Tremendous progress has been made in the treatment of patients with multiple myeloma (MM) over the past 2 decades. The 5-year relative survival ratio increased from 26.3% in 1975 to 45.1% in 2006, when only 3 drugs were approved for the treatment of MM. The arsenal of drugs approved by the FDA has now expanded to include thalidomide, lenalidomide, bortezomib, doxorubicin, carfilzomib, and pomalidomide.
“We have more treatment options, leading to more [treatment] heterogeneity,” said Ajay K. Nooka, MD, MPH, assistant professor of hematology and medical oncology, Winship Cancer Institute of Emory University, Atlanta, GA. “There is no consensus amongst us about what is optimal induction therapy and optimal salvage therapies.”
Although several molecular biomarkers are under development, genetic biomarkers are more acceptable for guiding therapy in MM. Chromosomal abnormalities
in MM are translocations involving 14q32: t(11;14), t(4;14), and t(14;16); chromosome 13 abnormalities: monosomy, del(13), 13q translocations; del(17p); and hyperdiploidy.
High-risk features include the presence or deletion of p53; deletion of 1p; immunoglobulin heavy chain translocations – t(4;14) or t(14;16) – by fluorescence in situ hybridization (FISH) or by metaphase cytogenetics; or presentation as plasma cell leukemia (?20% circulating plasma cells in peripheral blood).
A case report in high-risk MM was presented by Nooka at the Third Annual PMO Live Conference, a Global Biomarkers Consortium Initiative.
Case: Stage III MM
A 57-year-old Caucasian female diagnosed with stage III MM in October 2008 presents with back pain, fatigue, increasing shortness of breath, chest pain, and progressive anemia for 1 year. Her presenting laboratory values are as follows: total protein, 7.4 g/dL; protein, 2.1 g/dL (IgG kappa); ?2-microglobulin, 19.9; free kappa, 1407 mg/L; free lambda, 9 mg/L; ratio, 145; IgG, 3195 mg/dL; IgA, <40 mg/dL; IgM, <35 mg/dL; hemoglobin, 5.4; hematocrit, 16; platelet count, 241; creatinine, 1.8 mg/dL; calcium, 9.2 mg/dL.
A bone marrow biopsy showed 90% cellularity with 22% plasma cells. FISH revealed del(17p) in 43 of the 50 cells.
An MRI of the spine revealed a compression fracture at L5. The patient underwent kyphoplasty and then initiated induction therapy with lenalidomide, bortezomib, and dexamethasone (RVD).
Treatment
Although improvements in progression-free survival (PFS) and overall survival (OS) have been realized across all stratifications of patients with MM, progress has been less impressive among high-risk patients with del(17p), said Nooka. These patients have a PFS of close to 1 year and a median OS of 18 to 24 months.
The case patient is young with a high tumor burden and is transplant eligible, and the consensus is to treat with a combination of immunomodulatory therapy and proteasome inhibitor therapy. Obtaining a response with bortezomib-containing induction regimens is relatively easy, said Nooka, but the challenge is to maintain a response among high-risk patients such as this one.
Intense Maintenance
After induction with 4 cycles of RVD, a stringent complete response (sCR) is obtained in nearly 20%. After autologous stem cell transplant, the rate of CR plus sCR improves to about 40%. A consolidation/maintenance approach to treatment to continuously suppress malignant clones has been evaluated in high-risk patients with MM. With initiation of RVD maintenance, 51% of patients achieved sCR, and 96% achieved at least a very good/partial response as best response (Leukemia. 2014;28:690-693). The RVD maintenance regimen translated into a median PFS of 30 months and a 3-year OS of 93% in patients with del(17p). The regimen was well tolerated with no grade 3/4 neuropathy.
“If we’re able to give an initial induction therapy with a combination of a proteasome inhibitor, an immunomodulatory drug, and steroids, give it early after transplant, and maintain the response with a maintenance regimen consisting of those 3 agents, we are able to deliver good response rates, and the safety is acceptable,” he said. “We’ve never had a patient who was not able to tolerate this maintenance regimen.”
He continued, “I would treat this patient with initial induction therapy with RVD for 4 cycles, early transplant, and an intense maintenance approach.”
The question then becomes: how long should the intense maintenance approach be continued? In the case patient, intense maintenance was continued for 3 years, followed by single-agent lenalidomide maintenance. The patient continues to do well.
While on RVD maintenance (and single-agent lenalidomide), continuation of bisphosphonates, thromboprophylaxis, and prophylactic acyclovir is advised.
