Autologous stem cell transplantation (ASCT) has been the established standard of care in patients with multiple myeloma (MM) younger than 65 years with normal renal function, as well as in select fit elderly patients. Combination high-dose therapy and ASCT (HDT/ASCT) has been found to induce rates of overall response up to 80%, complete or very good partial response up to 45%, and progression-free survival (PFS) up to 30 months.1 However, most patients eventually experience relapse or disease progression.

In the past decade, highly effective emerging pharmacotherapies have challenged the transplantation as the therapeutic standard of care for MM. In a review published in Blood, Rama Al Hamed, of the hematology and cellular therapy department at the Saint-Antoine Hospital and Sorbonne University in France, and colleagues discussed the role of ASCT in the era of triple-agent induction therapies.2

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Induction Therapy

Studies evaluating proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) in the induction, consolidation, and maintenance treatment stages have shown significant increases in rates of stringent complete response, complete response, and very good partial response and no increase in toxicity.2

For induction therapy, both bortezomib, thalidomide, dexamethasone (VTD) and bortezomib, lenalidomide, dexamethasone (VRD) have been found to be superior to 2-drug regimens such as lenalidomide with dexamethasone (RD) or thalidomide with dexamethasone (TD). VTD is now considered the standard induction treatment.1,2  Early phase studies of carfilzomib as a replacement for bortezomib in induction regimens have reported high response rates with no additional safety concerns.2

Daratumumab, a monoclonal antibody that targets CD38+, is indicated in monotherapy in patients who relapse or are refractory to therapy. In the phase 3 ALCYONE trial (ClinicalTrials.gov Identifier: NCT02195479), daratumumab combined with bortezomib, melphalan, and prednisone (VMP) in patients ineligible for ASCT demonstrated superior outcomes compared with VMP alone. The combination of daratumumab and VMP led to significant improvements in PFS, complete response rate, and measurable residual disease (MRD) negativity.3 Based on these results, the US Food and Drug Administration extended the indication for daratumumab (in combination with VMP) to patients with newly diagnosed MM who were ineligible for transplantation.3,4 The authors of the review suggested that daratumumab may have a place in induction regimens for all patients.2

MRD, defined as less than 1 cancer cell per million bone marrow cells, at various points in the transplantation process is a prognostic indicator that is increasingly used to guide treatment decisions. MRD negativity was shown to predict long-term outcomes and PFS better than high-risk cytogenetics, which may make it valuable as a tool for risk stratifying patients when determining the optimal duration of maintenance treatment.2

“Using MRD as a clinical endpoint in trials will allow a more personalized approach to treatment, particularly in guiding the optimal duration of therapy,” said Maria Mateos, MD, PhD, of the University Hospital of Salamanca in Spain, in an interview with Hematology Advisor. “This will translate into cost savings and improvement in patients’ quality of life.”

Conditioning Prior to Transplantation

HDT prior to ASCT typically involves 200 mg/m2 melphalan delivered intravenously, though this dosage can be lowered in patients with renal impairment. Pharmacokinetic-directed strategies of melphalan dosing could assist with determining optimal dosing for individual patients and prevent unnecessary toxicities.

Stem cell mobilization, or the harvesting of hematopoietic stem cells from the bone marrow prior to ASCT, is usually performed with 2 g/m2 to 4 g/m2 cyclophosphamide followed by 10 µg/kg of the granulocyte colony-stimulating factors (G-CSF) filgrastim or lenograstim daily for 4 to 6 days. Plerixafor, a chemokine receptor 4 (CXCR4) antagonist, can be used to enhance the effects of G-CSF. Hematopoietic stem cells are then infused into the bone marrow after 48 hours of melphalan administration.2