Background
Multiple myeloma (MM) is a malignancy of plasma cells and is the second most common hematological malignancy. The incidence rate in Europe is 4-7/100,000 per year. Approximately 5,700 cases are diagnosed in Germany each year [ 1 ]. As the disease progresses, morbidity and eventually mortality are caused by impaired immune system, skeletal destruction, anemia and renal failure. Despite major advances in therapy, multiple myeloma is still an incurable malignancy in the majority of patients.
Currently an intensified treatment concept including induction therapy, high dose melphalan (200 mg/m 2 ) and subsequent consolidation/maintenance therapy is considered the standard treatment for MM patients up to the age of 70 years [ 1 – 4 ]. Incorporation of new drugs in induction treatment for tumor reduction and in maintenance therapy has resulted in increased CR rates. Median progression-free survival (PFS) after HDT in current standard approaches reaches 3 to 4, overall survival 9 to 11 years. Ten to 20% of intensively treated patients will be in remission more than 10 years [ 5 ]. Some of these long-term CR patients will likely be cured. To increase survival, deeper remissions (i.e. CR) translating into longer PFS need to be achieved, and patient outcome needs to be interpreted on the background of current substratification by molecular (gene expression profiling [GEP] and/or interphase fluorescence in situ hybridization [iFISH]) and imaging means.
The combination of bortezomib, lenalidomide and dexamethasone (VRD regimen) is a well-established three drug combination incorporating two “new drugs” for induction therapy in previously untreated multiple myeloma.
VRD has shown to be highly active and well tolerated [ 6 – 11 ] and is widely used in the US as standard therapy prior to and following HDT. VRD will be given in the GMMG-HD6 trial as background treatment for all study patients for induction therapy prior to a standard intensified therapy and for subsequent consolidation treatment.
Maintenance therapy after HDT prolongs duration of the response [ 12 , 13 ]. The benefit of lenalidomide maintenance after HDT in terms of prolongation of PFS has been shown in several randomized trials [ 14 , 15 ], with one of those also observing a superior OS [ 15 ]. Within the GMMG-HD6 trial, all patients are intended to receive lenalidomide maintenance.
Elotuzumab (BMS-901608; formerly known as HuLuc63) is a humanized recombinant monoclonal IgG1 antibody product directed to human SLAMF7 antigen (also known as CS1, CD2- subset-1), a cell surface glycoprotein that is highly expressed on MM cells. The proposed mechanism of action of elotuzumab involves natural killer (NK) antibody dependent cell-mediated cytotoxicity (ADCC), since elotuzumab kills MM cell lines in vitro in the presence of peripheral blood mononuclear cells (PBMCs) or purified NK cells. Because of its potent antitumor activity, elotuzumab is being developed for the treatment of MM. Data from a phase III trial (ELOQUENT-2) comparing elotuzumab in combination with lenalidomide and dexamethasone versus lenalidomide/dexamethasone alone, demonstrated an PFS advantage of 19.4 vs 14.9 months in relapsed/refractory MM patients [ 16 , 17 ].
The combination of VRD plus elotuzumab is investigated by the Southwest Oncology Group in the US in a phase I/II trial for newly diagnosed high risk myeloma patients [ 18 ]. Another phase IIa study investigating the VRD plus elotuzumab combination in patients eligible for HDT and ASCT showed a low incidence of high grade toxicities, although there were two deaths in the study group [ 19 ]. Main research question of the GMMG-HD6 trial is to evaluate the effect of elotuzumab in induction /consolidation and maintenance therapy in previously untreated myeloma patients in a randomized setting. Given the previously described study results, an improvement of the therapeutic results by the addition of this humanized monoclonal antibody can be expected. Elotuzumab was the first antibody in myeloma with an FDA and EMA approval. To date, two phase III studies evaluate elotuzumab in first line and in 1 st -3 rd relapse in the non-transplant setting. Results of phase I, II and phase III trials evaluating the combination of elotuzumab and bortezomib or lenalidomide and dexamethasone show very good tolerability and high response rates in patients with relapsed/refractory myeloma [ 20 , 21 ]. While the results of use of elotuzumab in monotherapy were modest with stable disease as best response [ 22 ] the combination with lenalidomide and dexamethasone has given excellent results with > 80% partial response in relapsed patients and prolonged PFS [ 20 , 23 , 24 ]. These data strongly support the evaluation of the combination of lenalidomide/dexamethasone plus bortezomib and elotuzumab within the context of an intensified therapy in newly diagnosed patients.
Within the GMMG-HD6 trial the best of four treatment strategies with respect to the PFS shall be determined. The four treatment strategies differ in the use of elotuzumab in addition to the background treatment of VRD induction/consolidation therapy (VRD +/- elotuzumab) and lenalidomide maintenance treatment (lenalidomide +/- elotuzumab), respectively.
The GMMG-HD6 trial will be the first phase III trial investigating the role of elotuzumab in combination with VRD and/or lenalidomide maintenance within a high dose concept. Results will be interpreted on the background of state of the art molecular profiling and imaging.
Methods
Design
GMMG-HD6 has a study population of 564 newly diagnosed multiple myeloma (NDMM) patients. It is a prospective, multicenter, randomized, parallel group, open, phase III clinical trial. There will be no blinding in this trial due to differences in the patient management in the treatment arms (premedication previous to application of elotuzumab and additional intravenous infusions for elotuzumab).
Trial objectives
Primary objective
The primary objective of the study is the determination of the best of four treatment strategies regarding progression-free survival (PFS) - defined as time from randomization to progression or death from any cause whichever occurs first, censored at the end of the study.
The four treatment strategies are: (arm A1): VRD (Bortezomib (Velcade) / Lenalidomide (Revlimid) / Dexamethasone) induction, intensification, VRD consolidation and lenalidomide maintenance, (arm A2): VRD induction, intensification, VRD + elotuzumab consolidation and lenalidomide maintenance + elotuzumab, (arm B1): VRD + elotuzumab induction, intensification, VRD consolidation and lenalidomide maintenance, (arm B2): VRD + elotuzumab induction, intensification, VRD + elotuzumab consolidation and lenalidomide maintenance + elotuzumab.
Secondary objectives
The secondary objectives of this trial are to assess and to compare treatment arms regarding overall survival (OS) CR rates after induction therapy CR rates after consolidation treatment best response to treatment during the study MRD-negativity measured by flow (FACS) and next generation sequencing (NGS) time to progression (TTP), censored at end of trial duration of response (DOR), censored at end of trial toxicity during induction treatment, consolidation and maintenance treatment with respect to adverse events of CTCAE grade ≥ 3 quality of life assessment of patients at baseline, during induction treatment, consolidation and maintenance treatment. Assessment of quality of life is performed using patient self-report questionnaires of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC- QLQC30) including the multiple myeloma module (EORTC-QLQMY20).
Setting
GMMG-HD6 is an investigator initiated trial by the German-speaking Myeloma Multicenter Group (GMMG) with a multicenter design.
Estimated timeline
The duration of the trial for each patients is expected to be 36-39 months (induction and intensification treatment: 7-10 months, 3 months rest between intensification and start of consolidation, consolidation 2 months, maintenance phase 24 months) The overall duration of the trial is expected to be approximately 8 years including preparatory phase. Recruitment of patients has started in Q2 2015. The actual overall duration or recruitment may vary. Total trial duration: [96 months] Duration of the clinical phase: [74 months] Beginning of the preparatory phase: [Q1 2014] FPI (First Patient In): [Q4 2015] LPI (Last Patient In): [Q4 2017] LPO (Last Patient Out): [Q1 2021] DBL (Data Base Lock): [Q3 2021] Statistical analyses completed: [Q4 2021] Trial report completed: [Q1 2022]
Ethical aspects, safety, consent
This study protocol is compliant with the declaration of Helsinki, the International Conference on Harmonization of Good Clinical Practice (ICH-GCP) guidelines, German law, regulations and organizations. A Data Safety Monitoring Board (DSMB) was installed before the start of the trial. The ethics committees/institutional review boards of all study sites gave a written approval before the start of this study.
Patients have to give written informed consent before any procedures regarding the trial are performed.
In the patient case report forms AEs are recorded and an assessment by the Investigator will be performed regarding intensity (according to CTCAE v4.0), seriousness and relatedness to the medication that is provided in the study.
For serious AEs (SAEs) there is an extra form that has to be filled out by the Investigator. This form has to be sent to the study administration within 24 hours after detection of the SAE. If a Suspected Unexpected Serious Adverse Reaction (SUSAR) occurs it will be reported to all investigators, ethics committees and the federal authorities.
Selection of trial patients
Inclusion and exclusion criteria are listed in Table 1 . Table 1 Inclusion and exclusion criteria for the GMMG-HD6 trial Inclusion criteria Patients meeting all of the following criteria will be considered for admission to the trial: Confirmed diagnosis of untreated multiple myeloma requiring systemic therapy (diagnostic criteria (IMWG updated criteria (2014). For some patients systemic therapy may be required though these diagnostic criteria are not fulfilled. In this case the GMMG study office has to be consulted prior to inclusion. Measurable disease, defined as any quantifiable monoclonal protein value, defined by at least one of the following three measurements Serum M-protein ≥ 10 g/l (for IgA ≥ 5 g/l) Urine light-chain (M-protein) of ≥ 200 mg/24 h Serum FLC assay: involved FLC level ≥ 10 mg/dl provided sFLC ratio is abnormal Age 18–70 years inclusive WHO performance status 0–3 (WHO = 3 is allowed only if caused by MM and not by co-morbid conditions) Negative pregnancy test at inclusion (women of childbearing potential) For all men and women of childbearing potential: patients must be willing and capable to use adequate contraception during the complete therapy. Patients must agree on the requirements regarding the lenalidomide pregnancy prevention programme. All patients must agree to abstain from donating blood while taking lenalidomide and for 28 days following discontinuation of lenalidomide therapy agree not to share study drug lenalidomide with another person and to return all unused study drug to the investigator or pharmacist Ability of patient to understand character and individual consequences of the clinical trial Written informed consent (must be available before enrollment in the trial) Exclusion criteria Patients presenting with any of the following criteria will not be included in the trial: Patient has known hypersensitivity to any drugs given in the protocol, notably bortezomib, lenalidomide, dexamethasone and elotuzumab or to any of the constituent compounds (incl. Boron and mannitol). Systemic AL amyloidosis (except for AL amyloidosis of the skin or the bone marrow) Previous chemotherapy or radiotherapy during the past 5 years except local radiotherapy in case of local myeloma progression. (Note: patients may have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy within 4 weeks prior to study entry.) Severe cardiac dysfunction (NYHA classification III-IV, see appendix IIIB) Significant hepatic dysfunction (serum bilirubin ≥ 1,8 mg/dl and/or ASAT and/or ALAT ≥ 2.5 times normal level), unless related to myeloma. (Note: if the mentioned limits for bilirubin or ASAT/ALAT are exceeded, but there is no significant hepatic dysfunction at investigator’s discretion, the GMMG study office has to be consulted prior to inclusion) Patients with renal insufficiency requiring hemodialysis HIV positivity Patients with active or history of hepatitis B or C Patients with active, uncontrolled infections Patients with peripheral neuropathy or neuropathic pain, CTC grade 2 or higher (as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0, see appendix V) Patients with a history of active malignancy during the past 5 years with the exception of basal cell carcinoma of the skin or stage 0 cervical carcinoma treated with curative intent Patients with acute diffuse infiltrative pulmonary and/or pericardial disease Autoimmune hemolytic anemia with positive Coombs test or immune thrombocytopenia Platelet count < 75 × 109/l, or, dependent on bone marrow infiltration by plasma cells, platelet count < 30 × 109/l (patients with platelet count < 75 × 109/l, but > 30 × 109/l may be eligible if percentage of plasma cells in bone marrow is ≥ 50%), (transfusion support within 14 days before the test is not allowed) Haemoglobin < 8.0 g/dl, unless related to myeloma Absolute neutrophil count (ANC) < 1.0 × 109/l (the use of colony stimulating factors within 14 days before the test is not allowed), unless related to myeloma Pregnancy and lactation Participation in other clinical trials. This does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months. No patient will be allowed to enrol in this trial more than once.
Table 1
Inclusion and exclusion criteria for the GMMG-HD6 trial
| Inclusion criteria |
| Patients meeting all of the following criteria will be considered for admission to the trial: |
| Confirmed diagnosis of untreated multiple myeloma requiring systemic therapy (diagnostic criteria (IMWG updated criteria (2014). For some patients systemic therapy may be required though these diagnostic criteria are not fulfilled. In this case the GMMG study office has to be consulted prior to inclusion. |
| Measurable disease, defined as any quantifiable monoclonal protein value, defined by at least one of the following three measurements |
| Serum M-protein ≥ 10 g/l (for IgA ≥ 5 g/l) |
| Urine light-chain (M-protein) of ≥ 200 mg/24 h |
| Serum FLC assay: involved FLC level ≥ 10 mg/dl provided sFLC ratio is abnormal |
| Age 18–70 years inclusive |
| WHO performance status 0–3 (WHO = 3 is allowed only if caused by MM and not by co-morbid conditions) |
| Negative pregnancy test at inclusion (women of childbearing potential) |
| For all men and women of childbearing potential: patients must be willing and capable to use adequate contraception during the complete therapy. Patients must agree on the requirements regarding the lenalidomide pregnancy prevention programme. |
| All patients must |
| agree to abstain from donating blood while taking lenalidomide and for 28 days |
| following discontinuation of lenalidomide therapy |
| agree not to share study drug lenalidomide with another person and to return all |
| unused study drug to the investigator or pharmacist |
| Ability of patient to understand character and individual consequences of the clinical trial |
| Written informed consent (must be available before enrollment in the trial) |
| Exclusion criteria |
| Patients presenting with any of the following criteria will not be included in the trial: |
| Patient has known hypersensitivity to any drugs given in the protocol, notably bortezomib, lenalidomide, dexamethasone and elotuzumab or to any of the constituent compounds (incl. Boron and mannitol). |
| Systemic AL amyloidosis (except for AL amyloidosis of the skin or the bone marrow) |
| Previous chemotherapy or radiotherapy during the past 5 years except local radiotherapy in case of local myeloma progression. (Note: patients may have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy within 4 weeks prior to study entry.) |
| Severe cardiac dysfunction (NYHA classification III-IV, see appendix IIIB) |
| Significant hepatic dysfunction (serum bilirubin ≥ 1,8 mg/dl and/or ASAT and/or ALAT |
| ≥ 2.5 times normal level), unless related to myeloma. (Note: if the mentioned limits for bilirubin or ASAT/ALAT are exceeded, but there is no significant hepatic dysfunction at investigator’s discretion, the GMMG study office has to be consulted prior to inclusion) |
| Patients with renal insufficiency requiring hemodialysis |
| HIV positivity |
| Patients with active or history of hepatitis B or C |
| Patients with active, uncontrolled infections |
| Patients with peripheral neuropathy or neuropathic pain, CTC grade 2 or higher (as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0, see appendix V) |
| Patients with a history of active malignancy during the past 5 years with the exception of basal cell carcinoma of the skin or stage 0 cervical carcinoma treated with curative intent |
| Patients with acute diffuse infiltrative pulmonary and/or pericardial disease |
| Autoimmune hemolytic anemia with positive Coombs test or immune thrombocytopenia |
| Platelet count < 75 × 109/l, or, dependent on bone marrow infiltration by plasma cells, platelet count < 30 × 109/l (patients with platelet count < 75 × 109/l, but > 30 × 109/l may be eligible if percentage of plasma cells in bone marrow is ≥ 50%), (transfusion support within 14 days before the test is not allowed) |
| Haemoglobin < 8.0 g/dl, unless related to myeloma |
| Absolute neutrophil count (ANC) < 1.0 × 109/l (the use of colony stimulating factors within 14 days before the test is not allowed), unless related to myeloma |
| Pregnancy and lactation |
| Participation in other clinical trials. This does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months. |
| No patient will be allowed to enrol in this trial more than once. |
Trial procedures
Randomisation and stratification
The patient has to be registered before the start of therapy. Patients need to be registered at the GMMG study office by sending the “Registration and Randomisation Form” by fax.
The following lab results are already necessary at registration, in addition to information regarding the eligibility criteria and the investigational site: Serum β -2 microglobulin value Serum albumin value Serum M-protein (concentration of monoclonal protein in serum) Urine M-protein (Bence Jones).
All eligibility criteria will be checked with a checklist. ISS stage will be calculated from the provided serum β -2 microglobulin value and serum albumin value in serum. If the patient needs to be registered before the requested lab results are available, the GMMG study office has to be consulted so that the patient can be included. The necessary laboratory investigations have to be initiated before start of treatment and the results have to be submitted to the GMMG study office as soon as possible. Each patient will be given a unique patient study number (“randomisation number”). Patients will be randomized using block randomization stratified by ISS stage (I vs. II vs. III) in order to achieve a balance of treatment groups with respect to this prognostic covariate. There will be no additional stratification by center. Influence of this covariate is considered to be less because of the long trial experience of most centers within the GMMG.
The probability for assignment in each of the four treatment arms (A1, A2, B1, B2) is 25%, the relation of treatment arms is 1:1:1:1.
Patient study number and result of randomization will be sent to the investigator by fax.
Screening
All patients have to undergo physical examination including assessment of WHO performance score, body weight, body height and concomitant diseases.
Before the inclusion into the trial for a patient is possible, the following laboratory investigations are necessary: C reactive protein, lactate dehydrogenase, β -2 microglobulin, albumin, total protein, pregnancy test (only for woman in childbearing age), immunoglobulins, monoclonal protein and free light chains in serum, monoclonal protein in urine, immunofixation in serum, immunofixation in urine, complete blood count including Absolute Neutrophil Count (ANC), electrolytes, renal parameters, hepatic parameters, thyroid stimulating hormone.
A bone marrow puncture has to be performed for bone marrow aspiration (cytology, iFISH) and bone marrow histology.
For the documentation of the skeletal status medical imaging with low dose, whole body computed tomography or conventional X-ray imaging is required.
An ECG and an echocardiogram have to be performed prior to study inclusion to document the cardiac condition of the patient.
Study visits
Monitoring will be done by personal visits from a clinical monitor according to SOPs of the coordination centers for clinical trials (KKS).
The monitor will review the entries into the CRFs on the basis of source documents (source data verification). The investigator must allow the monitor to verify all essential documents and must provide support at all times to the monitor.
By frequent communications (letters, telephone, fax), the site monitor will ensure that the trial is conducted according to the protocol and regulatory requirements.
Timepoints of clinical evaluations
The Table 2 shows the recommended timepoints of response evaluation. A non-essential deviation of these timepoints (e.g. for logistic reasons) is accepted, but it is important that the response to a treatment period will be assessed previous to the start of the subsequent period. Table 2 Recommended timepoints of response evaluation Treatment period Timepoint of response evaluation After induction treatment d21 – d35 after start of 4 th cycle VRD After first chemotherapy cycle of intensification regime (mobilization) d23 – d33 after start of this cycle (previous to high dose therapy) After subsequent chemotherapy cycles of inten sification regime According to local policy: d60 - d90 after start of high dose therapy cycle recommended (previous to next cycle) After VRD consolidation d21–35 after start of 2 nd cycle VRD During maintenance every 3 months Follow up, i.e. after individual “end of study”, (until 1 st PD) Evaluation is recommended every 3 months. As long as there is no change in response status, es- pecially no progressive disease, CRF documentation of the FU visit is sufficient every 6 months. The timepoint of diagnosis of progressive disease has to be documented in the eCRF, even if it doesn’t correspond to a regular 3- or 6-month visit, respectively. Follow up, after 1st PD There are no specific recommendations for the evaluation schedule after 1st PD as course of the disease and therapies for relapsed and/or refractory myeloma vary and the visits have to be adapted to the requirements of the individual patient. The requirements for eCRF documentation in FU after 1st PD are as follows: update of the survival status at least every 6 months (incl. Information on secondary primary malignancies and on the timepoint of diagnosis of subsequent “PD”). Each line of therapy should be recorded separately
Table 2
Recommended timepoints of response evaluation
| Treatment period | Timepoint of response evaluation |
| After induction treatment | d21 – d35 after start of 4 th cycle VRD |
| After first chemotherapy cycle of intensification regime (mobilization) | d23 – d33 after start of this cycle (previous to high dose therapy) |
| After subsequent chemotherapy cycles of inten sification regime | According to local policy: d60 - d90 after start of high dose therapy cycle recommended (previous to next cycle) |
| After VRD consolidation | d21–35 after start of 2 nd cycle VRD |
| During maintenance | every 3 months |
| Follow up, i.e. after individual “end of study”, (until 1 st PD) | Evaluation is recommended every 3 months. As long as there is no change in response status, es- pecially no progressive disease, CRF documentation of the FU visit is sufficient every 6 months. The timepoint of diagnosis of progressive disease has to be documented in the eCRF, even if it doesn’t correspond to a regular 3- or 6-month visit, respectively. |
| Follow up, after 1st PD | There are no specific recommendations for the evaluation schedule after 1st PD as course of the disease and therapies for relapsed and/or refractory myeloma vary and the visits have to be adapted to the requirements of the individual patient. The requirements for eCRF documentation in FU after 1st PD are as follows: update of the survival status at least every 6 months (incl. Information on secondary primary malignancies and on the timepoint of diagnosis of subsequent “PD”). Each line of therapy should be recorded separately |
Trial treatment
Figure 1 includes a compact overview of the trial treatment. Fig. 1 GMMG HD6 trial overview
After the inclusion in the study, all patients regardless of randomization will receive an induction treatment consisting of 4 VRD cycles of 21 days each (bortezomib 1.3 mg/m 2 s.c. on days 1,4,8,11, oral lenalidomide 25 mg on days 1-14, oral dexamethasone 20 mg on days 1,2,4,5,8,9,11,12, additionally in cycle 1 and 2 on day 15). Patients in arm B1 and B2 will additionally be treated with elotuzumab 10 mg/kg on days 1,8,15 in cycle 1 and 2, days 1 and 11 in cycles 3 and 4.
All eligible patients will be given an intensified therapy regime according to GMMG standard protocols. A commonly used regimen for intensified therapy is: stem cell collection after CAD mobilization followed by high dose melphalan (200 mg/m 2 ) and autologous stem cell rescue. GMMG standard is a single HDT and ASCT for patients who reach at least a CR and tandem HDT and ASCT for patients who do not reach CR. Although the details of stem cell collection, HDT and ASCT are not specified in the study protocol.
Three months after the beginning of the last HDT cycle patients should receive consolidation treatment consisting of 2 cycles of VRD of 21 days each with weekly administration of bortezomib (bortezomib 1.3 mg/m 2 s.c. on days 1,8,15, oral lenalidomide 25 mg on days 1-14, oral dexamethasone 20 mg on days 1,2,8,9,15,16). Patients in arm A2 and B2 will be treated with elotuzumab 10 mg/kg additionally in both cycles on days 1,8,15.
Maintenance therapy should start on d35 of the second VRD consolidation cycle and will be given until confirmed progression, for 2 years or until unacceptable toxicity, whichever occurs first. All patients should receive 26 cycles lenalidomide maintenance every 28 days (oral lenalidomide 10 mg d 1-28) together with dexamethasone (12 mg on days 1 and 15 in cycle 1-6 and day 1 thereafter). Patients in arm A2 and B2 will be treated with Elotuzumab 10 mg/kg i.v. additionally on days 1 and 15 in cycle 1-6 and day 1 thereafter). A two years maintenance therapy timeframe was chosen to define a clear endpoint for the trial as required by the German authorities. Benefits of prolonged maintenance therapy beyond 2 years had not been shown in trials at the time of submission of this study protocol. Nonetheless, after the end of the study, all patients not encountering disease progression or inacceptable toxicity are suggested continuing lenalidomide maintenance treatment.
Supportive treatment
It is mandatory to give anti-viral (Aciclovir 2 x 400 mg/d p.o.) and anti-bacterial (Cotrimoxazol 2 x 960 mg/d p.o. or Ciprofloxacin 2 x 500 mg/d p.o.) prophylactic treatment to all patients during induction and consolidation therapy. A venous thromboembolism (VTE) prophylaxis in conjunction with VRD (+/- elotuzumab) has to be given. It is recommended to give acetylsalicylic acid (ASA) 100 mg daily. Patients at an individual high risk of thromboembolic events, such as patients with previous history of thromboembolism, should receive a VTE prophylaxis with low molecular weight heparin (LMWH). It is strongly recommended to start treatment with i.v. bisphosphonates at diagnosis and to continue this treatment every 4 weeks for at least 2 years. A commonly used regimen consists of zoledronate 4 mg or pamidronate 90mg once every 4 weeks. Elotuzumab requires premedication with H1 blocker, H2 blocker and paracetamol administered 30-90 minutes prior to elotuzumab administration and i.v. dexamethasone at least 45 minutes prior to elotuzumab.
Concomitant medication and treatment
Bisphosphonate treatment is recommended for all patients in the trial. It is permitted to treat trial participants with red blood- and platelet-transfusions, G-CSF and intravenous immunoglobulins. Furthermore, it is allowed to treat myeloma- or treatment-related complications (e.g. vertebroplasty in case of vertebral compression fracture). Radiotherapy is permitted. Additional use of substances with antineoplastic features is not allowed.
Follow up
Regular follow ups after the discontinuation of the study treatment are part of the study protocol. During this timeframe additional data regarding survival, toxicities, efficacy and subsequent myeloma-specific treatment will be gathered.
Response assessment
Response will be assessed according to the International Myeloma Working Group (IMWG) uniform response criteria [ 25 ]. In addition and modification to the IMWG criteria “minimal response” (MR) as defined in the EBMT criteria [ 26 ], “near CR” (nCR) and “molecular CR” (mCR) have been added. According to the trial protocol, in case of a suspected CR based on routine testing at any time during therapy, a bone marrow puncture is performed to confirm the response. At the same time, MRD-analysis is performed. If CR is confirmed MRD assessment is repeated once after 6 months.
Discontinuation criteria
Discontinuation of trial participation of individual patients
The patient can discontinue the trial treatment at any point without having to give any reason. The investigator can stop the trial treatment for patients if further treatment could be harmful or disadvantageous for the patient, if exclusion criteria are met, if a SAE occurs that precludes further treatment, if a trial participant gets pregnant, if data acquisition is not possible due to patient incompliance and if serological PD or PD with end organ damage (CRAB criteria [ 27 ]) is present in the trial patient. The only exception for PD is the occurrence of PD after induction therapy or stem cell apheresis. In this case further treatment in the trial is possible.
Closure of individual trial sites
Individual trial sites can be closed if the data quality is not sufficient or if the trial site provides inadequate patient recruiting.
Premature termination of the trial
If unknown risks occur during the trial; or due to inadequate recruiting not enough patients are acquired to continue the study, the DSMB or the principal investigator may terminate the trial prematurely.
Statistical analysis
Sample size calculation
The GMMG-HD6 trial is designed to determine as primary objective the best of the four treatment arms with regard to progression-free survival (PFS), censored at end of trial. Assuming 2 years of recruitment, 3 years minimal follow-up time after end of recruitment, a total of 10% drop-outs and 5% high risk patients leaving the study prematurely after induction therapy, inclusion of 564 patients allows for rejecting the global null hypothesis of no difference between the four arms at the two-sided significance level of 5% with a power of 91%, if the arms achieve PFS rates of 60%, 70%, 70% and 80% after 3 years. This corresponds to hazard ratios relative to the worst arm of 0.698, 0.698 and 0.437. The PFS rates of the intermediate arms are conservatively chosen representing the least favorable distribution with respect to power. Further treatment comparisons will be realized within a closed testing procedure. The sample size calculation is based on the method of Barthel et al. for multi-arm survival trials [ 28 ]. An interim analysis with respect to PFS rates will be conducted after 2.5 years to rule out lack of efficacy. The strongest observed effect between the best and the worst arm will be used to recommend a potential stop for futility based on the conditional power (CP) as proposed by Lachin (2005) [ 29 ]. The study is recommended to be stopped if CP ≤ 20%. This possibility to stop for futility results in a power loss of maximally 9.6%, thus, the overall power to reject the global null hypothesis of no difference between the four arms achieves at least 81.4%. Assuming arm A1 as reference, we are mainly interested in the best-versus-reference comparison. Liu and Dahlberg [ 30 ] found for the comparison of the best versus reference arm that the power lies only slightly below the overall power of the study. Our own simulation studies under the specific study assumptions confirmed these results and showed 88.6% power for the best-versus-reference comparison. With the possibility to stop at interim if CP ≤ 20%, the power for the best-versus-reference comparison would still be larger than 79%.
Statistical methods
A detailed statistical analysis plan (SAP) will be finalized before closure of the database and the final analysis which has to be authorized by the biometrician, the sponsor, and the LKP. The analysis of the primary endpoint is confirmatory. All remaining analyses are exploratory and will be carried out at a two-sided significance level of 0.05 unless noted otherwise.
Primary endpoint
The primary endpoint is PFS, censored at end of trial. The four treatment arms will be compared in a closed testing procedure as introduced by Marcus, Peritz and Gabriel [ 26 ]. This hierarchical step-down approach controls the family-wise error rate in a multi-comparison setting if all null hypotheses are tested in a pre-defined hierarchical order at a the same significance level starting with the global null hypothesis of no treatment difference between the four arms down to the pairwise (elementary) null hypotheses of no treatment difference between two treatment arms. All null hypotheses will be tested confirmatory at the two-sided 5% significance level using the log-rank test stratified by ISS stage. Statistically significant different PFS of a treatment arm with respect to a comparator arm will be concluded if the adjusted p-value of the elementary hypothesis is below 0.05.
The analysis of the primary objective is performed after database closure and will be presented in the final biometrical report.
Discussion
An intensified treatment concept including induction therapy, high dose melphalan (200 mg/m 2 ) and subsequent consolidation/maintenance therapy is considered the standard treatment for fit MM patients [ 1 , 2 ].
Results of randomized phase III trials comparing HDT with treatment including new drugs showed a benefit for HDT in response, minimal residual disease (MRD) and PFS [ 10 , 31 – 33 ]. The data from the French study showed a strong correlation between MRD negativity (NGS [Sequenta] and FACS) and the normalization of lesions in PET-CT before maintenance [ 34 , 35 ]. Molecular data before treatment and MRD-monitoring during treatment will allow to define a subgroup of MM patients that can be cured. In addition to testing the anti-SLAMF7 antibody elotuzumab in upfront induction and maintenance treatment of transplant-eligible patients, the CD38 targeting antibodies daratumumab and isatuximab are currently tested in ongoing trials, e.g. by the Intergroupe Francophone du Myélome (IFM) (Cassiopeia, NCT02541383 ).
Given the previously described study results in the relapsed setting, an improvement of the therapeutic results by the addition of the humanized monoclonal antibody elotuzumab can be expected. This phase III trial is designed to evaluate whether the addition of elotuzumab to an intensified treatment concept with high dose melphalan chemotherapy plus autologous stem cell transplantation and induction, consolidation and maintenance treatment with bortezomib and lenalidomide is able to improve PFS compared to the same concept without elotuzumab.
Conclusion
We present the study protocol of the first phase III investigator initiated trial to explore the role of elotuzumab in combination with VRD and lenalidomide maintenance together with high dose melphalan and stem cell transplantation.
Results will be analyzed in comparison with molecular profiling and imaging.
Abbreviations
Antibody dependent cell-mediated cytotoxicity
Adverse event
Absolute neutrophil count
Acetyl salicylic acid
Autologous stem cell transplantation
Conditional power
Complete response
Calcium elevation/renal failure/anemia/bone lesions
Computed tomography
Common Terminology Criteria of Adverse Events
Duration of response
Data safety monitoring board
Electrocardiogram
Elotuzumab
First patient in
Gene expression
German-speaking Myeloma Multicenter Group
High dose (chemo)therapy
International Conference on Harmonization of good clinical practice
Interphase fluorescence in situ hybridization
International Myeloma Working Group
International staging system
Intent-to-treat
Coordination Center for Clinical Trials (Koordinierungszentrum für Klinische Studien)
Coordinating investigator (Leiter der Klinischen Prüfung)
Low molecular weight heparin
Last patient in
Last patient out
Multiple myeloma
Minimal response
Near CR
Newly diagnosed Multiple Myeloma
Natural killer
Overall response rate
Overall survival
Peripheral blood mononuclear cells
Progressive disease
Progression free survival
Response rate
Serious adverse event
Statistical analysis plan
SLAMF7 gene
Standard operation procedure
Suspected unexpected serious adverse reactions
Time to progression
Very good partial response
Bortezomib, lenalidomide and dexamethasone
Venous thromboembolism
World health organization
Acknowledgements
We thank the investigators, the study nurses and all the members of the study teams at the participating GMMG trial sites, the teams of the myeloma research laboratory, the molecular biology laboratory, the hematological laboratory, the FISH laboratory at the Institute of Human Genetics, the central laboratory and the Institute of Pathology at the University Hospital Heidelberg, the coordination center for clinical trials (KKS) in Heidelberg, the pharmacies at the trial sites and, most importantly, the participating patients and their families. This trial is supported by grants from Bristol Myers Squibb, Chugai and Celgene.
Funding
The GMMG HD6 trial is supported by grants from Bristol Myers Squibb, Chugai and Celgene. A peer review of the study protocol was done by the companies. Influence of the sponsors: This is an investigator initiated study. The study design was developed with the Department of Biostatistics at the German Cancer Research Center, Heidelberg, see section "Statistical analysis". The study design was discussed with the sponsors, who had accepted the IIT design.
Availability of data and materials
Not applicable at this time.
Authors’ contributions
HS, UB, KW, AB, IGB, CS and HG contributed to the development of the study concept and design. HS, UB, KW, JD, CK, IWB, MSR, JH, DH, SH, MHu, MA, AJ, ASG, HWL, MHe, SF, UM, TH, MW, UG, MM, RF, MHa, CS and HG contribute to data acquisition. AB contributes to data analysis. HS, UB, KW, JD, CK, IWB, MSR, JH, DH, SH, MHu, MA, AJ, ASG, HWL, MHe, SF, UM, TH, MW, UG, MM, RF, MHa, CS and HG contributed to the writing and revision of the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Documented approval from the appropriate ethics committees/institutional review boards (IRB) of the Medical Faculty of the Heidelberg University (main IRB) and all participating study sites has been obtained prior to study start and a data safety monitoring board (DSMB) has been installed to monitor the trial. Written informed consent from each patient is obtained before any study-specific procedures are performed. A full list of involved/ local ethics
committees is provided in the accepting assessment documents in a separate file.
Consent for publication
At this time (04/05/2018), only abstracts regarding the HD6 trial have been published (e.g. ASH Abstract 2016:
Evaluation of Stem Cell Mobilization in Patients with Multiple Myeloma after Lenalidomide-Based Induction Chemotherapy within the GMMG-HD6 Trial; P Wuchter et al; Blood 2016 128:3373). The trial protocol has not been openly published in a peer reviewed paper.
Competing interests
Author-specific disclosures: HS: Celgene: Honoraria, Travel grants; Bristol Myers Squibb: Honoraria and Research Funding; Amgen: Honoraria, Travel grants; Janssen: Honoraria and Research Funding; Novartis: Honoraria and Research Funding; Takeda: Honoraria. KW: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees and Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees and Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees and Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees and Research Funding Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees and Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees and Research Funding; Sanofi: Research Funding. JD: Celgene: Honoraria, Research Funding and Speakers Bureau; Janssen: Honoraria and Speakers Bureau . MSR: Celgene: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy and Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy and Research Funding; Morphosys: Research Funding. JH: Celgene: Consultancy, Honoraria and Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria; Amgen: Consultancy, Honoraria and Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria and Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria and Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Sanofi: Research Funding. DH: Celgene: Consultancy, Research Funding; MM: Janssen: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy; Amgen: Consultancy Celgene: Consultancy. RF: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. MHa: Roche: Honoraria; Novartis: Honoraria. HG: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding and Speakers Bureau; Chugai: Consultancy, Honoraria and Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding and Speakers Bureau Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding and Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding and Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding and Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding and Speakers Bureau. All other authors declare no conflict of interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
1. DGHO - German Society for Hematology and Oncology: Onkopedia guidelines multiple myeloma 2018 (09.02.2019).
2. Palumbo A Anderson K Multiple myeloma N Engl J Med 2011 364 11 1046 1060 10.1056/NEJMra1011442 21410373
3. Attal M Lauwers-Cances V Hulin C Facon T Caillot D Escoffre M Arnulf B Marco M Belhadj K Garderet L Autologous transplantation for multiple myeloma in the era of new drugs: a phase III study of the Intergroupe francophone Du Myelome (IFM/DFCI 2009 trial) Blood 2015 126 23 391
4. Cavo M Petrucci MT Di Raimondo F Zamagni E Gamberi B Crippa C Marzocchi G Grasso M Ballanti S Vincelli DI Upfront single versus double autologous stem cell transplantation for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study of the European myeloma network (EMN02/HO95 MM trial) Blood 2016 128 22 991
5. van Rhee F Giralt S Barlogie B The future of autologous stem cell transplantation in myeloma Blood 2014 124 3 328 333 10.1182/blood-2014-03-561985 24894774 PMC4102706
6. Richardson PG Weller E Lonial S Jakubowiak AJ Jagannath S Raje NS Avigan DE Xie W Ghobrial IM Schlossman RL Mazumder A Munshi NC Vesole DH Joyce R Kaufman JL Doss D Warren DL Lunde LE Kaster S Delaney C Hideshima T Mitsiades CS Knight R Esseltine DL Anderson KC Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma Blood 2010 116 5 679 686 10.1182/blood-2010-02-268862 20385792 PMC3324254
7. Roussel M Lauwers-Cances V Robillard N Hulin C Leleu X Benboubker L Marit G Moreau P Pegourie B Caillot D Fruchart C Stoppa AM Gentil C Wuilleme S Huynh A Hebraud B Corre J Chretien ML Facon T Avet-Loiseau H Attal M Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe francophone du Myélome J Clin Oncol 2014 32 25 2712 2717 10.1200/JCO.2013.54.8164 25024076
8. Kumar S Flinn I Richardson PG Hari P Callander N Noga SJ Stewart AK Turturro F Rifkin R Wolf J Estevam J Mulligan G Shi H Webb IJ Rajkumar SV Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma Blood 2012 119 19 4375 4382 10.1182/blood-2011-11-395749 22422823
9. Ludwig H Sonneveld P Davies F Blade J Boccadoro M Cavo M Morgan G de la Rubia J Delforge M Dimopoulos M Einsele H Facon T Goldschmidt H Moreau P Nahi H Plesner T San-Miguel J Hajek R Sondergeld P Palumbo A European perspective on multiple myeloma treatment strategies in 2014 Oncologist 2014 19 8 829 844 10.1634/theoncologist.2014-0042 25063227 PMC4122482
10. Attal M Lauwers-Cances V Hulin C Facon T Caillot D Escoffre M Arnulf B Macro M Belhadj K Garderet L Roussel M Mathiot C Avet-Loiseau H Munshi NC Richardson PG Anderson KC Harousseau JL Moreau P Autologous transplantation for multiple myeloma in the era of new drugs: a phase III study of the Intergroupe francophone Du Myelome. Abstract ASH 2015, 57th annual meeting 2015
11. Durie BG Hoering A Abidi MH Rajkumar SV Epstein J Kahanic SP Thakuri M Reu F Reynolds CM Sexton R Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial Lancet 2017 389 10068 519 527 10.1016/S0140-6736(16)31594-X 28017406 PMC5546834
12. Liu H McCarthy P New developments in post-transplant maintenance treatment of multiple myeloma Semin Oncol 2013 40 5 602 609 10.1053/j.seminoncol.2013.07.008 24135405
13. McCarthy PL Holstein SA Petrucci MT Richardson PG Hulin C Tosi P Bringhen S Musto P Anderson KC Caillot D Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis J Clin Oncol 2017 35 29 3279 3289 10.1200/JCO.2017.72.6679 28742454 PMC5652871
14. Attal M Lauwers-Cances V Marit G Caillot D Moreau P Facon T Stoppa A Hulin C Benboubker L Garderet L Decaux O Leyvraz S Vekemans M-C Voillat L Michallet M Pegourie B Dumontet C Roussel M Leleu X Mathiot C Payen C Avet-Loiseau H Harousseau J-L Lenalidomide maintenance after stem-cell transplantation for multiple myeloma N Engl J Med 2012 366 19 1782 1791 10.1056/NEJMoa1114138 22571202
15. McCarthy PL Owzar K Hofmeister CC Hurd DD Hassoun H Richardson PG Giralt S Stadtmauer EA Weisdorf DJ Vij R Moreb JS Callander NS Van Besien K Gentile T Isola L Maziarz RT Gabriel DA Bashey A Landau H Martin T Qazilbash MH Levitan D McClune B Schlossman R Hars V Postiglione J Jiang C Bennett E Barry S Bressler L Kelly M Seiler M Rosenbaum C Hari P Pasquini MC Horowitz MM Shea TC Devine SM Anderson KC Linker C Lenalidomide after stem-cell transplantation for multiple myeloma N Engl J Med 2012 366 19 1770 1781 10.1056/NEJMoa1114083 22571201 PMC3744390
16. Lonial S Dimopoulos M Palumbo A White D Grosicki S Spicka I Walter-Croneck A Moreau P Mateos MV Magen H Belch A Reece D Beksac M Spencer A Oakervee H Orlowski RZ Taniwaki M Rollig C Einsele H Wu KL Singhal A San-Miguel J Matsumoto M Katz J Bleickardt E Poulart V Anderson KC Richardson P Elotuzumab therapy for relapsed or refractory multiple myeloma N Engl J Med 2015 373 7 621 631 10.1056/NEJMoa1505654 26035255
17. Dimopoulos MA Lonial S White D Moreau P Palumbo A San-Miguel J Shpilberg O Anderson K Grosicki S Spicka I Walter-Croneck A Magen H Mateos MV Belch A Reece D Beksac M Bleickardt E Poulart V Sheng J Sy O Katz J Singhal A Richardson P Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth Br J Haematol 2017 178 6 896 905 10.1111/bjh.14787 28677826 PMC6084289
18. Southwest Oncology Group: S1211, bortezomib, dexamethasone, and lenalidomide with or without elotuzumab in treating patients with newly diagnosed high-risk multiple myeloma. www.clinicaltrials.gov NCT01668719 (05.08.2014).
19. Laubach J Nooka AK Cole C O'Donnell E Vij R Usmani SZ Orloff GJ Richter JR Redd R DiPietro H An open-label, single arm, phase IIa study of bortezomib, lenalidomide, dexamethasone, and elotuzumab in newly diagnosed multiple myeloma J Clin Oncol 2017 35 15_suppl 8002 10.1200/JCO.2017.35.15_suppl.8002
20. Richardson PG Jagannath S Moreau P Jakubowiak AJ Raab MS Facon T Vij R White D Reece DE Benboubker L Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study Lancet Haematology 2015 2 12 e516 e527 10.1016/S2352-3026(15)00197-0 26686406 PMC6871650
21. Jakubowiak AJ Benson DM Bensinger W Siegel DS Zimmerman TM Mohrbacher A Richardson PG Afar DE Singhal AK Anderson KC Phase I trial of anti-CS1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/refractory multiple myeloma J Clin Oncol 2012 30 16 1960 1965 10.1200/JCO.2011.37.7069 22291084 PMC4874204
22. Zonder JA Mohrbacher AF Singhal S van Rhee F Bensinger WI Ding H Fry J Afar DE Singhal AK A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma Blood 2012 120 3 552 559 10.1182/blood-2011-06-360552 22184404 PMC4467882
23. Lonial S Vij R Harousseau JL Facon T Moreau P Mazumder A Kaufman JL Leleu X Tsao LC Westland C Singhal AK Jagannath S Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma J Clin Oncol 2012 30 16 1953 1959 10.1200/JCO.2011.37.2649 22547589
24. Lonial S Jagannath S Moreau P Jakubowiak AJ Raab MS Facon T Vij R Bleickardt E Reece DE Benboubker L Phase (Ph) I/II study of elotuzumab (Elo) plus lenalidomide/dexamethasone (Len/dex) in relapsed/refractory multiple myeloma (RR MM): updated Ph II results and Ph I/II long-term safety J Clin Oncol 2013 31 15_suppl 8542
25. Durie BG Harousseau JL Miguel JS Blade J Barlogie B Anderson K Gertz M Dimopoulos M Westin J Sonneveld P Ludwig H Gahrton G Beksac M Crowley J Belch A Boccadaro M Cavo M Turesson I Joshua D Vesole D Kyle R Alexanian R Tricot G Attal M Merlini G Powles R Richardson P Shimizu K Tosi P Morgan G Rajkumar SV International uniform response criteria for multiple myeloma Leukemia 2006 20 9 1467 1473 10.1038/sj.leu.2404284 16855634
26. Blade J Samson D Reece D Apperley J Bjorkstrand B Gahrton G Gertz M Giralt S Jagannath S Vesole D Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation . Myeloma Subcommittee of the EBMT European Group for Blood and Marrow Transplant Br J Haematol 1998 102 5 1115 1123 10.1046/j.1365-2141.1998.00930.x 9753033
27. The international Myeloma Working Group Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the international myeloma working group Br J Haematol 2003 121 5 749 757 10.1046/j.1365-2141.2003.04355.x 12780789
28. Barthel FM Babiker A Royston P Parmar MK Evaluation of sample size and power for multi-arm survival trials allowing for non-uniform accrual, non-proportional hazards, loss to follow-up and cross-over Stat Med 2006 25 15 2521 2542 10.1002/sim.2517 16479563
29. Lachin JM A review of methods for futility stopping based on conditional power Stat Med 2005 24 18 2747 2764 10.1002/sim.2151 16134130
30. Liu PY Dahlberg S Design and analysis of multiarm clinical trials with survival endpoints Control Clin Trials 1995 16 2 119 130 10.1016/0197-2456(94)00030-7 7789135
31. Gay F Oliva S Petrucci MT Conticello C Catalano L Corradini P Siniscalchi A Magarotto V Pour L Carella A Malfitano A Petro D Evangelista A Spada S Pescosta N Omede P Campbell P Liberati AM Offidani M Ria R Pulini S Patriarca F Hajek R Spencer A Boccadoro M Palumbo A Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial Lancet Oncol 2015 16 16 1617 1629 10.1016/S1470-2045(15)00389-7 26596670
32. Palumbo A Cavallo F Gay F Di Raimondo F Ben Yehuda D Petrucci MT Pezzatti S Caravita T Cerrato C Ribakovsky E Genuardi M Cafro A Marcatti M Catalano L Offidani M Carella AM Zamagni E Patriarca F Musto P Evangelista A Ciccone G Omede P Crippa C Corradini P Nagler A Boccadoro M Cavo M Autologous transplantation and maintenance therapy in multiple myeloma N Engl J Med 2014 371 10 895 905 10.1056/NEJMoa1402888 25184862
33. Cavo M Upfront single versus double autologous stem cell transplantation for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study of the European myeloma network (EMN02/HO95 MM trial) Blood 2016 128 991
34. Hervé A-L Valerie L-C Jill C Philippe M Michel A Nikhil M Minimal residual disease in multiple myeloma: final analysis of the IFM2009 trial Blood 2017 130 435
35. Moreau P Attal M Caillot D Macro M Karlin L Garderet L Facon T Benboubker L Escoffre-Barbe M Stoppa AM Prospective evaluation of magnetic resonance imaging and [(18)F]Fluorodeoxyglucose positron emission tomography-computed tomography at diagnosis and before maintenance therapy in symptomatic patients with multiple myeloma included in the IFM/DFCI 2009 trial: results of the IMAJEM study J Clin Oncol Off J Am Soc Clin Oncol 2017 35 25 2911 2918 10.1200/JCO.2017.72.2975 PMC5578392 28686535