Multiple myeloma: 2013 update on diagnosis, risk-stratification, and management S. Vincent Rajkumar Am. J. Hematol. 88:226–235, R4 신재령

Introduction Multiple myeloma Disease Overview Diagnostic criteria for plasma cell disorders Multiple myeloma ▫Risk-Stratification ▫Options for initial treatment in patients eligible for ASCT / not eligible for ASCT ▫Role of hematopoietic stem cell transplantation ▫Post-transplant maintenance therapy ▫Treatment of relapsed multiple myeloma

Disease Overview 1% of all cancers and approximately 10% of all hematologic malignancies Each year over 20,000 new cases are diagnosed in the US The annual age-adjusted incidence in the US has remained stable for decades at approximately four per 100,000 Slightly more common in men than in women, and is twice as common in African-Americans compared with Caucasians The median age of patients at the time of diagnosis is about 65 years

Bone disease is the main cause of morbidity Anemia, hypercalcemia, renal failure, and an increased risk of infections. Approximately 1–2% of patients have extramedullary disease (EMD) at the time of initial diagnosis, while 8% develop EMD later on in the disease course

Multiple myeloma The M protein is considered to be measurable if it is ≥ 1gm/dL in the serum and or ≥200 mg/day in the urine Approximately 2% of patients with multiple myeloma have true non-secretory disease and have no evidence of an M protein on any of the above studies Gene expression profiling (GEP) if available can provide additional prognostic value Serum CrossLaps to measure carboxy-terminal collagen crosslinks (CTX) may be useful in assessing bone turnover and to determine adequacy of bisphosphonate therapy

Risk-Stratification Staging of myeloma using the Durie-Salmon Staging (DSS) or the International Staging System (ISS) provides prognostic information but is not helpful in making therapeutic choices Median OS of 6-7 years Median OS of 2-3 years

Risk-Adapted Therapy OS in myeloma has improved significantly in the last decade with the emergence of thalidomide, bortezomib, and lenalidomide. Bortezomib ( VELCADE ® ) is a proteasome inhbitor The mechanism of action of thalidomide and lenalidomide is unclear, but they are considered immunomodulatory agents and may require cereblon (the putative primary teratogenic target for thalidomide) expression for their anti-myeloma activity

Options for initial treatment in patients eligible for ASCT ; Rd or VCD PBSCT Eligible Criteria 1)Diagnosed as multiple myeloma 2)Disease status needs chemotheraphy 3)No previous melphalan containing chemotherapy 4)Age <65 years 5)No serious medical problem for PBSCT

Options for initial treatment in patients eligible for ASCT In patients presenting with acute renal failure suspected to be secondary to light-chain cast nephropathy prefer VCD or VTD as initial therapy in conjunction with plasma exchange In patients presenting with plasma cell leukemia or multiple extramedullary plasmacytomas prefer VDT-PACE(bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) as initial therapy followed by ASCT and then maintenance with a bortezomib based regimen

Options for initial treatment in patients not eligible for ASCT The melphalan-based regimens are falling out of favor due to concerns about stem cell damage and secondary myelodysplastic syndrome and leukemia. In the United States transplant eligibility is not determined by a strict age cut-off, and many patients enrolled in the melphalan- based clinical trials would be considered candidates for ASCT. MPT > MP A meta-analysis. Leukemia 2011;25:689–696 Blood 2011;118:1239–1247. VMP > MP N Engl J Med 2008;359:906–917. J Clin Oncol 2010;28:2259–2266. MP may still have a role in elderly patients who do not have access to Rd in whom therapy with MPT or VMP is not considered safe or feasible

Options for initial treatment in patients not eligible for ASCT ; Rd or VCD

Role of hematopoietic stem cell transplantation Autologous SCT improves median OS in multiple myeloma by approximately 12 months Three randomized trials show that OS is similar whether ASCT is done early (immediately following four cycles of induction therapy) or delayed (at the time of relapse as salvage therapy) Two randomized trials have found benefit with tandem (double) versus single ASCT, with the benefit primarily seen in patients failing to achive CR or VGPR with the first ASCT Two other randomized trials, however, have yet to show significant improvement in OS with double ASCT

Role of hematopoietic stem cell transplantation The role of allogeneic and nonmyeloablative-allogeneic transplantation in myeloma is controversial The TRM (Treatment related mortality) 10–20% and high GVHD rates It may be a consideration for young patients with high-risk disease who are willing to accept a high TRM and the unproven nature of this therapy for a chance at better long-term survival

Post-transplant maintenance therapy It is not clear whether all patients should receive maintenance therapy post ASCT with either thalidomide or lenalidomide, along with the pros and cons of maintenance versus therapy at first relapse Observation alone for most patients post-transplant except standard-risk patients who fail to achieve VGPR after ASCT (candidates for lenalidomide maintenance) and those with intermediate or high-risk disease (candidates for bortezomib based Maintenance)

Treatment of relapsed multiple myeloma The median PFS and OS in patients with relapsed myeloma refractory to lenalidomide and bortezomib is poor, with median times of 5 months and 9 months, respectively Alkylators, corticosteroids, and thalidomide are all known options for therapy Bortezomib and lenalidomide based regimens Approximately one-third of patients with relapsed refractory myeloma respond to bortezomib when used as a single agent Bortezomib and the immunomodulatory drugs (thalidomide or lenalidomide) can be combined effectively with each other and with other chemotherapy drugs such as cyclophosphamide

Treatment of relapsed multiple myeloma Liposomal doxorubicin A Phase III randomized trial median TTP was superior with bortezomib plus pegylated liposomal doxorubicin (PLD) compared with bortezomib alone, 9.3 months versus 6.5 months respectively, P<0.001 OS at 15 months was also superior, 76% compared with 65%, respectively, P=0.03. J Clin Oncol 2007;25:3892–3901

Treatment of relapsed multiple myeloma Carfilzomib(Pomalyst ® ) is a novel keto-epoxide tetra-peptide proteasome inhbitor recently approved for the treatment of relapsed refractory myeloma in patients who have been previously treated with lenalidomide and bortezomib. In a Phase II study (PX A1), 266 patients were treated with single-agent carfilzomib, including 80% of patients who were refractory or intolerant to both bortezomib and lenalidomide The overall response rate was 24%, and the median duration of response was 7.8 months. The most common side effects were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Neuropathy was minimal. Blood 2012;120:2817–2825.

Treatment of relapsed multiple myeloma Pomalidomide has significant activity in relapsed refractory myeloma, even in patients failing lenalidomide Response rate in patients refractory to lenalidomide and bortezomib is approximately 30% Blood 2011;118:2970–2975. MLN-9708 is an oral proteasome inhibitor that has shown promise in both the relapsed refractory setting and in newly diagnosed myeloma. Histone deacetylase inhibitors (vorinostat and panabinostat) Human anti-CD38 monoclonal antibody (daratumumab) Anti CS-1 monoclonal antibody (elotuzumab)