Cancer Treatment Today

A single or tandem autologous transplant is considered medically necessary for multiple myeloma. Autologous followed by allogeneic transplants are being explored because autologous transplants are not curative while allogeneic salvage transplants might be curative. Autologous stem cell transplantation has emerged as standard therapy for patients with multiple myeloma, primarily as a result of randomized trials performed in France over the past decade. Recent guidelines agree on several recommendations. An autologous stem cell transplant is recommended for patients with stage II or III multiple myeloma who have a good performance status. They state that evidence of benefit is strongest for patients who are younger than 55 years of age and have a serum creatinine level less than 1.7 mg/dL. They recommend using clinical judgement for patients who do not fit these criteria. Importantly, they advise early and integrated treatment with collection of stem cells before exposure to alkylating agents. They also support the use of peripheral blood stem cells over bone marrow. They suggest that early transplant produces the best results. They recommend a single transplant with high-dose Alkeran®, with or without total-body irradiation unless patients are on a clinical trial. Tandem is a prospectively planned double transplant whereas a second transplant is done only if the response to the first one is suboptimal. Tandem autologous transplants or second transplant are no longer investigational as per NCCN at this time. A second autologous stem cell transplant is sometimes performed in patients who have relapsed after an initial stem cell transplant. A second transplant is usually prospectively planned to take place within 6 months if there is not a complete response. Some myeloma centers automatically collect enough stem cells for two transplants and reserve them for a possible second transplant.

Analysis of data on 96 myeloma patients who received a second transplant following relapse, which was presented at the IXth International Workshop on Myeloma, showed that a second (salvage) transplant is a feasible option for refractory/relapsed disease. (Powles et al. Hematology J. 2003;4(suppl 1):S62. Abstract P10.3.1.) The median survival in patients receiving the salvage transplant (6.4 years) was equivalent to that typically seen with a planned tandem transplant. However, these patients represent a select subgroup of patients with relatively good prognosis. In a Czech study reported in 2004, toxicity of the first and second transplantation was similar and usually did not exceed grade II (SWOG). Transplant-related mortality was 3% (1/32). Event-free survival after second AT (EFS II) is known in 22 patients; 7 have achieved prolongation of EFS II versus EFS I. In the whole group median EFS I was 15.7 months, median EFS II was 12.9 months, median overall survival (OS) was 79.1 months; 20/32 patients were alive at the time of analysis. In a 2006 USA study, fourteen patients (median age, 52 yrs) received a second autograft for salvage, whereas 26 patients (median age, 51 yrs) underwent a reduced-intensity allogeneic transplantation (related in 18 patients and unrelated in 8 patients). The median interval between the first and the second transplant was 25 months in the autologous group and 17 months in the allogeneic group. The two groups were evenly matched with regard to other disease characteristics. After a median follow-up of 18 months for the autologous group and 30 months for the allogeneic group, the median progression-free survival (PFS) and overall survival (OS) in the 2 groups were 6.8 months versus 7.3 months and 29 months versus 13 months, respectively. Acute and chronic graft versus host disease (15%) was the most common cause of non-recurrence mortality in the allogeneic group and infections (14%) in the autologous group. Researchers from Italy have reported that an autologous stem cell transplant followed by a reduced intensity allogeneic stem cell transplant may be superior to tandem autologous transplants for newly diagnosed patients with multiple myeloma. Researchers from Spain have also reported a higher complete remission rate following auto–allo grafts versus tandem auto grafts. These two studies were presented at the 47th annual meeting of the American Society of Hematology in December 2005. The Italian study suggests benefit of a reduced intensity allogeneic stem cell transplant compared to a second autologous transplant, while the second study is equivocal with a high treatment-related mortality. A recent New England Journal of Medicine article reported superior results for an autologous, followed by allogeneic transplant. This was a prospectively planned, not a salvage transplant.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 Trial (Abstract 41) in 2010, reported disappointing results at the American Society of Hematology Annual Meeting. The trial compared tandem autologous haematopoietic stem cell transplant with or without maintenance therapy (auto-auto) versus single autologous transplant followed by HLA matched sibling non-myeloablative allogeneic hematopoietic stem cell transplant (auto-allo) for patients with standard-risk multiple myeloma.

Results showed that the auto-allo approach at three years added no benefit to progression-free or overall survival compared with use of auto-auto. NCCN MYEL-6, 2015  recommends a second autologous  transplant as Category 1 recommendation: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Conclusion:

Allogeneic transplants appeared to be a curative alternative for myeloma several years ago, but recent evidence has changed this perception and raised many questions. Autologous followed by allogeneic transplants were being explored because autologous transplants are not curative while allogeneic salvage transplants was thought to be curative. Recent studies are reversing this perception.

NCCN 2017 on p. MYEL-5 recommends additional allogeneic transplant on a clinical trial, or off trial but in relapse, not consolidation.. The International Myeloma Working Group recently published a consensus statement regarding the use of allogeneic hematopoietic stem-cell transplantation (HSCT) in myeloma. They conclude that new strategies are needed to make allogeneic HSCT safer and recommend reduced intensity conditioning in the context of clinical trials only.

Second ASCT is a feasible and safe option for salvage therapy in MM. The best outcome was observed in patients whose time to progression was >24 months after first ASCT, as these patients had a subsequent PFS lasting over 1 year and an OS of almost 6 years. NCCN recommends a second transplant, either autologous or allogeneic for progressive disease.

Gonsalves WI, Gertz MA, Lacy MQ, et al. Second auto-SCT for treatment of relapsed multiple myeloma. Bone Marrow Transplant. 2013; 48:568-573.

Ursina Gössi Barbara Jeker Behrouz Mansouri Taleghani Ulrike Bacher Urban Novak Daniel Betticher Thomas Egger Thilo Zander Thomas Pabst, Prolonged survival after second autologous transplantation and lenalidomide maintenance for salvage treatment of myeloma patients at first relapse after prior autograft. Hematologic ONCOLOGY Volume36, Issue April 2018
Pages 436-444t

NCCN myeloma 2022

Jimenez-Zepeda VH, Mikhael J, Winter A, Franke N, Masih-Khan E, Trudel S, Chen C, Kukreti V, Reece DE. Second autologous stem cell transplantation as salvage therapy for multiple myeloma: impact on progression-free and overall survival. Biol Blood Marrow Transplant. 2012 May;18(5):773-9.
NCCN MYEL-6 recommends a second transplant, either autologous or allogeneic for progressive disease.

Cook G, Liakopoulou E, Pearce R, et al. Factors influencing the outcome of a second autologous stem cell transplant (ASCT) in relapsed multiple myeloma: a study from the British Society of Blood and Marrow Transplantation Registry. Biol Blood Marrow Transplant. 2011;17:1638-1645.
Gonsalves WI, Gertz MA, Lacy MQ, et al. Second auto-SCT for treatment of relapsed multiple myeloma. Bone Marrow Transplant. 2013;48:568-573.
Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-152.
Attal M, Lauwers-Cances V, Hulin C, et al. Autologous transplantation for multiple myeloma in the era of new drugs: a phase III study of the Intergroupe Francophone du Myeloma (IFM/DFCI 2009 Trial). Blood. 2015;731:391.

Ursina Gössi Barbara Jeker Behrouz Mansouri Taleghani Ulrike Bacher Urban Novak Daniel Betticher Thomas Egger Thilo Zander Thomas Pabst, Prolonged survival after second autologous transplantation and lenalidomide maintenance for salvage treatment of myeloma patients at first relapse after prior autograft. Hematologic ONCOLOGY Volume36, Issue2 April 2018
Pages 436-444t