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Early HSCT prolongs PFS, not OS, for multiple myeloma
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SALT LAKE CITY — Upfront high-dose chemotherapy with early autologous hematopoietic stem cell transplantation prolonged PFS compared with standard-dose chemotherapy or delayed transplantation among patients with newly diagnosed multiple myeloma, according to results of a meta-analysis presented at the BMT Tandem Meetings.
However, this did not translate into an OS improvement, results also showed.
Upfront high-dose chemotherapy with HSCT — an approach often used for patients newly diagnosed with multiple myeloma — has shown inconsistent benefits in randomized controlled trials compared with standard-dose chemotherapy with or without delayed HSCT.
“The evolution of the therapeutic armamentarium in multiple myeloma has been tremendous, bringing us to the question of the appropriate timing of high-dose therapy with stem cell support,” Tania Jain, MBBS, chief hematology/oncology fellow at Mayo Clinic in Phoenix, Arizona, told HemOnc Today. “This progress has brought into question the role of HSCT as primary therapy for this disease. Given the variation in several clinical trials, we sought to review the data by conducting a meta-analysis and extracting combined information from the data available from randomized trials evaluating the comparison of early high-dose therapy with stem cell support vs. standard-dose therapy or delayed stem cell transplantation.”
Jain and colleagues evaluated the difference in OS and PFS between these treatment options using data from 12 randomized control trials of 3,829 patients.
Overall, 1,824 patients underwent early high-dose chemotherapy with HSCT, and 2,005 patients underwent standard-dose chemotherapy or delayed HSCT.
OS did not differ between patients who underwent early HSCT compared with those who underwent standard-dose chemotherapy or salvage HSCT (HR = 0.86; 95% CI, 0.7-1.04).
However, researchers did observe a significant PFS advantage with the early HSCT approach (HR = 0.73; 95% CI, 0.56-0.94).
Four randomized trials included treatments with novel agents. In a subgroup analysis of these studies, researchers observe no significant differences between the transplant groups with regard to OS (HR = 0.85; 95% CI, 0.46-1.6) and PFS (HR = 0.68; 95% CI, 0.27-1.25).
These results differ from the results of a study by Dhakal and colleagues — published in JAMA Oncology this year — which showed treatment with high-dose melphalan followed by autologous hematopoietic stem cell transplant conferred longer PFS with minimal toxic effects compared with novel agents among patients with multiple myeloma.
This can be explained by two factors, Jain said.
“Firstly, we included the IFM 99-06 trial, which included a thalidomide treatment arm and showed benefit in favor of standard therapy including thalidomide with melphalan and prednisone,” she said. “Secondly, we did not include abstracts in our meta-analysis, as the data are not peer reviewed at that stage, leading to the exclusion of the study by Cavo and colleagues, presented at ASH Annual Meeting and Exposition. This study — included in the meta-analysis by Dhakal and colleagues — reported PFS and response rate outcomes only.
“In fact, our criteria also led to the exclusion of another abstract showing results of comparison of melphalan/prednisone/lenalidomide [Revlimid, Celgene] with high-dose melphalan and autologous transplantation. Additionally, the data in the currently evolving era of novel agents — such as carfilzomib [Kyprolis, Amgen], pomalidomide [Pomalyst, Celgene] and daratumumab [Darzalex, Janssen], among others — are limited, as none of the studies included these agents. The ongoing DETERMINATION trial led by Dana Farber Cancer Institute (NCT01208662) is currently looking at this question with lenalidomide/bortezomib/dexamethasone in the standard therapy arm, which will shed some additional light in this regard.”
Overall, high-dose therapy with autologous HSCT remains an important therapeutic approach for multiple myeloma and should be offered as an integral part of front-line therapy, Jain said.
“In light of the ongoing improvements in the treatment options of multiple myeloma, optimal combinations with novel agents may result in deeper responses that may redefine the role of HSCT in this disease. Obviously, that remains to be studied in a clinical trial setting,” she said. “Also with the emergence of minimal residual disease evaluation, this approach could be integrated into determining the timing of autologous stem cell transplantation in these patients.” – by Alexandra Todak
Reference:
Jain T, et al. Abstract 24. Presented at: BMT Tandem Meetings; Feb. 21-25, 2018; Salt Lake City.
Disclosures: The authors report no relevant financial disclosures.
Perspective
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Saad Z. Usmani, MD, FACP
The early 2000s ushered in a new era of clinical investigation in multiple myeloma therapeutics, with immunomodulatory drugs and proteasome inhibitors being the two “novel and targeted” drug classes touting good activity and safer toxicity profiles than conventional chemotherapy. This led to the debate whether high-dose melphalan with autologous stem cell transplant (HDM/ASCT) can potentially be replaced with the novel agent therapies. The myeloma research community conducted several randomized phase 3 trials in the 1990s showing superior PFS benefit for HDM/ASCT compared with conventional chemotherapy. Additional studies using novel agent induction regimens replicating similar results of better PFS in the HDM/ASCT arms. Yet, the academic naysayers continue to question the trial results and point out similarities in OS while acknowledging inadequate long-term follow-up. There also is a concern for second primary malignancies after HDM/ASCT despite the relatively low risk — 2% to 3% without lenalidomide (Revlimid, Celgene) maintenance, 7% to 8% with lenalidomide maintenance and no increased risk with bortezomib (Velcade, Takeda/Millennium) maintenance — and, in part, due to the significant improvement in OS of patients with multiple myeloma. The focus should perhaps remain on the first malignancy while discussing the risk for second primary malignancy with each individual patient.
In a study published in JAMA Oncology this year, Dhakal and colleagues performed a meta-analysis of four randomized phase 3 trials comparing HDM/ASCT after novel agent induction to no or delayed HDM/ASCT, demonstrating a combined HR of 0.55 (95% CI, 0.41-0.74; P = .004), indicating a statistically significant PFS benefit with HDM/ASCT. But, results showed a modest trend in OS in favor of HDM/ASCT (HR = 0.76; 95% CI, 0.42-1.36). The authors suggested that longer follow-up and differences in availability of postrelapse therapies — or lack thereof — will influence OS in a disease with median OS approaching 9 to 10 years.
Jain and colleagues presented a meta-analysis that combined all the pre-/postnovel therapy era randomized trials showing prolonged PFS, but no statistically significant difference in OS (HR = 0.86, 95% CI, 0.7-1.04). Taken together, these results maintain that HDM/ASCT remains standard of care for eligible patients as part of frontline therapy in the era of novel agent induction.
Yet, we know from Center for International Blood and Marrow Transplant Research data that only about a third of HDM/ASCT-eligible patients with multiple myeloma get referred to a transplant center. One can argue that the progression-free period is the time when patients can really get back to their lives and enjoy normalcy — so why short-change them? I sometimes wonder if the progress in academic research would be faster if we, the investigators, were more receptive to objective data and softened our academic stance with time. Perhaps we should use data to treat patients and academic stance for research investigations only. There may come a time in the future when HDM/ASCT is obsolete, but we are not there yet.
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