Disease that has progressed during or within  months of coming off therapy with bortezomib and lenalidomide (either sequentially or concurrent); progressive disease is defined as any of the following:\r\n* An increase of >= % from lowest response value in any of the following:\r\n** Serum M-protein (absolute increase must be >= . g/dL) AND/OR\r\n** Urine M-protein (absolute increase must be >=  mg/ hours) AND/OR\r\n** For patients without a measurable serum or urine M-protein but measurable disease by serum free light chain testing: Difference between the involved and uninvolved serum free light chain level (absolute increase must be >=  mg/dL) AND/OR\r\n** For patients without a measurable serum or urine M-component or serum free light chain level: % marrow involvement with myeloma (absolute increase must be >= %) AND/OR\r\n* Definite development of new bone lesions or extramedullary plasmacytomas or definite increase in the size of existing bone lesions or extramedullary plasmacytomas AND/OR\r\n* Hypercalcemia (corrected serum calcium > . mg/dL) attributable to myeloma (e.g. not due to omitted doses of biophosphonate)
Progressive disease defined by any of following: % increase in serum M-protein from lowest response value during (or after) last therapy and/or absolute increase in serum M-protein of > or equal to . g/dL; % increase in urine M-protein from lowest response value during (or after) last therapy and/or absolute increase in urine M-protein of > or equal to  mg/h; % increase in bone marrow plasma cell percentage from lowest response value during (or after) last therapy - absolute bone marrow plasma cell percentage must be > or equal to % unless prior complete response when absolute bone marrow plasma cell percentage must be > or equal to %; % increase in serum FLC level from the lowest response value during (or after) last therapy - the absolute increase must be >  mg/dL; new onset hypercalcemia > . mg/dL
Key Inclusion Criteria:\n\n        Individuals eligible to participate in this study must meet the following key criteria and\n        additional criteria as specified in the protocol:\n\n          . Male or female, aged ?  years\n\n          . Confirmed diagnosis of MM per IMWG criteria\n\n          . Measurable disease as defined by one or more of the following:\n\n               -  Serum M-protein ? . g/dL\n\n               -  Urine M-protein ?  mg/ hours\n\n               -  Serum Free Light Chain (FLC) assay: involved FLC level ?  mg/dL provided serum\n                  FLC ratio is abnormal\n\n               -  In cases where SPEP is unreliable, serum quantitative immunoglobulin (qIgA) ? \n                  mg/dL (. g/dL) is acceptable\n\n          . Relapsed or refractory (Rajkumar, ) to  or more different prior lines of therapy\n             for MM, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs),\n             chemotherapies, or monoclonal antibodies, and not a candidate for, or intolerant to\n             established therapy known to provide clinical benefit.\n\n          . Eastern Cooperative Oncology Group (ECOG) Performance Status of  - \n\n          . Adequate organ and marrow function at Screening, as defined by the study protocol.\n\n        Key Exclusion Criteria:\n\n          . Monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma,\n             Waldenstrom's macroglobulinemia, or IgM myeloma\n\n          . Active plasma cell leukemia (? .  /L circulating plasma cells by standard\n             differential)\n\n          . POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and\n             skin changes)\n\n          . Prior treatment directed to B-cell Activating Factor (BAFF; BLyS), B-cell Maturation\n             Antigen (BCMA;TNFSF) or Transmembrane Activator and CAML interactor (TACI;\n             TNFSFB), including antibodies or BCMA- or TACI-directed Chimeric Antigen Receptor\n             (CAR)-T cell therapy
High-risk MGUS: must have < % plasma cells and < .g/dL M-spike and at least  of the following  criteria:\r\n* Abnormal free light-chain (FLC) ratio (< . or > .)\r\n* M-protein concentration (>= . g/dL)\r\n* Reduction of =<  non-involved immunoglobulin isotype levels (immunoparesis)\r\n* Abnormal ratio of plasma cells in the bone marrow > %\r\n* Non-IgG M protein (including IgA)
Low-risk smoldering multiple myeloma: must only present with  of the following criterion:\r\n* Monoclonal Protein >=  g/dL\r\n* >= % bone marrow plasma cells\r\n* FLC ratio < . or > 
No evidence of hypercalcemia, renal-failure, anemia and bone-lesions (CRAB) criteria or new criteria of active MM which including the following:\r\n* Increased calcium levels (corrected serum calcium > . mmol/dL above the upper limit of normal or > . mmol/dL)\r\n* Renal insufficiency (attributable to myeloma)\r\n* Anemia (hemoglobin [Hb]  g/dL below the lower limit of normal or <  g/dL)\r\n* Bone lesions (lytic lesions or generalized osteoporosis with compression fractures)\r\n* No evidence of the following new criteria for active MM including the following: bone marrow plasma cells > %, serum involved/uninvolved FLC ratio >= , and magnetic resonance imaging (MRI) with more than one focal lesion\r\n** Participants with CRAB criteria that are attributable to conditions other than the disease under study may be eligible
Must meet criteria of high-risk smoldering multiple myeloma (MM) based on the criteria described below:\r\n* Definition of high-risk smoldering multiple myeloma (SMM):\r\n** Bone marrow clonal plasma cells >= % and =< % and any one or more of the following:\r\n*** Serum M protein >= . g/dL (immunoglobulin [Ig]A, IgG, IgM, or IgD)\r\n*** IgA SMM\r\n*** Immunoparesis with reduction of two uninvolved immunoglobulin isotypes\r\n*** Serum involved/uninvolved free light chain ratio >=  (but less than )\r\n**** Free light chain smoldering myeloma patients are not excluded\r\n*** Progressive increase in M protein level (evolving type of SMM)\r\n**** Increase in serum monoclonal protein by >= % on two successive evaluations within a  month period\r\n*** Bone marrow clonal plasma cells -%\r\n*** Abnormal plasma cell immunophenotype (>= % of bone marrow plasma cells are clonal) and reduction of one or more uninvolved immunoglobulin isotypes\r\n*** t (;) or del p or q gain\r\n*** Increased circulating plasma cells\r\n*** Magnetic resonance imaging (MRI) with diffuse abnormalities or  focal lesion\r\n*** Positron emission tomography (PET)-computed tomography (CT) with one focal lesion with increased uptake without underlying osteolytic bone destruction\r\n*** Urine monoclonal light chain excretion >=  mg/ hours
No evidence of hypercalcemia, renal failure, anemia, and bone lesions (CRAB) criteria or new criteria of active MM which including the following:\r\n* Increased calcium levels (corrected serum calcium > . mmol/dL above the upper limit of normal or > . mmol/dL) related to MM\r\n* Renal insufficiency (attributable to MM)\r\n* Anemia (hemoglobin [Hb]  g/dL below the lower limit of normal or <  g/dL) related to MM\r\n* Bone lesions (lytic lesions or generalized osteoporosis with compression fractures)\r\n* Bone marrow plasma cells > %\r\n* Serum involved/uninvolved free light chain (FLC) ratio >= , provided the absolute level of the involved free light chain is at least  mg/L and repeated twice\r\n* MRI with two or more focal lesion that is at least  mm or greater in size\r\n** Participants with CRAB criteria that are attributable to conditions other than the disease under study may be eligible
Patient must have relapsed or refractory myeloma that fits or did fit International Myeloma Working Group (IMWG) diagnostic criteria for symptomatic myeloma (although new or worsening end organ damage is not required to be eligible) as defined below:\r\n* Presence of clonal bone marrow plasma cells\r\n* Presence of serum and/or urinary measurable monoclonal protein or light chains\r\n* Evidence of any end organ damage criteria listed below (at any time) attributed to the patients myeloma:\r\n** Hypercalcemia: serum calcium > . mg/dL or\r\n** Renal insufficiency: serum creatinine >  mg/dL\r\n** Anemia >  g/dL below the lower limit of normal or a hemoglobin value <  g/dL\r\n** Bone lesions: lytic lesions, severe osteopenia or pathologic fractures
In addition to having SMM, patients must also be classified as high-risk SMM per Mayo Clinic or Spanish Programa Espanol de Tratamientos en Hematologia (PETHEMA) criteria; NOTE:\r\n* Criteria set forward by Rajkumar, Landgren, Mateos may also be used to define high risk disease, namely clonal bone marrow plasma cells >= % and any one or more of the following:\r\n** Serum M protein >=  g/L\r\n** IgA SMM\r\n** Immunoparesis with reduction of  uninvolved immunoglobulin isotypes\r\n** Serum involved/uninvolved FLC ratio >=  (but < )\r\n** Progressive increase in M protein level (evolving type of SMM; increase in serum M protein by >= % on  successive evaluations within a -month period)\r\n** Clonal bone marrow plasma cells (BMPCs) %-%\r\n** Abnormal PC immunophenotype (>= % of BMPCs are clonal) and reduction of >=  uninvolved immunoglobulin isotypes\r\n** t(;) or del(p) or q gain\r\n** Increased circulating plasma cells (PCs)\r\n** MRI with diffuse abnormalities or  focal lesion\r\n** PET-CT with focal lesion with increased uptake without underlying osteolytic bone destruction
Patients with multiple myeloma who demonstrate evidence of serologic relapse/progression while on lenalidomide maintenance given as part of first line therapy (including upfront high-dose chemotherapy followed by autologous hematopoietic cell transplantation [HCT]) without symptomatic relapse/progression.\r\n* Lenalidomide maintenance is defined as single agent lenalidomide therapy of any doses up to  mg PO daily for - days (-day cycle). Relapse/progression is defined as increase of % from lowest confirmed response value in one or more of the following criteria:\r\n** Serum M protein (absolute increase must be >= .g/dl)\r\n** Serum M-protein increase > g/dl, if the lowest M component was >  g/dl\r\n** Urine M protein (absolute increase must be >  mg in  hours)\r\n** In patients without measurable serum and urine M-protein levels, the difference between involved and uninvolved free light chain (FLC) levels (absolute increase must be >  mg/dl)\r\n * For patients relapsing from complete remission, relapse is defined as: reappearance of serum or serum M-protein by immunofixation or electrophoresis
Patients with clinical relapse/progression as per the International Myeloma Working Group (IMWG) uniform criteria defined as one or more of the following criteria:\r\n* Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute progression)\r\n* Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a % (and >=  cm) increase as measured serially of the measurable lesion\r\n* Hypercalcemia (>  mg/dL)\r\n* Decrease in hemoglobin of >=  g/dL not related to therapy or other non-myeloma-related conditions\r\n* Rise in serum creatinine by  mg/dL or more from the start of the therapy and attributable to myeloma\r\n* Hyperviscosity related to serum paraprotein
Clinically overt myeloma a.) Lytic bone lesions or biopsy proven plasmacytoma b.) Hypercalcemia (corrected for albumin) >  mg/dL unexplained by other causes
Patients must have been previously diagnosed with histologically or cytologically confirmed symptomatic multiple myeloma, which require the presence of all three of the following International Myeloma Working Group criteria, except as noted:\r\n* Clonal bone marrow plasma cells >= %\r\n* A monoclonal protein in either serum or urine\r\n* Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder (to include one of the following)\r\n** Hypercalcemia (corrected calcium > . mmol/L or . mg/dL); OR\r\n** Renal insufficiency attributable to myeloma (serum creatinine > . mg/dL); OR\r\n** Anemia; normochromic, normocytic with a hemoglobin value >=  g/dL below the lower limit of normal, or a hemoglobin or <  g/dL; OR\r\n** Bone lytic lesions (magnetic resonance imaging [MRI], computed tomography [CT] or positron emission tomography [PET]/CT with >  focal lesions >=  mm in size), severe osteopenia or pathologic fractures\r\n* Patients with a biopsy-proven plasmacytoma and either a serum or urine monoclonal protein will also be considered to have met the diagnostic criteria for multiple myeloma in the absence of clonal marrow plasmacytosis of >= %\r\n* Patient with bone marrow plasma cells of >= % or serum free light chain ratio of >=  will also be considered to have met the diagnostic criteria for multiple myeloma
Patients must have disease that has relapsed after carfilzomib therapy, with progressive disease (PD) being defined as an increase of % from the lowest response value in any one or more of the following:\r\n* Serum M-component (the absolute increase must be >= . g/dL) and/or\r\n* Urine M-component (the absolute increase must be >=  mg/ hours) and/or\r\n* Only in patients without a measurable serum and urine M protein level: the difference between involved and uninvolved free light chain (FLC) levels (absolute increase) must be >  mg/dL\r\n* Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas\r\n* Development of hypercalcemia (corrected serum calcium > . mg/dL) that can be attributed solely to the plasma cell proliferative disorder\r\nPatients with relapsed disease will be considered to be those who have had progression, as defined above, off of any therapy, and who completed their therapy more than  days prior to the finding of progression; patients with relapsed and refractory disease will be considered to be those who have had progression, as defined above, while still on their last line of therapy, or who progressed within  days of finishing their most recent therapy
Patients must have histologically confirmed smoldering multiple myeloma (SMM) based on the following criteria; both criteria must be met: (a) serum monoclonal protein (IgG or IgA) >=  g/dL or urinary monoclonal protein >=  mg per  hours and/or clonal bone marrow plasma cells -% (b) absence of myeloma defining events or amyloidosis
Evidence of myeloma defining events or biomarkers of malignancy due to underlying plasma cell proliferative disorder meeting at least ONE of the following: \r\n* . Hypercalcemia: serum calcium > . mmol/L (>  mg/dL) higher than the upper limit of normal or > . mmol/L (>  mg/dL) \r\n* . Renal insufficiency: creatinine clearance <  ml/min or serum creatinine >  mg/dL \r\n* . Anemia: hemoglobin value <  g/dL or  g/dL < normal reference \r\n* . Bone lesions: one or more osteolytic lesions on skeletal radiography, computerized tomography (CT) or -deoxy-[F-] fluoro-D-glucose positron emission tomography CT (PET-CT) \r\n* . Clonal bone marrow plasma cell percentage >= % \r\n* . Involved: uninvolved serum free light chain ratio >=  measured by freelite assay\r\n* . >  focal lesions on magnetic resonance imaging (MRI) studies (each focal lesion must be  mm or more in size)
No end organ damage attributable to a plasma cell disorder, defined as having ANY of the following:\r\n* Hypercalcemia: serum calcium >  mg/dL above the upper limit of normal or >  mg/dL\r\n* Renal insufficiency: serum creatinine >  mg/dL or creatinine clearance <  mL per min\r\n* Anemia: hemoglobin value >  g/dL below the upper limit of normal or a hemoglobin value <  g/dL\r\n* Bone lesions: one or more lytic lesions on skeletal radiography, computed tomography (CT), MRI, PET-CT, or PET-MRI
Clonal bone marrow plasma cells >= % or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events:\r\nEvidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:\r\n* Serum calcium > . mmol/L (>  mg/dL) higher than the upper limit of normal or > . mmol/L (>  mg/dL)\r\n* Creatinine clearance <  mL per min (measured or estimated by validated equations) or serum creatinine >  umol/L (>  mg/dL)\r\n* Hemoglobin value of >  g/L below the lower limit of normal, or a hemoglobin value\r\n* One or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)-CT; if bone marrow has less than % clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement\r\n* Any one or more of the following biomarkers of malignancy: \r\n** Clonal bone marrow plasma cell percentage ?%; clonality should be established by showing kappa/lambda-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence; bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used\r\n** Involved:uninvolved serum free light chain ratio >=  mg/L; these values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK); the involved free light chain must be >=  mg/L\r\n** >  focal lesions on magnetic resonance imaging (MRI) studies; each focal lesion must be  mm or more in size
Subjects must have disease that has relapsed and/or refractory after their most recent therapy, with progressive disease (PD) being defined as an increase of % from the lowest response value in any one or more of the following: \r\n* Serum M-protein (the absolute increase must be >= . g/dL) and/or\r\n* Urine M-protein (the absolute increase must be >=  mg/ hours) and/or\r\n* Only in subjects without a measurable serum and urine M protein level: the difference between involved and uninvolved free light chain (FLC) levels (absolute increase) must be >  mg/dL\r\n* Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas\r\n* Development of hypercalcemia (corrected serum calcium > . mg/dL) that can be attributed solely to the plasma cell proliferative disorder
Subjects must have measurable disease on study entry, which must include at least  of the following:\r\n* Serum M-spike >= . g/dL\r\n*  hr urine M-spike >=  mg\r\n* Involved serum free light chain (FLC) >=  mg/L with abnormal ratio\r\n* Measurable plasmacytoma on exam or imaging\r\n* Bone marrow plasma cells >= % (bone marrow biopsy only required at screening if no other measurable disease is present)\r\n** Note: patients with immunoglobulin (Ig)A myeloma in whom serum protein electrophoresis is deemed unreliable, due to co-migration of normal serum proteins with the paraprotein in the beta region, may be considered eligible as long as total serum IgA level is elevated above normal range
Subjects must have documented multiple myeloma as defined by the criteria below:\r\n* Clonal bone marrow plasma cells >= % or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following calcium, renal failure, anemia, bone lesions (CRAB) features and myeloma-defining events (MDEs)\r\n* Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:\r\n** Hypercalcemia: serum calcium > . mmol/L (>  mg/dL) higher than the upper limit of normal or > . mmol/L (>  mg/dL)\r\n** Renal insufficiency: creatinine clearance <  mL per minute or serum creatinine >  umol/L (>  mg/dL)\r\n** Anemia: hemoglobin value of >  g/L below the lowest limit of normal, or a hemoglobin value <  g/L\r\n** Bone lesions: one or more osteolytic lesion on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)/CT\r\n* Any one or more of the following biomarkers of malignancy (MDEs)\r\n** % or greater clonal plasma cells on bone marrow examination\r\n** Serum involved / uninvolved free light chain ratio of  or greater, provided the absolute level of the involved free light chain is at least  mg/L (a patients involved free light chain  either kappa or lambda  is the one that is above the normal reference range; the uninvolved light chain is the one that typically is in, or below, the normal range)\r\n** More than one focal lesion on magnetic resonance imaging (MRI) that is at least  mm or greater in size
Subjects must have disease that has relapsed and/or refractory after their most recent therapy, with progressive disease (PD) being defined as an increase of % from the lowest response value in any one or more of the following:\r\n* Serum M-component protein (the absolute increase must be >= . g/dL) and/or\r\n* Urine M-component protein (the absolute increase must be >=  mg/ hours) and/or\r\n* Only in subjects without a measurable serum and urine M protein level: the difference between involved and uninvolved free light chain (FLC) levels (absolute increase) must be >  mg/dL\r\n* Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas\r\n* Development of hypercalcemia (corrected serum calcium > . mg/dL) that can be attributed solely to the plasma cell proliferative disorder
Patient has confirmed SMM according to a definition derived from the International Myeloma Working Group (IMWG) definition (International Working Group, ): serum M-protein >=  g/dL or bone marrow plasma cells (BMPC) > %, or both, along with normal organ and marrow function (CRAB) within  weeks before baseline\r\n* C: absence of hypercalcemia, evidenced by a calcium < . mg/dL\r\n* R: absence of renal failure, evidenced by a creatinine < . mg/dL ( umol/L) or calculated creatinine clearance (using the Modification of Diet in Renal Disease [MDRD] formula) >  mL/min\r\n* A: absence of anemia, evidenced by a hemoglobin >  g/dL\r\n* B: absence of lytic bone lesions on standard skeletal survey
Criteria for cohort B (multiply relapsed multiple myeloma)\r\n* Must have measurable MM, as defined by: serum myeloma protein (M-protein) >=  g/dL, urine M-protein >=  mg/ hours, involved serum free light chain (FLC) level >=  mg/dL, biopsy proven plasmacytoma, or more than % bone marrow plasma cells\r\n* Must have received at least  different treatment regimens for MM
Participants must have a diagnosis of MM, according to International Myeloma Foundation  Diagnostic Criteria; according to these criteria, the following must be met:\r\n* Monoclonal plasma cells in the bone marrow >= % (or proven plasmocytic infiltration in bone marrow biopsy) and/or presence of a biopsy-proven plasmacytoma within  days of initiation of protocol therapy\r\n* Monoclonal protein (M-protein) present in the serum and/or urine\r\n* Myeloma-related organ dysfunction ( or more) of the following; a variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for therapy; Note: laboratory assessments used to support the calcium, kidney (renal) failure, anemia, bone lesions (CRAB) criteria in the International Myeloma Foundation (IMF)  Diagnostic Criteria of MM are performed at the time of diagnosis; these assessments are not required to be performed within the  days of initiation of protocol therapy\r\n** [C] Calcium elevation in the blood, defined as serum calcium > . mg/dl or upper limit of normal\r\n** [R] Renal insufficiency (defined as serum creatinine above normal)\r\n** [A] Anemia, defined as hemoglobin <  g/dl or  g < normal\r\n** [B] Lytic bone lesions or osteoporosis; if a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) are the sole defining criteria, then >= % plasma cells are required in the bone marrow or proven plasmocytic infiltration in bone/bone\r\n* Note: these criteria identify stage IB (if the creatinine is >  mg/dl at marrow biopsy presentation) and stages II and III A/B myeloma by Durie-Salmon stage; stage IA becomes smoldering or indolent myeloma
Patients diagnosed with symptomatic multiple myeloma based on International Myeloma Working Group (IMWG) diagnostic criteria; according to these criteria, patient must have monoclonal plasma cells in the bone marrow >= % and/or presence of a biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events:\r\n* Clonal bone marrow plasma cell percentage >= % (Note: clonality should be established by showing kappa/lambda-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence; bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate, the highest value should be used) \r\n* Involved: uninvolved serum free light chain ratio >=  (values are based on the serum Freelite assay); the involved free light chain must be >=  mg/dL\r\n* >  focal lesions on magnetic resonance imaging (MRI) studies (each focal lesion must be  mm or more in size) \r\n* (C) Calcium elevation in the blood, defined as serum calcium >  mg/dL or >  mg/dL higher than the upper limit of normal\r\n* (R) Renal insufficiency, defined as serum creatinine >  mg/dl or creatinine clearance <  mL/min\r\n* (A) Anemia, defined as hemoglobin <  g/dl or >  g/dl below the lower limit of normal\r\n* (B) Lytic bone lesions, one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)-CT (if bone marrow has less than % clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement)
Must meet criteria of high risk smoldering MM based on the criteria described below:\r\n* Definition of high-risk smoldering multiple myeloma (SMM):\r\n** Bone marrow clonal plasma cells >= % and =< % and any one or more of the following:\r\n*** Serum monoclonal (M) protein >= . g/dL (IgA, IgG, IgM, or IgD)\r\n*** IgA SMM\r\n*** Immunoparesis with reduction of two uninvolved immunoglobulin isotypes\r\n*** Serum involved/uninvolved free light chain ratio >=  (but less than )\r\n**** Free light chain smoldering myeloma patients are not excluded\r\n*** Progressive increase in M protein level (evolving type of SMM)\r\n**** Increase in serum monoclonal protein by >= % on two successive evaluations within a  month period\r\n*** Bone marrow clonal plasma cells -%\r\n*** Abnormal plasma cell immunophenotype (>= % of bone marrow plasma cells are clonal) and reduction of one or more uninvolved immunoglobulin isotypes\r\n*** t (;) or del p or q gain\r\n*** Increased circulating plasma cells\r\n*** Magnetic resonance imaging (MRI) with diffuse abnormalities or  focal lesion\r\n*** Positron emission tomography (PET)-computed tomography (CT) with one focal lesion with increased uptake without underlying osteolytic bone destruction\r\n*** Urine monoclonal light chain excretion >=  mg/ hours
No evidence of increased calcium levels, renal insufficiency, anemia or bone lesions (CRAB criteria) or new criteria of active MM which including the following:\r\n* Increased calcium levels (corrected serum calcium > . mmol/dL [> mg/dL] above the upper limit of normal or > . mmol/dL [mg/dL]) related to MM\r\n* Renal insufficiency (attributable to MM)\r\n** Participants with creatinine levels =< . mg/dL not attributable to myeloma are eligible\r\n* Anemia (hemoglobin [Hb]  g/dL below the lower limit of normal or <  g/dL) related to MM\r\n* Bone lesions (lytic lesions or generalized osteoporosis with compression fractures)\r\n* Bone marrow plasma cells >= %\r\n* Serum involved/uninvolved free light chain (FLC) ratio >= , provided the absolute level of the involved free light chain is at least  mg/L and repeated twice (light chain smoldering myeloma is not an exclusion criteria)\r\n* MRI with two or more focal lesions that are at least  mm or greater in size\r\n* Participants with CRAB criteria that are attributable to conditions other than the disease under study may be eligible
Adult patients with intermediate or high-risk smoldering multiple myeloma (SMM) are eligible; patients need to have clonal bone marrow plasma cells >= % and/or monoclonal spike in blood of >=  g/dL and/or monoclonal urine component (Bence jones proteinuria) >=  mg/ hours and need to meet subject inclusion criteria and exclusion criteria as per below
Evidence of myeloma defining events or biomarkers of malignancy due to underlying plasma cell proliferative disorder meeting at least one of the following\r\n* ) Hypercalcemia: serum calcium > . mmol/L (>  mg/dL) higher than the upper limit of normal or > . mmol/L (>  mg/dL)\r\n* ) Renal insufficiency: creatinine clearance <  ml/min or serum creatinine >  mg/dL\r\n* ) Anemia: hemoglobin value <  g/dL or  g/dL < normal reference\r\n* ) Bone lesions: one or more osteolytic lesions on skeletal radiography, computerized tomography (CT) or -deoxy-[F-] fluoro-D-glucose positron emission tomography CT (PET-CT)\r\n* ) Clonal bone marrow plasma cell percentage >= %\r\n* ) Involved: uninvolved serum free light chain ratio >=  measured by Freelite assay (The Binding Site Group, Birmingham, United Kingdom [UK])\r\n* ) >  focal lesions on magnetic resonance imaging (MRI) studies (each focal lesion must be  mm or more in size), if clinically indicated
One or more of the following biomarkers of malignancy:\r\n* Clonal bone marrow plasma cell percentage >= %\r\n* Involved: uninvolved serum free light chain ratio >= \r\n* >  focal lesions on magnetic resonance imaging (MRI) studies
Participants must have a diagnosis of multiple myeloma (MM) according Revised International Myeloma Working Group diagnostic criteria, which require the following findings,\r\n* Clonal bone marrow plasma cells >= % or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events:\r\n** End organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:\r\n*** Hypercalcemia: serum calcium > . mmol/L (>  mg/dL) higher than the upper limit of normal or > . mmol/L (>  mg/dL)\r\n*** Renal insufficiency: creatinine clearance <  mL per min or serum creatinine >  umol/L (>  mg/dL)\r\n*** Anemia: hemoglobin value of >  g/L below the lower limit of normal, or a hemoglobin value <  g/L\r\n*** Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)-CT\r\n** One or more of the following biomarkers of malignancy:\r\n*** Clonal bone marrow plasma cell percentage >= %\r\n*** Involved: uninvolved serum free light chain ratio >= \r\n*** >  focal lesions on magnetic resonance imaging (MRI) studies
Must meet criteria of high risk smoldering MM as described with one of the below criteria:\r\n* Bone marrow clonal plasma cells >= % and any one or more of the following: \r\n** Serum M protein >= . g/dL \r\n** Immunoglobulin A (IgA) smoldering multiple myeloma (SMM)\r\n** Immunoparesis with reduction of two uninvolved immunoglobulin isotypes\r\n** Serum involved/uninvolved free light chain ratio >=  (but less than )\r\n*** Free light chain smoldering myeloma patients are not excluded\r\n** Progressive increase in M protein level (evolving type of SMM)\r\n** Bone marrow clonal plasma cells -%\r\n** Abnormal plasma cell immunophenotype (>= % of bone marrow plasma cells are clonal) and reduction of one or more uninvolved immunoglobulin isotypes\r\n*** All patients should have four or six color flow cytometry performed on the baseline bone marrow sample, as feasible; patients evaluated for eligibility by Spanish Criteria must have their result confirmed by four color flow cytometry; if four or six color flow cytometry is not available at the site, the baseline bone marrow must be sent to Dana-Farber Cancer Institute to confirm eligibility prior to enrollment\r\n** t (;) or del p or q gain\r\n** Increased circulating plasma cells\r\n** Magnetic resonance imaging (MRI) with diffuse abnormalities or  focal lesion (>=  mm)\r\n** Positron emission tomography (PET)-computed tomography (CT) with one focal lesion (>=  mm) with increased uptake without underlying osteolytic bone destruction\r\n*** Increase in serum monoclonal protein by >= % on two successive evaluations within a  month period
No evidence of Calcium, Renal, Anemia, and Bone (CRAB) criteria or new criteria of active MM which including the following:\r\n* Increased calcium levels: corrected serum calcium > . mmol/L (>  mg/dL) above the upper limit of normal or > . mmol/L (>  mg/dL)\r\n* Renal insufficiency (attributable to myeloma)\r\n* Anemia (hemoglobin [Hgb]  g/dL below the lower limit of normal or <  g/dL)\r\n* Bone lesions (lytic lesions or generalized osteoporosis with compression fractures)\r\n* No evidence of the following new criteria for active MM including the following:\r\n** Bone marrow plasma cells > %, serum involved/uninvolved free light-chain (FLC) ratio >= , and MRI with more than one focal lesion\r\n* Participants with CRAB criteria that are attributable to conditions other than the disease under study may be eligible
Participant must have documented multiple myeloma satisfying the calcium elevation, renal insufficiency, anemia, and bone abnormalities (CRAB) diagnostic criteria, monoclonal plasma cells in the bone marrow greater than or equal to  percent (%) or presence of a biopsy proven plasmacytoma, and measurable secretory disease, as assessed by the central laboratory, and defined in protocol
Multiple Myeloma according to the International Myeloma Working Group definition () i.e.: clonal bone marrow plasma cells >= % or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events and/or one or more of the biomarkers for malignancy at the time of diagnosis:\r\n* Myeloma defining events:\r\n** Hypercalcemia: serum calcium > . mmol/L (>  mg/dL) higher than the upper limit of normal or > . mmol/L (>  mg/dL)\r\n** Renal insufficiency: creatinine clearance <  mL per minimum (min) or serum creatinine >  umol/L (>  mg/dL)\r\n** Anemia: hemoglobin value of >  g/L below the lower limit of normal, or a hemoglobin value <  g/L\r\n** Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)-CT\r\n* Biomarkers of malignancy:\r\n** Clonal bone marrow plasma cell percentage >= %\r\n** Involved: uninvolved serum free light chain ratio >= \r\n** >  focal lesions on magnetic resonance imaging (MRI) studies
Evidence of underlying end organ damage and/or myeloma defining event attributed to underlying plasma cell proliferative disorder meeting at least one of the following:\r\n* Hypercalcemia: serum calcium > . mmol/L (>  mg/dL) above upper limit of normal or >= . mmol/L ( mg/dL)\r\n* Anemia: hemoglobin value <  g/dL or >  g/dL below lower limit of normal\r\n* Bone disease: >=  lytic lesions on skeletal X-ray, computed tomography (CT), or positron emission tomography (PET)-CT; for patients with  lytic lesion, bone marrow should demonstrate >= % clonal plasma cells\r\n* Clonal bone marrow plasma cell percentage >= %\r\n* Involved/un-involved serum free light chain ratio >=  and involved free light chain >  mg/L\r\n* >  focal lesion on magnetic resonance imaging study (lesion must be >  mm) in size
Clonal bone marrow plasma cells >= % or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events: \r\n* Myeloma defining events: \r\n** Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:\r\n*** Hypercalcaemia: serum calcium > . mmol/L (>  mg/dL) higher than the upper limit of normal or > . mmol/L (>  mg/dL) \r\n*** Renal insufficiency: creatinine clearance <  mL per min or serum creatinine >  mol/L (>  mg/dL)\r\n*** Anemia: hemoglobin value of >  g/L below the lower limit of normal, or a hemoglobin value <  g/L\r\n*** Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)-CT \r\n* Any one or more of the following biomarkers of malignancy: \r\n** Clonal bone marrow plasma cell percentage % \r\n** Involved:uninvolved serum free light chain ratio  >  focal lesions on magnetic resonance imaging (MRI) studies\r\n* If bone marrow has less than % clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement
Relapsed/refractory MM with failure to at least two lines of MM treatment which must include at least one IMiD (thalidomide, lenalidomide) and proteosome inhibitor (bortezomib) and measurable levels of myeloma paraprotein in serum ( >/= . g/dl), urine ( >/= . g excreted in a -hour collection sample), or abnormal free light chain (FLC) ratio. Oligo or non secretory myeloma patients may be included, if there is measurable plasmacytosis in the bone marrow biopsy or measurable extramedullary disease.
Evidence of underlying end organ damage and/or myeloma defining event attributed to underlying plasma cell proliferative disorder meeting at least one of the following:\r\n* Hypercalcemia: serum calcium > . mmol/L (>  mg/dL) above upper limit of normal or >= . mmol/L ( mg/dL)\r\n* Anemia: hemoglobin value <  g/dL or >  g/dL below lower limit of normal\r\n* Bone disease: >=  lytic lesions on skeletal X-ray, computed tomography (CT) or positron emission tomography (PET)-CT; for patients with  lytic lesion, bone marrow should demonstrate >= % clonal plasma cells\r\n* Clonal bone marrow plasma cell percentage >= %\r\n* Involved/un-involved serum free light chain ratio >=  and involved free light chain > mg/L\r\n* >  focal lesion on magnetic resonance imaging study (lesion must be >  mm) in size
Myeloma relapsing from partial response or better\r\n* Patients relapsing >  months from transplant if not on maintenance, or\r\n* If off maintenance, discontinued at least  months ago, or\r\n* If relapsing on maintenance, at least  years from transplant, or\r\n* Off prior myeloma therapy at least  months ago\r\n* Sufficient tumor burden that is assessable for response\r\n** Serum M-spike >= . g/dL, or\r\n** If immunoglobulin A (IgA) myeloma, IgA >  mg/dL, or\r\n** Difference between involved and uninvolved free light chain (dFLC) >  mg/dL, or\r\n** Urine M-spike >=  mg/ hours, or\r\n** Bone marrow plasmacytosis >= %, or\r\n** Plasmacytoma >=  cm in diameter
Patients with relapsed or progressive multiple myeloma (progressive disease), defined as a  percent increase from the lowest response value in ANY of the following:\r\n* Serum M-protein (absolute increase >= . g/dL)\r\n* Urine M-protein (absolute increase of >=  mg/ hours)\r\n* Bone marrow plasma cell percentage (at least  percent absolute increase) in patients who lack measurable M protein levels\r\n* Difference in the kappa and lambda free light chain (FLC) levels (FLC ratio must be abnormal and absolute change must be >  mg/dL)
Patients must have a history of symptomatic multiple myeloma according to the International Myeloma Working Group criteria (IMWG, ), as defined as the following three criteria:\r\n* Clonal plasma cells > % on bone marrow biopsy\r\n* A monoclonal protein (paraprotein) in either serum or urine (except in cases of non-secretory myeloma)\r\n* Evidence of end-organ damage felt related to the plasma cell disorder (related organ or tissue impairment, ROTI, commonly referred to by the acronym \calcium, renal failure, anemia, and bone lesions [CRAB]\):\r\n* Hypercalcemia serum calcium (Ca) >= . mg/dL or\r\n* Renal insufficiency attributable to myeloma; serum creatinine > mg/dL\r\n* Anemia: Normochromic, normocytic with a hemoglobin value > g/dL below the lower limit of normal or a hemoglobin <  g/dL\r\n* Bone lesions (lytic lesions, severe osteopenia or pathologic fractures)
Participants must have confirmed high-risk monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM) as defined below:\r\n* MGUS\r\n** Serum monoclonal protein level <  g/dL but > . g/dl\r\n** Non-immunoglobulin (Ig)G MGUS (i.e. IgA, IgM, IgD MGUS)\r\n** Abnormal serum free light chain ratio (i.e. ratio of kappa to lambda free light chains < . or > .)\r\n* SMM (also referred to as asymptomatic multiple myeloma)\r\n** Serum monoclonal protein (IgG or IgA) level >=  g/dL,\r\n** And/or bone marrow plasma cells >= %\r\n** Absence of end-organ damage, such as lytic bone lesions, anemia, hypercalcemia, or renal failure, that can be attributed to a plasma cell proliferative disorder
Diagnosis of any stage of multiple myeloma based on standard criteria as follows:\r\n* Major criteria\r\n. Plasmacytomas on tissue biopsy\r\n. Bone marrow plasmacytosis (> % plasma cells)\r\n. Monoclonal immunoglobulin spike on serum electrophoresis (immunoglobulin G [IgG] > . G/dL or immunoglobulin A [IgA] > . G/dL) or kappa or lambda light chain excretion >  G/day on  hour urine protein electrophoresis\r\n* Minor criteria\r\na. Bone marrow plasmacytosis ( to % plasma cells)\r\nb. Monoclonal immunoglobulin present but of lesser magnitude than given under major criteria\r\nc. Lytic bone lesions\r\nd. Normal immunoglobulin M (IgM) <  mg/dL, IgA <  mg/dL, or IgG <  mg/dL\r\n* Any of the following sets of criteria will confirm the diagnosis of multiple myeloma:\r\n** Any two of the major criteria\r\n** Major criterion  plus minor criterion b, c, or d\r\n** Major criterion  plus minor criterion a or c\r\n** Minor criteria a, b and c or a, b and d