CTD, Cyclophosphamide, thalidomide, and dexamethasone dex, dexamethasone; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TAD, thalidomide, adriamycin, and dexamethasone; Thal, thalidomide; TTP, time to progression.

Table 38-2 Lenalidomide Regimens in Relapsed or Refractory Multiple Myeloma

CRD, Carfilzomib, lenalidomide, dexamethasone; NR, not reported; ORR, overall response rate; OS, overall survival; RAD, lenalidomide, adriamycin, dexamethasone; TTP, time to progression; VRD, bortezomib, lenalidomide, dexamethasone.

Table 38-3 Bortezomib Regimens in Relapsed or Refractory Multiple Myeloma

ORR, Overall response rate; OS, overall survival; PFS, progression-free survival; PLD, Liposomal doxorubicin; TTP, time to progression; VMPT, bortezomib, melphalan, prednisone, thalidomide.

Treatment of Newly Diagnosed Multiple Myeloma

Confirm that the patient has symptomatic myeloma. Patients with MGUS or SMM should not be treated outside of a clinical trial.

Perform risk stratification using ISS staging, FISH, or cytogenetics, and assessment of renal function and measurement of LDH level to develop long-term plan based on estimate of prognosis. Although initial treatment is not affected by risk category, later consideration of more aggressive consolidation or use of allogeneic SCT in eligible patients can be considered in high-risk younger patients.

Induction: Both transplant-eligible and ineligible patients can be treated with a triple-drug regimen (bortezomib and dexamethasone with lenalidomide, with thalidomide or cyclophosphamide, or cyclophosphamide, thalidomide, dexamethasone) for 3 to 6 cycles before transplant or 9 to 12 months for transplant-ineligible patients. For transplant-ineligible patients, additional options include a two-drug regimen (dexamethasone with lenalidomide, with bortezomib, or with thalidomide) or melphalan containing regimen such as melphalan with prednisone in combination with any of the newer agents, MPT, MPV, or MPR.

Drug Selection should be influenced depending on patient characteristics.

Renal dysfunction: agents that can be considered for use are bortezomib, cyclophosphamide, thalidomide, and dexamethasone (VCD or VTD)

Neuropathy: agents that can be considered for use are lenalidomide, cyclophosphamide, and dexamethasone

Advanced age: consider dose or scheduled attenuation

Convenience: use of oral vs. intravenous agent regimen

Transplant-eligible patients can undergo a single autologous transplant with melphalan with a second autologous transplant being optional depending on the overall response or on the protocol in which the patient is participating.

Maintenance: After transplant or optimal induction therapy (to best response), patients can receive maintenance with thalidomide, lenalidomide, or bortezomib. For high-risk patients, both bortezomib and lenalidomide or thalidomide combination can be used. Selection can be influenced based on their induction regimen.

Improving complete response rates is a key goal of current trials, but patients can live a long time with residual paraprotein.

FISH, Fluorescent in situ hybridization; ISS, International Staging System; LDH, lactate dehydrogenase; MGUS, monoclonal gammopathy of unknown significance; MPR, melphalan, prednisone, lenalidomide; MPT, melphalan, prednisone, thalidomide; MPV, melphalan, prednisone, bortezomib; SCT, stem cell transplantation; VCD, bortezomib, cyclophosphamide, dexamethasone; VTD, bortezomib, thalidomide, dexamethasone.

Figure 38-1 A, Multiple myeloma (MM) average annual age- and gender-specific incidence per 100,000 population in the United States in 2009. B, MM average annual race-specific incidence per 100,000 population in the United States in 2009. An increase in incidence is noted with advancing age, men are affected more than women, and a higher incidence is observed in blacks than whites.

Figure 38-2 MORPHOLOGIC SPECTRUM OF NEOPLASTIC PLASMA CELLS IN MULTIPLE MYELOMA.

There is significant morphologic heterogeneity in the plasma cells as seen on the bone marrow aspirate (A to E) and biopsy (F to J). The plasma cells can sometimes be fairly normal appearing (A and F); they can be “lymphocyte-like” and difficult to distinguish from lymphoplasmacytic lymphoma (B and G); they frequently can exhibit cytologic atypia with prominent nucleoli and nuclear to cytoplasmic dyssynchrony (C and H); they can exhibit anaplastic features (D and I), and they can show “blastic” features (E and J). Myeloma can also have a leukemic phase (K) and can be associated with osteosclerosis (L), as sometime seen in association with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes).

Figure 38-3 A and B, Typical skeletal changes on radiography. Example of “punched-out” lytic lesions in the skull and humerus. C to E, Magnetic resonance imaging pattern in multiple myeloma in the spine and pelvis showing diffuse involvement with focal lesions.

(Courtesy Dr. Nikhil Ramaiya, MD.)

Figure 38-4 International Staging System (ISS) predicts both event-free survival (A) and overall survival (B) and overall survival with both standard-dose therapy (SDT) (C) and high-dose therapy (HDT) (D).

(A and B from Avet-Loiseau H, Attal M, Moreau P, et al: Genetic abnormalities and survival in multiple myeloma: The experience of the Intergroupe Francophone du Myélome. Blood 109:3489, 2007; C and D from Greipp PR, San Miguel J, Durie BG, et al: International staging system for multiple myeloma. J Clin Oncol 23:3412, 2005.)

Figure 38-5 KAPLAN-MEIER ESTIMATES OF SURVIVAL ACCORDING TO THE INTERNATIONAL STAGING SYSTEM (ISS) STAGES AND t(4;14) OR del(17p).

Overall survival (in months). Blue lines indicate patients presenting t(4;14) or del(17p); red lines indicate those lacking the aberrations.

(From Avet-Loiseau H, Attal M, Moreau P, et al: Genetic abnormalities and survival in multiple myeloma: The experience of the Intergroupe Francophone du Myélome. Blood 109:3489, 2007.)

Table 38-4 Phenotypic Characterization of Plasma Cells

Adhesion Molecule	Normal Plasma Cells	Multiple Myeloma Cells
CD138	+	+
CD19	+	−
CD28	−	−
CD38	+	+
CD40	+	+
CD45	+	−*
CD27	−	+
CD11a	+	−
CD11b	−	−
CD44	+	+
CD54	+	+
CD56	−	+
CD58	−	+
LFA-1	−	−/+
RHAMM	−	+
VLA-4	+	+
VLA-5	+	+

RHAMM, Hyaluronan-mediated motility receptor; VLA, very late antigen.

^*CD45 on immature myeloma cells.

Table 38-5 Clinical Features of Multiple Myeloma

Bone Destruction
Pain Fractures Spinal cord compression Radicular pain

Hypercalcemia

Renal Failure

Amyloidosis

Peripheral neuropathy

Dependant edema

Organomegaly

Bone Marrow Infiltration

Anemia

Bleeding tendency

Reduced Globulins

Cryoglobulins

Hyperviscosity

Transient ischemic attacks

Deep venous thrombosis

Retinal hemorrhage

Epistaxis

Table 38-6 Diagnostic Criteria for Multiple Myeloma, Myeloma Variants, and Monoclonal Gammopathy of Unknown Significance

Monoclonal Gammopathy of Undetermined Significance or Monoclonal Gammopathy, Unattributed/Unassociated
M protein in serum <30 g/L Bone marrow clonal plasma cells <10% No evidence of other B-cell proliferative disorders No myeloma related organ or tissue impairment (no end-organ damage, including bone lesions)
Asymptomatic Myeloma (Smoldering Myeloma)
M protein in serum >30 g/L or Bone marrow clonal plasma cell ≥10% No related organ or tissue impairment (no end-organ damage, including bone lesions) or symptoms
Symptomatic Multiple Myeloma
M protein in serum or urine * Bone marrow (clonal) plasma cells * or plasmacytoma Related organ or tissue impairment (end-organ damage, including bone lesions)
Solitary Plasmacytoma of Bone
No M protein in serum or urine ^† Single area of bone destruction caused by clonal plasma cells Bone marrow not consistent with MM Normal skeletal survey (and MRI of spine and pelvis if done) No related organ or tissue impairment (no end-organ damage other than solitary bone lesion)^†
Nonsecretory Myeloma
No M protein in serum or urine with immunofixation Bone marrow clonal plasmacytosis ≥10% or plasmacytoma Related organ or tissue impairment (end-organ damage, including bone lesions)
Extramedullary Plasmacytoma
No M protein in serum or urine ^† Extramedullary tumor of clonal plasma cells Normal bone marrow Normal skeletal survey No related organ or tissue impairment (end organ-damage including bone lesions)
Multiple Solitary Plasmacytomas (± Recurrent)
No M protein in serum or urine ^† More than one localized area of bone destruction or extramedullary tumor of clonal plasma cells, which may be recurrent Normal bone marrow Normal skeletal survey and MRI of spine and pelvis if done No related organ or tissue impairment (no end-organ damage other than the localized bone lesions)
Myeloma-Related Organ or Tissue Impairment (End-Organ Damage)
Calcium levels increased: serum calcium >0-25 mmol/L above the upper limit of normal or >2-75 mmol/L Renal insufficiency: creatinine >173 mmol/L Anemia: hemoglobin 2 g/dL below the lower limit of normal or hemoglobin <10 g/dL Bone lesions: lytic lesions or osteoporosis with compression fractures (MRI or CT may clarify) Other: symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (more than two episodes in 12 months)

CT, Computed tomography; MM, multiple myeloma; MRI, magnetic resonance imaging.

^*If flow cytometry is performed, most plasma cells (>90%) will show a neoplastic phenotype.

^†A small M component may sometimes be present.

Table 38-7 Imaging Modalities for Disease Assessment in Myeloma

CT, Computed tomography; MM, multiple myeloma; MRI, magnetic resonance imaging; PET, positron emission tomography.

Table 38-8 Risk Stratification in Multiple Myeloma

Investigation Recommended for Risk Stratification
Serum albumin and β₂-microglobulin to determine ISS stage BM examination for t(4;14); t(14;16) and del(17p) on identified PC by FISH LDH Immunoglobulin type: IgA Histology: plasmablastic disease or plasma cell leukemia
Additional Investigation for Risk Stratification
Cytogenetics Gene expression profiling Labeling index MRI or PET DNA copy number alteration by CGH/SNP array

BM, Bone marrow; CGH, comparative genomic hydridization; FISH, fluorescent in situ hybridization; ISS, International Staging System; MRI, magnetic resonance imaging; PC, plasma cells; PET, spositron emission tomography; SNP, single nucleotide polymorphism.

Table 38-9 International Staging System of Multiple Myeloma Patients

Stage	Criteria	Median Survival (mo)
I	Serum β₂ microglobulin <3.5 mg/L	62
	Serum albumin ≥3.5 g/dL
II*	Not stage I or III	44
III	Serum β₂ microglobulin ≥5.5 mg/L	29

^*There are two categories for stage II: serum β₂ microglobulin <3.5 mg/L but serum albumin <3.5 g/dL; or serum β₂-microglobulin 3.5 to <5.5 mg/L irrespective of the serum albumin level.

Data from Greipp PR, San Miguel J, Durie BG, et al: International staging system for multiple myeloma. J Clin Oncol 23:3412, 2005.

Table 38-10 Evaluation of Multiple Myeloma Patients

Evaluation for Diagnosis Evaluation for Monoclonal Protein
Serum protein electrophoresis, immunofixation Quantitative immunoglobulin by nephelometric method 24-hour urine collection for electrophoresis and Bence Jones protein assessment and immunofixation Serum-free light chain and ratio
Evaluation for Clonal Plasma Cells
BM aspirate and biopsy for Histology Clonality by immunostaining or flow cytometry by κ/λ staining Fine-needle aspiration of plasmacytoma if indicated Evaluation for end-organ damage Hemogram to detect anemia Chemistry panel for renal function and calcium Radiologic evaluation: skeletal survey MRI as indicated for confirmation Evaluation for risk stratification β₂-microglobulin and serum albumin for ISS stage Cytogenetics and FISH on BM sample LDH CRP
Other Investigations for Selected Patients
Abdominal fat pad or rectal biopsy for amyloid Solitary lytic lesion biopsy Serum viscosity if IgM component or high IgA levels or serum M-component >7 g/dL Immunofixation for IgD or IgE in select cases

BM, Bone marrow; CRP, C-reactive protein; FISH, fluorescent in situ hybridization; Ig, immunoglobulin; ISS, International Staging System; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging.

Table 38-11 Lenalidomide Regimens in Newly Diagnosed Multiple Myeloma

BiRD, Biaxin, lenalidomide, dexamethasone; ORR, overall response rate; PFS, progression-free survival; Rd, lenalidomide, low-dose dexamethasone; RD, lenalidomide, high-dose dexamethasone; SCT, stem cell transplantation.

Table 38-12 Bortezomib Regimens in Newly Diagnosed Multiple Myeloma

MP, Melphalan and prednisone; NA, not applicable; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; SCT, stem cell transplantation; TTP, time to progression; VAD, vincristine, dexamethasone, and Adriamycin.

Table 38-13 Single Versus Double ASCT for Newly Diagnosed Multiple Myeloma

ASCT, Autologous stem cell transplant; CR, complete remission; EFS, event-free survival; NS, not significant; OS, overall survival; SCT, stem cell transplantation.

* Complete remission + minimum residual disease.

† Complete remission + very good partial response.

Table 38-14 Studies of Myeloablative and Reduced Intensity Allogeneic Stem Cell Transplantation for Newly Diagnosed Myeloma

CR, Complete remission; DFS, disease-free survival; EFS, event-free survival; NR, not reported; OS, overall survival; PFS, progression-free survival; TRM, treatment-related mortality.

* T-cell depleted.

References

1 Barlogie B, Desikan R, Eddlemon P, et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: Identification of prognostic factors in a phase 2 study of 169 patients. Blood. 2001;98:492.

2 Yakoub-Agha I, Mary J, Hulin C, et al. Low-dose vs. high-dose thalidomide for advanced multiple myeloma: A prospective trial from the Intergroupe Francophone du Myélome. Eur J Haemato. 2012;l88:249.

3 Neben K, Moehler T, Benner A, et al. Dose-dependent effect of thalidomide on overall survival in relapsed multiple myeloma. Clin Cancer Res. 2002;8:3377.

4 Palumbo A, Bertola A, Falco P, et al. Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma. Hematol J. 2004;5:318.

5 Dimopoulos MA, Zervas K, Kouvatseas G, et al. Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol. 2001;12:991.

6 Kyriakou C, Thomson K, D’Sa S, et al. Low-dose thalidomide incombination with oral weekly cyclophosphamide and pulsed dexamethasoneis a well tolerated and effective regimen in patients with relapsed and refractory multiple myeloma. Br J Haematol. 2005;129:763.

7 García-Sanz R, González-Porras JR, Hernández JM, et al. The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma. Leukemia. 2004;18:856.

8 Offidani M, Corvatta L, Marconi M, et al. Low-dose thalidomide with pegylated liposomal doxorubicin and high-dose dexamethasone for relapsed/refractory multiple myeloma: A prospective, multicenter, phase II study. Haematologica. 2006;91:133.

9 Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133.

10 Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123.