Ask The Hematologist

S. Vincent Rajkumar, M.D.

Dr. Rajkumar is Associate Professor of Medicine and Consultant, Division of Hematology, Mayo Clinic.

A 45-YEAR-OLD MAN WITH NEWLY-DIAGNOSED MULTIPLE MYELOMA

This patient presented with back pain. Spine radiographs revealed compression fractures at multiple levels; lytic lesions were seen on the skull and right femur on skeletal survey. MRI of the spine showed a paraspinal mass at T8 causing minimal narrowing of the spinal canal but no cord compromise. Hemoglobin was 11.1 gm/dl, serum calcium 9.2 mg/dL, creatinine 1.1 mg/dL, and beta2 microglobulin 2.6 g/ml. Serum protein electrophoresis with immunofixation showed a monoclonal IgG kappa paraprotein measuring 5 g/dL. Bone marrow biopsy revealed 60 percent involvement by neoplastic plasma cells; plasma cell labeling index was 0.4 and no abnormalities were seen on karyotypic analysis.

HOW DOES ONE APPROACH A PATIENT WITH NEWLY-DIAGNOSED MULTIPLE MYELOMA?

I start by addressing four fundamental management issues: Does the patient need treatment? Is the patient a candidate for autologous stem cell transplantation? Is the patient a candidate for a clinical trial? Does the patient have high-risk prognostic features?

Does the patient need treatment?
I consider this question to ensure that the diagnosis is correct, and that patients with monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM) are not subjected to chemotherapy. Patients with MGUS and SMM do not have lytic lesions, renal failure, hypercalcemia, or anemia. The patient described clearly has active multiple myeloma, given the extensive bone lesions and anemia, and thus needs immediate treatment.

Is the patient a candidate for autologous stem cell transplantation (ASCT)?
The initial treatment of myeloma depends on the answer to this question because it is important to avoid prolonged alkylator-based therapy (such as melphalan) prior to stem cell harvest. Two randomized trials have shown that survival is prolonged by a median of about 18-24 months when ASCT is included in the treatment strategy. Although there are now three other randomized trials showing that delayed transplantation (done at relapse as salvage therapy) can be equally beneficial compared to upfront transplantation, stem cells still need to be harvested and cryopreserved early in the disease course. My patient is clearly a transplant candidate given his age and the absence of comorbidity. He should therefore be treated with a non-alkylator-based induction therapy to get the disease under control prior to stem cell harvest. In contrast, for patients who are not candidates for ASCT because of advanced age or poor performance status, oral melphalan-prednisone (MP) remains the standard; so far no treatment has shown improvement in overall survival compared to MP for this population.

Is the patient a candidate for a clinical trial?
Currently all standard therapies for myeloma are suboptimal. Therefore, an appropriate clinical trial if available should be the leading choice for initial therapy regardless of whether or not the patient is a candidate for ASCT.

Does the patient have high-risk disease?
Myeloma patients with hypodiploidy or deletion 13 by karyotypic studies, certain translocations such as t (4;14) or t (14;16) by molecular studies, or a high labeling index >3 percent do poorly even with tandem (double) ASCT. These patients therefore require consideration for alternative management strategies such as novel agents early in the disease course; mini-allogeneic transplantation, if a suitable donor is available; or routine maintenance therapy following ASCT.

HOW SHOULD THIS PATIENT BE TREATED?

This depends on whether or not an active clinical trial is available. In this particular case, there was a clinical trial available and the patient was treated on a phase II experimental drug regimen.

What does one do outside of a protocol setting? The patient in this case has clear-cut myeloma needing therapy, is a candidate for ASCT, and does not have high-risk features. For many years, infusional vincristine/adriamycin/dexamethasone (VAD) had been the standard initial therapy in patients who were candidates for ASCT. However, VAD has fallen out of favor. The oral combination of thalidomide plus dexamethasone (Thal/Dex) can produce equivalent response rates. Preliminary results of a recent randomized trial showed that Thal/Dex has a significantly higher response rate compared to dexamethasone alone in newly diagnosed myeloma. However, this has to be balanced with the added toxicities, particularly deep vein thrombosis. For patients with less advanced disease in whom upfront ASCT is being considered, I typically use dexamethasone alone as initial therapy. If this fails to produce a response in one to two months, I add thalidomide. On the other hand, for patients with advanced lytic lesions, renal function impairment, or, as in the case of our patient (with impending cord compromise), Thal/Dex would be my initial therapeutic choice.

Incidentally, the experimental regimen the patient received was lenalidomide plus dexamethasone. Lenalidomide (CC-5013) is a new analog of thalidomide, with fewer side-effects, and comparable or superior efficacy. Lenalidomide plus dexamethasone is now undergoing phase III testing for newly-diagnosed myeloma in a randomized trial recently activated by ECOG.

HOW DID THIS PATIENT DO?

The patient achieved a dramatic response to therapy with minimal side effects. After four cycles of therapy, I will recommend a stem cell harvest in preparation for ASCT. At that point, he will either proceed directly to ASCT or continue the induction regimen, reserving transplantation for relapse.

FURTHER READING

• Kyle RA, Rajkumar SV. Multiple Myeloma. N
  Engl J Med 2004; 351:1860-1873.
• Sirohi B, Powles R. Multiple myeloma. Lancet
  2004; 363:875-87.

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