Tumor Board Multiple Myeloma

Ranjita Pallavi, MDMedicine Department

Patient Course at Bellevue

Patient presented with obstructive jaundice at an outside hospital. ERCP was done and biopsy taken from ampulla of vater mass was consistent with Plasmacytoma. Also pancreatic mass was noted on CT but no biopsy could be taken secondary to friability of the mass. Multiple myeloma diagnosis was made based on SPEP, FLCA, Bone Marrow Exam and Bone Survey and plan was to start on Bortezomib and Lenalidomide which was changed to Bortezomib and Cyclophosphamide secondary to renal failure. She got 2 cycles and patient was then transferred to Metropolitan due to the storm and off chemotherapy, with a prior diagnosis of sepsis.

• Multiple myeloma is a neoplastic plasma-cell disorder that is characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment, monoclonal protein in the blood or urine, and associated organ dysfunction.

• It accounts for approximately 1% of neoplastic diseases and 13% of hematologic cancers.

• In Western countries, the annual age-adjusted incidence is 5.6 cases per 100,000 persons.

• It is estimated that 21,700 men and women (12,190 men and 9,510 women) will be diagnosed with and 10,710 men and women will die of myeloma in 2012.

• Median age at diagnosis is approximately 70 years.• In recent years, the introduction of autologous stem-cell transplantation and

the availability of agents such as thalidomide, lenalidomide, and bortezomib have changed the management of myeloma and extended overall survival.

• In patients presenting at an age under 60 years, 10-year survival is approximately 30%.

• .

Introduction

N Engl J Med 2011; 364:1046-1060 March 17,2011

Multistep Pathogenesis of Multiple Myeloma

N Engl J Med 2011; 364:1046-1060 March 17,2011

Diagnostic Criteria for Plasma-Cell Disorders

Disorder Disease definition

Monoclonal gammopathy ofundeterminedsignificance (MGUS)

All three criteria must be met Serum monoclonal protein <3 g/dL Clonal bone marrow plasma cells <10%, and Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) that can be attributed to the plasma cell-proliferative disorder; or in the case of IgM MGUS no evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder

Smoldering multiple myeloma(also referred to asasymptomatic multiplemyeloma)

Both criteria must be met Serum monoclonal protein (IgG or IgA) 3 g/dL and/or clonal bone marrow plasma cells 10% and 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

Multiple myeloma

All three criteria must be met Clonal bone marrow plasma cells 10% or biopsy proven plasmacytoma Presence of serum and/or urinary monoclonal protein (except in patients with true nonsecretory multiple myeloma) and Evidence of end organ damage that can be attributed to the underlying plasma-cell proliferative disorder, specifically Hypercalcemia: serum calcium 11.5 mg/dL or Renal insufficiency: serum creatinine > 1.73 mmol/L (or >2 mg/dL) or estimated creatinine clearance less than 40 mL/min Anemia: normochromic, normocytic with a hemoglobin value of >2 g/dL below the lower limit of normal or a hemoglobin value <10 g/dLBone lesions: lytic lesions, severe osteopenia, or pathologic fractures

Extramedullary Plasmacytoma

• ~3% of plasma cell neoplasms• Isolated plasma cell tumors of soft tissues

– Upper respiratory tract common, GI involvement rare

• Uninvolved marrow, negative skeletal survey• M-protein present ~25% cases

– Disappears following treatment• Curable with local radiation therapy

Multiple Myeloma Staging

Risk-Stratification of Myeloma

Standard-risk• Hyperdiploidy• t (11;14)• t (6;14)Intermediate-risk• t (4;14)• Deletion 13 or hypodiploidy by conventional karyotypingHigh-risk• 17p deletion• t (14;16)• t (14;20)• High-risk gene expression profiling signature

Initial Diagnostic Workup

Serum Free Light Chain Assays• Free light chains circulate in blood at abnormally high levels

in: >90% of multiple myeloma >66% of non secretory myeloma• They measure levels of free kappa and lambda light chains in

blood• Involved and Uninvolved Free Light chain ratio: determines

tumor burden• Kappa producing disease: ratio > 1.65• Lambda producing disease: ratio < 0.26• Kappa Light Chain disease worse prognosis than Lambda

Primary Treatment and Surveillance

Primary Treatment and Surveillance

Autologous Hematopoietic Stem-Cell Transplantation for Multiple Myeloma-Eligibility Criteria

• Recommended for patients with active myeloma who are relatively young and do not have serious coexisting illnesses.

• In Europe, transplantation is generally considered only in patients 65 years of age or younger, whereas in the United States, a formal age limit is not imposed.

• Free of significant renal dysfunction (usually with a creatinine level of <2.3 mg per deciliter [203 μmol per liter]).

• Other coexisting illnesses of concern include serious cardiac, hepatic, neurologic, or pulmonary disease.

• Good functional status - (a performance status of less than grade 2, according to the Eastern Cooperative Oncology Group scale)

June 18, 2009 Harousseau J.-L. and Moreau P.N Engl J Med 2009; 360:2645-2654

Suggested Approach to the Treatment of Newly Diagnosed Multiple Myeloma

n engl j med 364;11 nejm.org march 17, 2011

Cyclophosphamide, bortezomib and dexamethasone (CyBorD) induction for newly diagnosed multiple myeloma: High response rates in a phase II clinical trial

• Mean 80% decline in the sentinel monoclonal protein at the end of two cycles.• The overall intent to treat response rate (≥ partial response) was 88% with 61% ≥VGPR and

39% CR/nCR. • For the 28 patients ( total 33) that completed all 4 cycles of therapy the CR/nCR rate was 46%

and ≥VGPR rate 71%. • All patients undergoing stem cell harvest had a successful collection.• Twenty three patients underwent SCT and are evaluable through day 100 with CR/nCR

documented in 70% and ≥VGPR in 74%. • In conclusion, CyBorD produces a rapid and profound response in patients with newly

diagnosed multiple myeloma with manageable toxicity and adequate stem cells can be collected from all patients using G-CSF alone or G-CSF plus cyclophosphamide allowing patients to undergo SCT.

Leukemia. 2009 July; 23(7): 1337–1341.

ConclusionsMPR-R significantly prolonged progression-free survival in patients with newly diagnosed multiple myeloma who were ineligible for transplantation, with the greatest benefit observed in patients 65 to 75 years of age.

Myeloma Therapy

Mechanism of action-Bortezomib/Thalidomide

N Engl J Med 2004;351:1860-73.

Novel Drugs

Treatment and Surveillance

Additional Treatment

Additional Treatment

Salvage Therapy for Relapsed/Refractory Myeloma

A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma.

• 95% were refractory to their last therapy; 80% were refractory or intolerant to both bortezomib and lenalidomide.

• Patients had median of 5 prior lines of therapy, including bortezomib, lenalidomide, and thalidomide. • Overall response rate was 23.7% with median duration of response of 7.8 months.• Median overall survival was 15.6 months.• Common AEs were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Thirty-three

patients (12.4%) experienced peripheral neuropathy, primarily grades 1 or 2. • Carfilzomib can be safely administered in patients with renal failure and adverse cytogenetics do not seem

to interfere with its activity.

Blood. 2012 Oct 4;120(14):2817-25. doi: 10.1182/blood-2012-05-425934. Epub 2012 Jul 25

Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory

disease

Blood.2011 Sep 15;118(11):2970-5. Epub 2011 Jun 20

Response criteria for multiple myeloma

Response criteria for multiple myeloma

Adjunctive Treatment