initial long PFS post first AuSCT (eg 18m): Repeat HDT and AuSCT if adequate viable stem cells are available (grade B recommendation, level 2A evidence) - AuSCT followed by mini AlloSCT for selected patients, preferably in clinical trials setting (grade C, level IV evidence) - If relapse occurs 6 months post cessation of initial treatment, the initial chemotherapy regimen could be re-instituted. However, an inferior duration and quality of response is to be expected. YES Entry into Clinical Trial (Grade C recommendation)

Table 10: Supportive measures. Localised bony lesions Venothromboembolism (VTE) repo IV Ig Infection Other prophylaxis urgent radiotherapy in combination with corticosteroids if spinal cord compression is due to soft tissue mass arising from vertebrae. treatment of multiple myeloma - [17] - - is dependent on individual assessment of prothrombotic risks[18] may be considered in selected patients especially those with renal failure (indication maglobulinaemia are eligible for IVIg. www.nba.gov.au for criteria for the clinical use of intravenous immunoglobulin in Australia. - other pathogens deemed necessary because of epidemiologic prevalence. Live vaccines should be avoided. Non-immune close contacts of patients should also be vaccinated[19] patients receiving ongoing corticosteroids 10

3. MANAGEMENT OF AN OVERVIEW Despite the much improved survival outcome since the introduction of novel therapeutic agents including the immunomodulatory drugs (IMiDs) and proteasome inhibitors, multiple myeloma (MM) is still an incurable disease. However, the expansion of effective treatment option over the last two decades, has converted what was once a 7 years or more. While we continue to strive towards to ultimate goal of cure for the future, currently, the treatment 3.1. THE DECISION TO COMMENCE MYELOMA THERAPY: Early intervention in patients with monoclonal gammopathy of have an increased risk of progression compared to those with Monitoring of MGUS and asymptomatic MM should be patients with low risk of progression. Monitoring should include that asymptomatic myeloma with no evidence of bone disease but with abnormal marrow appearance on MRI are at higher risk discriminatory only in patients with other adverse factors such as high levels of serum or urine para-protein [25]. Recommendation for monitoring of MGUS and Asymptomatic MM: Monitoring of MGUS and asymptomatic MM should be depending on the individual s risk of progression (Grade C Three to 12 monthly visits are individual risk assessment for progression towards symptomatic Monitoring should include a clinical assessment, full blood evaluation, renal function, electrolytes including calcium levels, serum ± urinary paraprotein, and targeted radiographic 11

3.2. UPFRONT TREATMENT OF - AN OVERVIEW: Currently, the standard upfront treatment for patients with symptomatic MM depends on their eligibility for HDT and AuSCT based on the patient s age, comorbidities and functional status. Whether or not an upfront AuSCT approach is undertaken, the aim is to induce a maximal depth of response, especially complete response (CR), without unacceptable toxicities. CR is the prognostic impact of CRs on survival may be less important in patients in whom symptomatic myeloma had progressed from a previous prolonged period of to the inherent indolent biology of the disease in these patients. Conversely, the prognostic impact of CR on survival outcome was more evident in patients of upfront treatment. 3.2.1 Patients eligible for AuSCT: The superiority of HDT and AuSCT compared to conventional-dose chemotherapy with respect to PFS and OS has randomized control trials prior to the era of novel agents, AuSCT was shown to improve PFS, with a combined novel therapeutic agents, newer anti-mm therapies can now induce remission rates similar to or surpassing those achieved by AuSCT in the pre-novel agent era, raising the possibility of deferral of AuSCT in patients with excellent responses to novel-agent induction therapy. Indeed, prospective clinical trials are underway to compare early AuSCT versus ongoing maintenance after novel-agent containing induction therapy. However, until results from these trials improves depth of response from novel-agent containing induction regimens, and remains a necessary tool to maximise the rate of CR in transplant-eligible patients. At present, HDT and AuSCT remains the standard upfront treatment for all eligible patients; deferral of AuSCT in eligible patients should only be done in a clinical trial setting. 12

3.2.2 Tandem vs. single AuSCT: attempt to increase dose intensity to achieve a deeper and sustained remission. Reported CR rates with single AuSCT 40% with a median EFS and OS of 49 months and 62 months, respectively superior to historical controls with by thalidomide maintenance was superior to tandem transplant with respect to PFS (p=0.02) and OS (p=0.04)[41]. In Overall, tandem AuSCT did not result in improved OS or EFS compared to single AuSCT. However, the trials that were included in this meta-analysis were heterogeneous; one of which compared tandem AuSCT to single AuSCT followed by maintenance thalidomide. Indeed, consolidation or maintenance therapies with novel agents, and effective salvage therapies in the current era, may well mitigate any OS advantage of tandem AuSCT over single AuSCT. We recommend that tandem AuSCT, when considered, only be used in patients who have achieved less than a [44] which have been shown to further improve depth of response post AuSCT in some patients, and abrogated the impact of failing to achieve CR or VGPR post AuSCT with respect to PFS. Recommendation for transplant eligible patients: High dose therapy (HDT) and autologous stem cell transplant (AuSCT) patients between 65-70 years with good performance status and organ 2A evidence for patients aged 65) 13

3.2.3 Induction therapy prior to AuSCT: The ideal induction regimen for transplant-eligible patients should rapidly reduce tumour burden and reverse disease related complications, to allow patients to proceed promptly to transplant without antecedent toxicities. Deeper pre-transplant responses have been shown to be associated with better post transplant outcome[45]. For many years, infusional vincristine, doxorubicin, dexamethasone (VAD) was used as pre-transplant induction therapy for patients who were candidates for AuSCT. Since the introduction of thalidomide, lenalidomide and bortezomib, many novel agent-based combinations have been shown to induce a deeper response rate compared to VAD which then with three-drug combination, with the addition of a cytotoxic drug such as doxorubicin or cyclophosphamide, to a novel agent and corticosteroid. However, some induction regimens not containing novel-therapeutic agents (table 6A) such as CID (cyclophosphamide, idarubicin, dexamethasone) and PCAB (doxorubicin, carmustine, cyclphpsphamide, centres. Patients eligible for AuSCT should receive stem cell-sparing induction therapy (i.e. regimens not containing choice is often dependent on local treatment guidelines and access to novel agents. Thalidomide-based induction: increasing to approximately 60-75% with addition of dexamethasone (thal-dex) [49, 51, 52]. Thal-dex is superior to VAD with respect to ORR (76% vs. 52%, p<0.001) [47], and does not compromise stem cell harvest. However, the use of thal-dex as induction is not completely free of toxicity, and is associated with a higher incidence of grade thromboembolism (VTE), that necessitates routine thrombo-prophylaxis. When compared to other novel-agent improved. As a result, a three-combination regimen is more commonly used when thalidomide-based induction is considered. Bortezomib-based induction: 10% when used as upfront treatment [54]. ORR and CR/nCR rates increases to approximately 65-70% and 20-25% respectively, when dexamethasone is added [54, 55]. In combination with chemotherapy, ORR further increases to vincristine in VAD, the so-called PAD (bortezomib, doxorubicin, dexamethasone) regimen, 95% of patients achieved Whilst the VTE risk is low (<5%), the main drawbacks with bortezomib-based regimen are the need for parenteral (IV particularly useful in patients with renal failure or high-risk disease (see high risk disease section). Indeed, several studies have suggested that bortezomib may be able to overcome the effect of unfavourable cytogenetics, except 17p deletion[5, 14

bortezomib early in the disease course should be considered in patients with high-risk myeloma (see table 5) or rapidly progressive renal impairment. Of note, the use of bortezomib does not affect stem cell yield and thrombo-prophylaxis is not necessary. However, the incidence of Varicella Zoster Virus (VZV) reactivation is reported to be approximately 11% and up to 19% when combined with dexamethasone[64]. As such, anti-viral prophylaxis against VZV reactivation is recommended in all patients receiving combination bortezomib-corticosteroids. Lenalidomide-based induction: Lenalidomide (len), as part of the immumomodulatory drug group (IMiDs), has multiple anti-myeloma effects In the upfront setting, phase II studies have shown that combination len and dexamethasone (len-dex) induced an ORR of in using low-dose dexamethasone (40mg per week as opposed to 40mg days 1-4, 9-12, 17-20) in combination with len and less toxicity[67]. From these data, len-dex induction is certainly superior compared to VAD or thal-dex. The main and VTE in the order of 25%, which appears to be reduced by the use of aspirin, to an incidence comparable to the (40mg weekly), VTE risk was reduced to 9%. Newer regimens incorporating combination of two novel agents, such as bortezomib + lenalidomide+ the present time, HDT and AuSCT remains the standard upfront treatment for MM patients who are eligible. Recommendation for induction therapy prior to AuSCT: Transplant-eligible patients should be treated with 3-6 cycles of induction prior to AuSCT evidence) Induction regimens incorporating thalidomide, lenalidomide or proteasome inhibitors improve response rates, however the choice of induction therapy (table 6A) is dependent on local availability/access to novel therapeutic agents, and should take into consideration patient s comorbidities, for example: thalidomide and lenalidomide, although not absolutely contraindicated, should be avoided recommendation, level 4 evidence) 15

3.2.4 Stem cell mobilization. The most common regimen used to mobilise peripheral blood stem cells (PBSC) for MM patients is recombinant cyclophosphamide with rhg-csf. The addition of high dose cyclophosphamide for mobilization does not necessarily improve depth of response over induction therapy, and does not improve CR rates or time to progression (TTP) in patients undergoing AuSCT.[70] However, using cyclophosphamide for mobilisation has the advantage of increasing rhgcsf. There are also data indicating that cyclophosphamide mobilization regimen decreases lymphocyte yield, and that T cells/lymphocyte count recovery post AuSCT improves PFS and OS in many haematological malignancies (unpublished communication). initial attempt at stem cell mobillization although many centres continue to use rhg-csf in addition to high-dose cyclophosphamide as part of institutional protocol. In fact, recent reports have indicated that thalidomide and oral cyclophosphamide, two agents that have not been shown to impact stem cell mobilization individually, may induce a may be inferior to combination therapy using rhg-csf and high-dose cyclophosphamide[74], and the latter should be considered for stem cell mobilization, especially in patients who have received more than 4 cycles of lenalidomidebased induction therapy. Recommendation for stem cell mobilization: patients who have received more than 4 treatment cycles (Grade B 16

3.2.5 Monitoring of patients after AuSCT: The average time to progression for patients after HDT and AuSCT is in the order of 2-4 years for younger patients, and shorter for older patients. The followed up monthly for about 1 year with clinical and laboratory assessments, looking for evidence of relapse/ progression. Testing should include serum or urinary para-protein levels (SFLC levels is used in patients with unmeasureable paraprotein in blood or urine), FBC, serum calcium levels, and renal function. If patients are appears to be disease stability. Please refer to Durie et al. 2006 [75], for uniform response criteria to assess response and relapse after treatment. Recommendation for follow up after AuSCT: Patients should be monitored every month initially for clinical and biochemical assessment with serum or urinary paraprotein levels (SFLC levels is used in patients with unmeasurable 3.2.6 Allogeneic Stem Cell Transplant A Graft versus myeloma (GVM) has been shown to exist in the setting of allogeneic stem cell transplantion (allosct) [76]. While this may give rise to some long-term durable remissions [77], myeloablative allosct is associated with a high TRM of up to 50%. Reduced intensity conditioning (RIC) allosct has TRM, to approximately 10-15% at 1 year, whilst donor had a second AuSCT in the companion IFM99-04 study. At the time of initial reporting median EFS and OS inferior in patients assigned to RICalloSCT [79]. An Italian randomized study, also comparing tandem AuSCT vs. AuSCT features for selection demonstrated a superior long-term outcome in those who had available sibling donors (OS: p=0.001) and a plateau in PFS was also seen in this group. However, due to a higher TRM and GVHD, no statistical difference in EFS and OS was observed. Similarly, interim results from the BMT-CTN (Blood and Marrow Transplant myeloablative conditioning regimen in the allo-sct arm. There was a trend to lower late PFS and time to progression/ in the standard-risk group over tandem AuSCT due to increased TRM. Recommendation regarding AlloSCT: Currently, allosct is still considered investigational and should ideally be Young patients with poor prognostic disease who are deemed suitable for AlloSCT should be referred early to the transplant physician at the outset of 17

3.2.7 Patients not eligible for AuSCT: Conventional-dose chemotherapy using oral melphalan and prednisolone (MP) in this group consistently gives an chemotherapy regimens have been tried, and despite some showing a higher initial ORR, none have shown any (thalidomide, lenalidomide and bortezomib) to standard conventional MP has demonstrated impressive improvement in response and survival outcome compared to MP alone (please see table 6B). MPT (melphalan, prednisolone, thalidomide): was used as maintenance post initial induction treatment with MPT did not show superiority in OS in the MPT arm compared to MP. This was attributed to the fact that patients progressing on MP were successfully salvaged on thalidomide appeared to be more resistant to salvage and achieved a shorter PFS. In contrast, the two French both PFS and OS (p=0.0006) in the MPT arm compared to MP. The superior PFS (p<0.001) and OS (p<0.001) of myelosupression, VTE, and peripheral neuropathy. Higher doses of thalidomide, up to 400mg, as used in the Nordic trial resulted in greater toxicity, whereas lower doses (100-200mg) were better tolerated and did not compromise MPT is applied to patients aged 75 years or older[90]. MPV [melphalan, prednisolone, bortezomib (Velcade )]: Like MPT, combination bortezomib and MP (VMP) has been shown in prospective phase II trials to give an ORR randomized phase III VISTA trial showed convincing superiority of VMP compared to MP with regards to ORR was demonstrated in poor prognostic groups including those patients with high-risk cytogenetics, renal impairment and advanced age. induced peripheral neuropathy, diarrhoea, constipation, and thrombocytopenia[94, 95], and this scheduling is worthy of consideration in elderly patients who are less likely to tolerate therapy. As of October 2012, bortezomib will be MPR [melphalan, prednisolone, lenalidomide (Revlimid )] In the international phase III randomised trial (MM-015) comparing combination lenalidomide with MP (MPR) to MPR followed by lenalidomide maintenance (MPR-R) and MP, response was highest in the MPR-R arm [ORR 77% in the MP arm. However, the incidence of myelosuppression was low during single-agent lenalidomide maintenance 18

Regimens incorporating two novel agents: Combinations of two novel agents with chemotherapy (table 6B), such as the addition of thalidomide to VMP (VMPT) followed by maintenance VT (bortezomib and thalidomide) appear to induce impressive response with a lenalidomide, bortezomib, and dexamethasone is emerging as an effective combination for elderly patients [69, haematological toxicities were low. Whether these results hold up for the elderly subgroup, remains to be seen in the ongoing phase II trial. Other non-melphalan containing induction regimens: Non-melphalan containing induction regimens outlined in table 6A could also be used in patients not eligible for AuSCT. However, these have yet to show superior survival compared to MPT. In the phase III Eastern Cooperative Oncology more toxic compared to low-dose dexamethasone (40mg weekly, Rd), especially in patients aged over 65, with increased with ORR between 64-76%[46, 51, 99]. In fact, compared to conventional MP, one study showed that OS was shorter in the thal-dex group (41.5 vs. 49.4 months, p=0.02), despite a better response rate initially due to treatment related complications, especially in patients aged over 75 years [100]. Overall, the upfront incorporation of novel agents to conventional therapy, have achieved impressive rate and depth of OS. Alkylating agents remain an important treatment component for MM, and their incorporation with novel agents appear trials[101, 102], and could be used in place of melphalan when the latter is not preferred. Recommendation for patients not eligible for AuSCT: (MPV) can be considered as standard upfront treatment for patients who are ineligible for AuSCT October 2012, lenalidomide is not reimbursed on the Australian PBS for the upfront treatment of 19

could be used in place of melphalan when the latter is not preferred (Grade A recommendation, 3.2.8 Patients with high risk MM. FISH) tend to do poorly with median OS of approximately 2 years, even with tandem AuSCT[7-9]. More recently, same may apply for lenalidomide[107]. The role of AlloSCT in patients with high-risk MM remains uncertain but is an area of active investigation. Recommendation for patients with high risk MM: The optimal management for patients with high-risk multiple myeloma discussions with both the transplant and treating haematologist early in the disease course (Grade C recommendation) 20

3.3 CONSOLIDATION / MAINTENANCE THERAPY. Consolidation refers to a short treatment-course post induction-therapy that aims to further reduce tumour bulk and depth of response to initial treatment, whereas maintenance refers to a prolonged course of therapy that aims to maintain maximal response and delaying progression. Consolidation or maintenance therapy with novel-agents after induction treatment or AuSCT aims to improve PFS, if not OS, but must be weighed up against the potential treatment-related toxicities in a group that would otherwise therapy, as seen in some studies in which thalidomide maintenance was used post MPT induction, may poten- In the setting of post AuSCT, thalidomide maintenance was shown to improve PFS with a trend towards improve- of the 6 studies [44, 109-112] of thalidomide maintenance <65 years) who responded to previous tandem transplant were randomized to one of three arms; no maintenance, maintenance with the bisphosphonate pamidronate (P), or maintenance with both pamidronate plus thalidomide (PT). PT resulted in a superior 4-year OS compared to persistent superiority in the thalidomide arm with respect - were not in CR/VGPR after AuSCT, and were attributed to a further improvement in depth of response, with an increased in CR/VGPR rates post AuSCT [109]. Achieve- - the MM6 study from the Australian Leukaemia Lymphoma Group (ALLG)[44] showed an improved PFS and OS in patients in the thalidomide maintenance arm. Importantly, improvement in OS was also seen in patients who achieved CR. In the total-therapy-2 (TT2) study[111], patients who were randomised to the thalidomide arm (which was given during all phases of treatment) were initially shown to reap possessing metaphase cytogenetic abnormalities. Of note, both the TT2 study and ALLG[44] trials used thalidomide in combination with other anti-myeloma agents (dexamethasone with interferon, and prednisolone, respectively), compared to single-agent thalidomide used in the other studies, including the British Myeloma Research Council (MRC) Myeloma IX study[115], that did not demonstrate post AuSCT, or post induction therapy in the non-transplant setting. A further important distinction between the ALLG and IFM trials from the MRC Myeloma IX is that patients from the former 2 trials had access to effective salvage therapy including lenalidomide and bortezomib upon progression on maintenance, which would have impacted on OS. Indeed, the MRC Myeloma IX study showed that thalidomide maintenance did in fact improve OS for the subset of patients who were salvaged with novel agents other than thalidomide. However, thalidomide was found to have a negative impact on OS in patients with adverse del17p)[115]. The failure of thalidomide to overcome the adverse impact of high-risk cytogenetics has also been reported by others [116]. The lowest effective dose of thalidomide should be used in maintenance to minimise toxicity, and indeed, the studies that used 50-100mg have demonstrated similar outcome those that used higher doses. The optimal duration of thalidomide maintenance beyond 12 months, also bearing in mind that thalidomideinduced peripheral neuropathy is related to both cumulative dose and treatment duration. In patients not proceeding towards ASCT, the impact of thalidomide maintenance post induction is unclear. The results from the MRC Myeloma IX trial, as outlined above, included that for elderly patients who received thalidomide maintenance post induction with either MP or CTD. In the setting of MPT induction, thalidomide maintenance appears to result in a shorter post relapse induce drug-resistance, that would potentially compromise duration of response and survival post relapse. Compared to thalidomide, lenalidomide is better tolerated and is emerging as an attractive drug for maintenance therapy. Two phase-iii studies have assessed the role of lenalidomide maintenance post AuSCT. In the IFM-2005-02 (Intergroupe Francophone du Myélome) study, 614 patients post single or double AuSCT were given 2 cycles of lenalidomide consolidation prior to being randomized to either lenalidomide maintenance or placebo[117]. Consolidation improved CR rate from 14% to - 0.5, p<0.0000001) but OS was similar between the two groups. In contrast, the CABG100104 (Cancer and Leukemia Group B) study that randomised 460 patients post AuSCT to either lenalidomide maintenance or placebo, - 21

nalidomide was well tolerated, both studies demonstrated, ary primary malignancies including myelodysplasia/acute myeloid leukemia, solid tumours and lymphoproliferative the non-transplant setting, lenalidomide maintenance post Bortezomib, like thalidomide and lenalidomide, has the ment, and improve PFS when used as maintenance either post AuSCT or post induction therapy. However, many schedule, and route of administration. In the non-transplant setting, 2 phase III studies have assessed bortezomib in maintenance. The Spanish PETHEMA study ran- with VMP or VTP (botezomib, thalidomide, prednisone) (bortezomib; prednisone 50mg po alternate days) mainte- increased from 24% after induction to an impressive 46% Recommendation for maintenance therapy: respectively, certainly compares favourably to that seen with VMP induction without maintenance[92]. In the Ital- randomised to either VMP or VMPT (VMP+ thalidomide) Thalidomide 50mg po daily) maintenance for 2 years. CR vs. 24% (VMP), p<0.001) to a level that is unprecedented was similar. The effect of maintenance therapy is hard to delineate in this study due to the different induction regimen used between the two arms. Importantly, combination bortezomib and thalidomide, at attenuated dose in both the GEMEMA and PETHEMA studies, did not increase peripheral neuropathy. In the transplant setting, the HONVON-65/GMMG-HD4 study assessed bortezomib daily) maintenance post AuSCT in patients who underwent induction with either PAD (bortezomib, doxorubicin, dexamethasone) or VAD (vincristine, doxorubicin, dexa- perior in the PAD/AuSCT/bortezomib arm compared to HR 0.74, p<0.04, respectively). Again, due to the different maintenance here, except to say that it can be tolerated for up to 2 years. is recommended in patients post upfront treatment with HDT and AuSCT (Grade B lenalidomide maintenance is yet to be routinely recommended in Australia, pending longer follow agents post induction treatment is still unclear, pending longer-term follow up from ongoing 22

3.4 TREATMENT OF RELAPSED : Despite improved therapies, MM remains an incurable disease approximately one third of patients not respond- relapse occurring in virtually all patients who obtain an initial response. If the rate of disease progression is slow and there are no clinical indications to recommence treatment patients can continue to be monitored for a while. The same criteria as used for initiating front line treatment can be used to decide the timing of salvage therapy. Currently, there is no one standard treatment for patients with relapsed myeloma. Management should be individualised taking into account of previous therapy, duration of response and physical status. The main treatment options for relapsed/resistant disease are novel agents (thalidomide, bortezomib, lenalidomide), alkylating agents, anthracyclines, and corticosteroids administered alone or in various combinations, with selected patients undergoing HDT with AuSCT. The various agents can be used in different combinations and table 9). Thalidomide monotherapy can induce a RR in relapsed with median EFS of 6-12 months and median OS of 14 months.[121, 122] Thalidomide and dexamethasone is associated with a superior RR of approximately 50-55% in an alkylating agent (eg.cyclophosphamide or melphalan) Lenalidomide monotherapy induces an ORR of 22-25% in relapsed/refractory MM. Len-dex combination increases the RR to approximately 60%. Two pivotal phase III randomised, double-blind, placebo controlled trials conducted in parallel (US MM-009 and European MM- shows superiority in the len-dex arm. RR and CR rates MM-010 trial, respectively. Importantly, the results of the toxicities and improved survival outcome with the use of lower dose dexamethasone (40mg/weekly), especially in patients aged 65 years, however, this was in the front line setting. Bortezomib monotherapy induces an ORR of approxi- - - in patients not responding to single agent bortezomib in the SUMMIT and CREST trials. Due to the heterogeneity and effectiveness of salvage OS outcome between different treatment regimens. How- to produce superior outcome compared to their use as choice of which agent to use at relapse not only depends on availability, but also on individual preference (oral vs. intravenous route of administration), and importantly, co-morbidities. Drug selection may indeed depend on pre-existing morbidities. In patients with pre-existing neuropathy, exacerbation may occur with bortezomib or thalidomide. For patients with a previous history of VTE, or who are at high-risk of VTE events, thalidomide and lenalidomide, although not absolutely contraindicated, should be avoided if other effective induction options are available. VTE risks are highest when these immunomodulatory drugs are used with high-dose dexamethasone or anthracycline chemotherapy. Prophylactic or therapeutic-dose anticoagulation should therefore be instituted as appropriate. Lenalidomide cleared by the kidneys, and gener- or bortezomib are usually preferred in such patients[92]. In patients with relapsed disease that is rapidly progressive, intensive regimens combining novel agents with chemotherapy can be considered if the patient has good performance status and organ function. In contrast, patients with slow disease relapse may do well with singleagent novel therapy with or without dexamethasone, or indeed ongoing observation in the absence of end-organ damage, especially if they cannot tolerate more intensive treatment. HDT and AuSCT can be considered in patients who have had a durable response to this treatment modality in the 23

past. Similarly, if relapse occurs 6 months following cessation of the last treatment regimen, the same regimen can again be considered, however, an inferior duration all novel agents and different treatment combinations have been exhausted, conventional doses of cyclophos- - viable options, as is palliation in patients who cannot tolerate any further therapy. Recommendation for the treatment of relapsed multiple myeloma: Management should be individualised taking into account of prior therapy, duration of response to prior therapy, tempo of disease progression, and current physical response is to be expected conventional moderate doses of cyclophosphamide, non-myeloablative doses of melphalan, or low-modest doses of corticosteroids remain viable options, as is 24

3.5 LENALIDOMIDE-INDUCED MALIGNANCIES: IS THIS A CONCERN? Recently, there has been concern regarding possible increased risk of secondary malignancies in the setting randomized phase III trials, that otherwise demonstrated In the previously discussed IFM-2005-02 study that compared lenalidomide maintenance to placebo therapy post HDT-ASCT, 26 patients developed second primary malignancies (SPM) (including acute leukaemia, myelodysplasia, Hodgkin s lymphoma, and a range on solid tumours), in the lenalidomide-arm versus 11 in the placebo arm. This was in the context of a clear improvement in PFS with lenalidomide maintenance on multivariate analysis (p<0.0001); median PFS was 41 months from randomization with lenalidomide maintenance Similarly, the CALGB study of lenalidomide maintenance post AuSCT showed that despite the higher cumulative incidence of SPMs in the lenalidomide maintenance arm and death (p=0.02) were higher among patient in the MP arm. rate (IR) of malignancies in patients treated with lenalidomide does indeed exceed that seen in age-matched normal population, and if so, is this risk related to duration of lenalidomide treatment (as MM itself is associated with increased risk of haematologic SPM), and ultimately, ment for MM? sponsored studies of lenalidomde ± prednisolone, an melanoma skin cancers) per 100 patient-years was seen, a rate which is similar to that seen in aged-matched normal - cance increase of IR of malignancies over time. Similarly, in a pooled analysis of 2 large phase III trials of len-dex versus dex alone in patients with relapsed/refractory MM (MM009 and MM010 trial), the overall IR of SPMs placebo-dex arm, however, IR of invasive SPM were 1.71 and 0.91, respectively. The author commented that the higher IR of SPM in patients receiving lenalidomide was mainly due to increased non-invasive skin cancers. According to the SEER (Surveillance, Epidemiology and End Results) database from the US National Cancer Institute, the incidence rate of invasive cancers for patients aged 65 or above is in the order of 2.1 per 100 patient Given these data, it is currently premature to make lidomide-induced SPMs, and this indeed needs to be observed closely with time. Given the clear PFS and OS any change to the current practice of lenalidomide s use in the treatment of MM. This stance is the same as that recently taken by the European regulatory body, the EMEA. Recommendation regarding secondary primary malignancies: The risk of secondary primary especially in patients with a past history of SPM, prior to initiating lenalidomide- the current available data, the survival outweighs the risk for SPM, and no change is recommended to the current practice of lenalidomide-use for the Patients should be evaluated for preexisting SPM prior to commencement of lenalidomide and be monitored for SPM during lenalidomide treatment by routine 25

4 CONCLUDING REMARKS. The treatment for multiple myeloma has changed substantially over the last decade and what is considered as standard therapy will continue to change as trial data matures with respect to novel-therapeutic agents. At present, MM remains an incurable disease. However, treatment options continue to increase, rendering this a treatable chronic condition. Foundation of Australia are based on current published data and clinical experience. We believe a National consensus for a treatment algorithm of MM will not only improve patterns of care, but will establish a foundation for future clinical studies. The above guideline is based on up-to-date information as of December 2012. Some aspect of this guideline may change in the future depending on emerging data from clinical studies. This guideline is due for review in December 2013. The authors of this guideline declare no potential conflict of interest. This guideline was unsolicited and was established by members of the MSAG without the assistance of or influence by any other organisational body or pharmaceutical company. 26

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McCarthy, P., et al., Phase III Intergroup Study of Lenalidomide Versus Placebo Maintenance Therapy Following Single Autologous Hematopoietic Stem Cell Transplantation (AHSCT) for Multiple Myeloma: CALGB 100104. Blood, 142. Dimopoulos, M., et al., Lenalidomide and dexamethasone (LEN plus DEX) treatment in relapsed/refractory multiple myeloma (RRMM) patients (pts) and risk of second primary malignancies (SPM): Analysis of MM-009/010. J Clin Oncol, 144. Morgan, G., et al., Long-term safety of lenalidomide (LEN) in relapsed/refractory multiple myeloma (RRMM) patients (Pts): Analysis of pooled data. J Clin 29

Table 6A: Induction treatment regimens for upfront treatment of myeloma prior to autologous stem cell transplantation. Induction regimen Efficacy Main Toxicities Thalidomide - based Chemotherapy - based CD [1] CID [2]: Cycles repeated every 21 days for 2 to 3 cycles prior to AuSCT PCAB [3] Doxorubicin 30mg/m2 IV D1, Carmustine 30mg/m2 IV D1, Cyclophosphamide 600mg/m2 IV D1, Prednisolone 60mg/m2 po D1-5, TD [4-6]: CTD [7,8]: Thalidomide 200mg po daily Cycles repeat every 4 weeks for 3-4 cycles prior to AuSCT Cycles repeated every 28 days for 3-4 cycles prior prior to AuSCT Thalidomide 200mg po daily Cycles repeated every 28 days for 3-4 cycles prior to Post transplant ORR 81% (similar ORR 48% (41% PR, 7% CR) Pre-transplant ORR varies from CR+VGPR higher post AuSCT in Grade 3-4 haematological toxicities ciation with greater toxicities makes this regimen a less ideal choice of induction therapy) Grade 3-4 adverse events similar in

Table 6A: Induction treatment regimens for upfront treatment of myeloma prior to autologous stem cell transplantation. Induction regimen Efficacy Main Toxicities Bortezomib - based ** (Vel/Dex) [10, 11]: PAD [12-14] CyBorD/ VCD [15-17] Cycles repeat every 21 days for 3-4 cycles prior to AuSCT IV D1,2,3,4 (daily bolus or continuous infusion), Cycles repeated every 3 weeks for 3-4 cycles prior to AuSCT Cyclophosphamide 300mg/m2 po D1,8,15,22 Dex 20mg po on day of and day after velcade, Cycles repeated every 21 days x for 3-4 cycles prior to AuSCT This translated to trend for better Assessment following ± AuSCT: ORR Prior to AuSCT: neuropathy is in the order of 30% [10] - Grade 3-4 neutropenia 6% Grade 3-4 thrombocytopenia 7% All grade peripheral neuropathy - Lenalidomide - based Rd [18] 20] Cycles repeated every 28 days for 3-4 cycles prior to Cycles repeated every 28 days for 3-4 cycles prior to AuSCT, Newly diagnosed patients age 18 years, After 4 cycles, CR/VGPR 42%, PR 70% 2 year OS 87% (superior to Lenalidomide+ high dose dex (RD) of 40mg ORR 83%, PR 43%, VGPR 38%, CR 2% Grade 3 or 4 VTE 11% (compared to 25% with RD) Grade 3 or 4 infection 8% (compared to 16% with RD) 5% with RD) Haematological toxicities were the cyclophosphamide 300mg/m2 in patient cohort 1 compared to Combination on novel agents ** VTD[21]: Thalidomide 200mg po d1-21 Cycles repeated every 21 days for 3-4 cycles prior to AuSCT, Pretransplant CR/nCR 31% compared to 11% in Thal/dex arm Post AuSCT CR was 57% compared ~8% VZV reactivation 2% with acyclovir

Table 6A: Induction treatment regimens for upfront treatment of myeloma prior to autologous stem cell transplantation. Induction regimen Efficacy Main Toxicities Combination on novel agents ** (VTDC) [22] Thalidomide 100mg po daily Cycles repeated every 21 days for 3 cycles prior to AuSCT, or additional 4 cycles for patient who became CR+ ncr = 44% Grade 3-4 peripheral neuropathy high-dose melphalan and autologous stem cell transplantation in patients with newly diagnosed mul tiple myeloma: results of a randomized comparison with vincristine, doxorubicin, and dexamethasone. Cancer, 2. Spencer, A., et al., Induction with oral chemotherapy (CID) followed by early autologous stem cell transplanta alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology 6. Cavo, M., et al., Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood, 2005. 7. Wu, P., et al., The combination of cyclophosphomide, thalidomide and dexamethasone is an effective alternative to cyclophosphamide - vincristine - doxorubicin - methylprednisolone as induction chemotherapy prior to autologous transplantation for multiple myeloma: a case-matched analysis. Leuk Lymphoma, 2006. methasone is a well tolerated and effective regimen in patients with relapsed and refractory multiple myeloma. Br dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with 10. Jagannath, S., et al., Bortezomib therapy alone and in combination with dexamethasone for previously untreated 11. Harousseau, J.L., et al., Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexa methasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed previously untreated patients with multiple myeloma. Br J Haematol, 2005. 129(6): p. 755-62. 14. Sonneveld, P., et al., Bortezomib Induction and Maintenance Treatment in Patients With Newly Diagnosed Multiple Myeloma: Results of the Randomized Phase III HOVON-65/ GMMG-HD4 Trial. J Clin Oncol, 2012. 15. Reeder, C.B., et al., Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed 16. Reeder, C.B., et al., Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple 17. Einsele, H., et al., Velcade, Intravenous Cyclophosphamide and Dexamethasone (VCD) Induction for Previously methasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol, 2009. 19. Morgan, G.J., et al., Lenalidomide (Revlimid), in combination with cyclophosphamide and dexamethasone 20. Kumar, S.K., et al., Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple 21. Cavo, M., et al., Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexametha sone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in 22. Ludwig, H., et al., Bortezomib, Thalidomide, and Dexametahsone (VTD) Versus VTD Plus Cyclophosphamide as Induction Therapy in Previously Untreated Multiple Myeloma Patients Eligible for HDT-ASCT:

Table 6B: Upfront treatment regimen for patients not eligible for AuSCT 1. MPT GIMEMA Palumbo et al.[1] IFM 99-06 Facon et al.[2] Melphalan 4mg/m 2 po D1-7 Prednisone 40mg/m 2 po D1-7 Thalidomide 100mg po daily. Cycles repeated every 4 weeks x 6, thalidomide continued until relapse. ORR~85%, CR 15.6% Med TTP 24.7m. Melphalan 0.25mg/kg (consider 0.2mg/kg for patients aged 75 years) po D1-4 Prednisone 2mg/kg po D1-4 Thalidomide 200mg (consider 50-100mg for patients aged 75 years) po daily ORR 76%, CR 13% Med OS 51m. Cycles repeated every 6 weeks x 12, then stop. Melphalan 9mg/m 2 po D1-4 Prednisone 60mg/m 2 po D1-4 Bortezomib 1.3mg IV D 1,4,8,11,22,25,29,32 during Cycles 1-4 1,8,22,29 during cycles 5-9 MPV VISTA San Miguel et al.[3] Harousseau et al. [4] ORR 70%, CR 35% Med duration response 19.9m. Med OS not reached at med follow up of 16m. Cycles repeated every 6 weeks x 9, then stop. VMP vs. Mateos et al[5]. Melphalan 9mg/m 2 po D1-4 Prednisone 60mg/m 2 po D1-4 Bortezomib 1.3mg/m 2 IV D 1,4,8,11,22,25,29,32 during Cycles 1 1,8,22,29 during cycles 2-6 vs. VMP: Post induction: ORR 80%, CR 20% VTP Thalidomide 100mg po daily (50mg day 1-15) Prednisone 60mg/m 2 po D1-4 Bortezomib 1.3mg/m 2 IV D 1,4,8,11,22,25,29,32 during Cycles 1 1,8,22,29 during cycles 2-6 After 4 cycles of induction, patients were randomized to receive VT (bortezomib thalidomide) or VP (bortezomib prednisolone) as maintenance until disease progression. VTP: Post induction: ORR 81%, CR 28% No difference in efficacy between VMP and VTP; VMP better tolerated. CR rates further improved with maintenance VT (CR 44%) or VP (39%).

Table 6B: Upfront treatment regimen for patients not eligible for AuSCT 1. MPR-(R) MM-015 Palumbo et al[6] Melphalan 0.18mg/kg po D1-4 Prednisone 2mg/kg po D1-4 Lenalidomide 10mg po daily Cycles repeated every 4 weeks x 9 ± lenalidomide continued until relapse. VMPT-VT Palumbo et al.[7] Thalidomide 50mg po d Melphalan 9mg/m 2 po D1-4 Prednisone 60mg/m 2 po D1-4 Bortezomib 1.3mg/ m 2 IV D 1,4,8,11,22,25,29,32 during Cycles 1-4 Lenalidomidebortezomibdexamethasone 1,8,22,29 during cycles 5-9 Cycles repeated every 6 weeks x 9, followed by maintenance with: Bortezomib 1.3mg/m 2 IV every 14 days Thalidomide 50mg po daily Continued for 2 years or until progression/relapse whichever is earlier. Richardson et al.[8] Lenalidomide 25mg po D1-4 Bortezomib 1.3mg/m 2 IV D1,4,8,11 Dexamethasone 20mg (10mg for cycles 5-8) po D1,2,4,5,8,9,11,12. Cycles repeated every 3 weeks x 8 followed by ASCT (after min 4 cycles) or further maintenance with: Lenalidomide 25mg po D1-4 Bortezomib 1.3mg/m 2 IV D1, and 8. Dexamethasone 10mg po D1,2,8,9. MPR-R: ORR 77%, CR 16% Med TTP 24.7m 2 yr OS 86.2% ORR 89%, CR 38% Responses were superior compared to VMP at the cost of greater toxicity. Grade 3 or 4 neutropenia 38% and cardiologic events 10%. Phase II cohort (n=35): ORR 100%, CR 37%. 1 At the time of publication: *Thalidomide is available for upfront treatment through the Pharmaceutical Benefit Scheme Highly Specialised Drug Program. Please visit http://www.health.vic.gov.au/hsdp *Bortezomib, as monotherapy or in combination with a corticosteroid and/or cyclophosphamide, is available available through the Pharmaceutical Benefit Scheme for patients with multiple myeloma who has progressive disease after at least 1 prior therapy, and who has undergone or is ineligible for a primary stem cell transplant. The patient must have experienced treatment failure after a trial of at least four (4) weeks of thalidomide at a dose of at least 100 mg daily or have failed to achieve at least a minimal response after eight (8) or more weeks of thalidomide-based therapy for progressive disease Applications are made through Medicare Australia, please visit http://www.medicareaustralia.gov.au *Lenalidomide as monotherapy or in combination with corticosteroid is available through the Pharmaceutical Benefit Scheme Highly Specialised Drug Program (http://www. health.vic.gov.au/hsdp) for patients with multiple myeloma who has progressive disease after at least 1 prior therapy, and who has undergone or is ineligible for a primary stem cell transplant. The patient must have experienced treatment failure after a trial of at least four (4) weeks of thalidomide at a dose of at least 100 mg daily or have failed to achieve at least a minimal response after eight (8) or more weeks of thalidomide-based therapy for progressive disease. Applications are made through Medicare Australia, please visit http:// www.medicareaustralia.gov.au

Table 6B: Upfront treatment regimen for patients not eligible for AuSCT 1. 2. Facon, T., et al., Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet, 2007. 5. Mateos, M.V., et al., Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients Duration Regimens [abstract]. Blood, 2010. 116: p. 662a. 7. Palumbo, A., et al., Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin

Table 7: Phase III studies comparing MP (melphalan and prednisolone) to MPT (MP + thalidomide) in the upfront treatment for patients with multiple myeloma. Study Regimen N CR+PR TTP OS Statistical for OS MP 168 68 11 31 MP 6 cycles) 60 38 14 28 M=melphalan; P=prednisolone; T=thalidomide, PD=progressive disease, CR=complete response; PR=partial 1. Palumbo, A., et al., Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a 2. Facon, T., et al., Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autolo gous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet, 2007. 4. Waage, A., et al., Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood, 2010. 116(9): p. 1405-12. 6. Beksac, M., et al., Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for trans 36

Table 8: Studies investigating the role of thalidomide maintenance. Study n AuSCT Thalidomide maintenance Med follow up. Spencer et al.[1] ALLG MM6 269 Single Thal 200mg/d + prednisolone 50mg alternate days post AuSCT for 12 months. Attal et al.[2] 597 Double - until PD Survival outcome. 3 years 3 year PFS p<0.001. 3 year OS p=0.004 40m 3 year EFS - 668 Double - - Lokhorst et al.[4] 556 Single Initial randomisation: TAD AuSCT Thal maintenance vs. VAD AuSCT IFN maintenance. Feyler et al.[5] Morgan et al.[6] 818 Single after 4 weeks if good tolerance. 42m 52m 66m 4 year OS 5 year EFS p=0.01. 5 year OS p=0.90 EFS p<0.001 OS p=0.77 Improved PFS with Thal maintenance (HR no improvement in OS Stewart et al.[7] 332 Single Thal 200mg/d + prednisolone 50mg alternate days. Adverse effect on OS for patients with poor-risk cytogenetics on FISH. 4 years PFS OS 1. Spencer, A., et al., Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single 5. Feyler, S., et al., Thalidomide maintenance following high-dose therapy in multiple myeloma: a UK myeloma forum phase 2 study. Br J Haematol, 2007. 7. Stewart, A.K., et al., A Randomized Phase III Trial of Thalidomide and Prednisolone as Maintenance Therapy Following Autologous Stem Cell Trans 37

Table 9: Salvage treatment regimens for relapsed/refractory MM TD [1] Thalidomide 200mg po. daily Dexamethasone 40mg po. D1-4 REGIMEN EFFICACY COMMENTS Cycles repeated every 4 weeks until disease progression. Phase II trial. ORR ~50-60% CR ~6% DVT developed in 8% of patients (without prophylaxis) Gde 3 Sensory neuropathy up to 30%. CTD [2, 3] Thalidomide 100mg po. Daily Cyclophosphamide 500mg po. weekly Dexamethasone 40mg po. D1-4, 12-15 or 40mg po. weekly. Phase II trial. ORR 79% CR 17% Minimal infective complications. Moderate emesis, fatigue, myelosuppression. THALIDOMIDE - BASED ThaDD[4] Cycles repeated every 4 weeks until best response. Thal 100mg po. daily Dexamethasone 40mg po. D1-4, 9-12, Peg liposomal doxorubicin 40mg/m 2 IV. D1 Cycles repeated every 28 days for up to 6 cycles, followed by thalidomide and dexamethasone (40mg D1-4 every 28 days) maintenance until disease progression. DTPACE [5] Dexamethasone 40mg po. D1-4 Thalidomide 400mg po. daily Cisplatin 10mg/m 2 daily IV. continuous infusion D1-4. Cyclophosphamide 400mg/m 2 daily IV. continuous infusion D1-4. Etoposide 40mg/m 2 daily IV. continuous infusion D1-4. Doxorubicin 10mg/m 2 daily IV. continuous infusion D1-4. Cycles repeated every 4 weeks for 3-6 cycles DCEP-T[6] Dexamethasone 40mg po. D1-4 Thalidomide 400mg po. daily Cisplatin 15mg/m2 daily IV. continuous infusion D1-4. Cyclophosphamide 400mg/m2 daily IV. continuous infusion D1-4. Etoposide 40mg/m2 daily IV. continuous infusion D1-4. Cycles repeated every 4 weeks for 3-6 cycles. Phase II trial. N=47 ORR 92%, CR/nCR 30% Phase II trial. ORR post 2 cycles 48%. CR/nCR 16% Phase II trial. ORR after 3 cycles 36% compared to 18% with DCEP alone. High rates of hematologic toxicity DVT developed in 16% of patients. DVT developed in 2.5% of patients.

Table 9: Salvage treatment regimens for relapsed/refractory MM REGIMEN EFFICACY COMMENTS Len-dex [7-9] Lenalidomide 25mg po. D1-21q28 Dexamethasone 40mg po. D1-4,9-12,17-20 (C1-4), 40mg po. D1-4 (C5 onwards) Consider using low dose dexamethasone (40mg per week) in view of the ECOG trial showing higher toxicity with standard dose dex [9] Phase III trial (MM009/010) RR 60% CR~14-16% Gde 3 neutropenia 30-40% Gde 3 thrombocytopenia 11% DVT 11-15% (no thrombo-prophylaxis) Gde 3 fatigue 6% LENALIDOMIDE BASED RCD [10] Cycles repeated every 28 days until disease progression. Lenalidomide 25mg po. D1-21. Cyclophosphamide 500mg po. weekly Dexamethasone 40mg po. D1-4 and D12-15. Cycles repeated every 28 days for a maximum of 9 cycles. Ongoing maintenance with single agent lenalidomide may be considered. Consider using low dose dex (40mg per week) in view of the ECOG trial showing higher toxicity with standard dose dex [9] Phase II trial. ORR 65%. CR 5% (one patient in 20) Median time to best response is prompt (31 days). After 3 cycles, 48% of patients required dose reduction or withdrawal of cyclophosphamide, and 24% of patients required dose reduction of lenalidomide. G-CSF required in 57% of patients to maintain neutrophil count 1. RAD[11] Lenalidomide 25mg po. D1-21 Adriamycin 9mg/m 2 IV. D1-4 Dexamethasone 40mg po. D1-4 and D17-20 Cycles repeated every 28 days for 6 cycles. Phase I/II ORR 73% CR+VGPR 74% Grade 3 and 4 neutropenia 48% Grade 3 and 4 thrombocytopenia 38. Severe infections 10.5%. Thromboembolic events 4.5%.

Table 9: Salvage treatment regimens for relapsed/refractory MM Bortezomib and Dexametahsone [12] REGIMEN EFFICACY COMMENTS Bortezomib1.3mg/m 2 IV. D1,4,8,11 ever y 21 day for cycles 1-8 D1,8,15,22 every 35 day for cycles 9-12 Dex 20mg po. on day of and day after bortezomib. Phase III trial. (SUMMIT/APEX) RR ~38% CR ~6% Gde 3 fatigue 5% Gde 3 peripheral neuropathy 8% Gde 3 thrombocytopenia 30% Gde 3 anaemia 10% Gde 3 neutropenia 14% VELCADE -BASED CyBorD/ VCD [13, 14] PAD [15, 16] [17] Cyclophosphamide 300mg/m 2 po. weekly. Bortezomib 1.3mg/m 2 IV. D1,4,8,11 every 21 days, for cycles 1-8 D1,8,15,22 every 35 days, for cycles 9-14 Dex 20mg on the day of and day after bortezomib Alternate dosing regimen of CyBorD as per table 6 can also be used. Bortezomib 1.3mg/m 2 IV. D1,4,8,11, Doxorubicin 20mg/m 2 IV.D1 and 4 Dexamethasone 40mg po.d1,2,4,5,8,9,11,12. Cycles repeated every 28 days x 6. Phase II trial RR (CR+PR) 82%, CR 16% Phase II trial. ORR 67%, CR/VGPR 25% (no difference in efficacy between doxorubicin vs liposomal doxorubicin. Gde 3 AE = leukopenia, thrombocytopenia infection, herpes zoster Gde 3 thrombocytopenia 23% Gde neutropenia 20%. Gde 3 anaemia 11% Gde 3 peripheral neuropathy 10% Bortezomib + Melphalan [18] Bortezomib 1mg/m 2 IV. D1,4,8,11 Melphalan 0.1mg/kg po. D1-4 Cycles repeated every 28 days for a maximum of 9 cycles. Phase I/II trial. N=35 ORR (PR+CR)= 47% CR/nCR=14% Main gde 3 toxicities = myelosuppression. BMPT[19] Bortezomib 1.3mg/m2 IV. D1,4,15,22 Melphalan 6mg/m2 po. D1-5 Prednisolone 60mg/m2 po D1-5 Thalidomide 50mg po. daily Cycles repeated every 35 days for 6 cycles. Phase I/II trial. n=30 ORR 67%, VGPR 43% Gde 3 AE = infections, fatigue, peripheral neuropathy.

Table 9: Salvage treatment regimens for relapsed/refractory MM ALKYLATOR-BASED Non-myeloablative melphalan [20] ] High dose cyclophosphamide [21] REGIMEN EFFICACY COMMENTS Melphalan 25mg/m 2 IV _ Myelosupression. Cyclophosphamide 600mg/m 2 IV daily x 4 (total dose 2400mg/ m 2 ) Or Single dose of 2 to 4g/m 2 IV could also be used. Phase II trial, N=56, ORR 43%, PFS 3m, OS 9m. Myelosuppression. Haemorrhagic cystitis. Induction regimens used in upfront treatment (Table 6A and 6B) could also be used in the relapsed setting. *Thalidomide is available for upfront treatment through the Pharmaceutical Benefit Scheme Highly Specialised Drug Program. Please visit http://www.health.vic.gov.au/hsdp *Bortezomib, as monotherapy or in combination with a corticosteroid and/or cyclophosphamide, is available through the Pharmaceutical Benefit Scheme for patients with multiple myeloma who has progressive disease after at least 1 prior therapy, and who has undergone or is ineligible for a primary stem cell transplant. The patient must have experienced treatment failure after a trial of at least four (4) weeks of thalidomide at a dose of at least 100 mg daily or have failed to achieve at least a minimal response after eight (8) or more weeks of thalidomide-based therapy for progressive disease Applications are made through Medicare Australia, please visit http://www.medicareaustralia.gov.au *Lenalidomide as monotherapy or in combination with corticosteroid is available through the Pharmaceutical Benefit Scheme Highly Specialised Drug Program (http://www.health.vic. gov.au/hsdp) for patients with multiple myeloma who has progressive disease after at least 1 prior therapy, and who has undergone or is ineligible for a primary stem cell transplant. The patient must have experienced treatment failure after a trial of at least four (4) weeks of thalidomide at a dose of at least 100 mg daily or have failed to achieve at least a minimal response after eight (8) or more weeks of thalidomide-based therapy for progressive disease. Applications are made through Medicare Australia, please visit http://www.medicareaustralia.gov.au 1. Anagnostopoulos, A., et al., Thalidomide and dexamethasone for resistant multiple 2. Kyriakou, C., et al., Low-dose thalidomide in combination with oral weekly cyclophosphamide and pulsed dexamethasone is a well tolerated and effective regimen in patients with relapsed and refractory multiple myeloma. Br J Haematol, 2005. 129(6): ethasone is an effective alternative to cyclophosphamide - vincristine - doxorubicin - methylprednisolone as induction chemotherapy prior to autologous transplantation for multiple myeloma: a case-matched analysis. Leuk Lymphoma, 2006. 47(11): p. rubicin vs. thalidomide-dexamethasone: a case-matched study in advanced multiple 5. Lee, C.K., et al., DTPACE: an effective, novel combination chemotherapy with 6. Zangari, M., et al., Thrombogenic activity of doxorubicin in myeloma patients 7. Weber, D.M., et al., Lenalidomide plus dexamethasone for relapsed multiple my- - mide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol, 2009. 10. Morgan, G.J., et al., Lenalidomide (Revlimid), in combination with cyclophosphamide and dexamethasone (RCD), is an effective and tolerated regimen for myeloma 11. Knop, S., et al., Lenalidomide, adriamycin, and dexamethasone (RAD) in patients with relapsed and refractory multiple myeloma: a report from the German Myeloma Study Group DSMM (Deutsche Studiengruppe Multiples Myelom). Blood, 2009. 12. Richardson, P.G., et al., Bortezomib or high-dose dexamethasone for relapsed ethasone and continuous low-dose oral cyclophosphamide for relapsed multiple 14. Reeder, C.B., et al., Once- versus twice-weekly bortezomib induction therapy with 15. Morris, T.C., et al., PAD Given at Relapse is More Effectve than VAD Given as Induction Therapy -Results of a Phase II Study [abstract]. Blood, 2007. 110: p. 2724. 16. Palumbo, A., et al., Bortezomib, doxorubicin and dexamethasone in advanced ezomib, Doxorubicin, Dexamethasone (PAD) Induction Treatment Followed by High-Dose Melphalan (HDM): A Subgroup Analysis From the HONVON-65/ GMMG-HD4 Randomized Phase III trial for Newly Diagnosed Multiple Myeloma bination therapy for the treatment of patients with relapsed or refractory multiple 19. Palumbo, A., et al., Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma. Blood, 2007. 109(7): p. 2767-72. 20. Petrucci, M.T., et al., Intermediate-dose (25 mg/m2) intravenous melphalan for patients with multiple myeloma in relapse or refractory to standard treatment. Eur J 21. Lenhard, R.E., Jr., et al., High-dose cyclophosphamide. An effective treatment for