MM: High-Dose Chemo with SCT Associated with Longer PFS (CME/CE) | IUK Med Online
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MM: High-Dose Chemo with SCT Associated with Longer PFS (CME/CE)

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MM: High-Dose Chemo with SCT Associated with Longer PFS

Autologous stem cell transplant remains preferred therapy for eligible patients

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  • by Contributing Writer, MedPage Today

Action Points

  • Note that this meta-analysis of four phase III randomized trials found good evidence that high-dose melphalan plus autologous bone marrow transplant is superior to conventional dosing in terms of progression-free survival.
  • The survival benefit seemed to increase over time, suggesting that some initial toxicity may mask the true benefit of this approach.

The use of high-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) in patients with multiple myeloma (MM) is associated with longer progression free survival (PFS) and minimal toxic effects, compared with use of standard-dose therapy (SDT), according to investigators.

The results of the systematic review and meta-analysis of phase III randomized controlled trials evaluating the role of HDT/ASCT, the team wrote, show that ASCT remains the preferred therapy in transplant-eligible patients with MM.

Results of the systematic review and meta-analysis, led by Binod Dhakal, MD, of Medical College of Wisconsin, were published online in JAMA Oncology.

He and his colleagues note that the role of HDT/ASCT in MM patients has long been debated, considering the “unprecedented efficacy” of novel agents. Consequently, the researchers performed this analysis of the relevant phase III randomized clinical trials to “establish the role of HDT/ASCT compared to SDT in the context of novel agents.”

Studies meeting the following criteria were included in the analysis:

  • Phase III randomized controlled trials
  • Enrolled and reported outcomes for patients with newly diagnosed MM undergoing HDT/ASCT
  • Comparison of combination chemotherapy with novel agents followed by consolidation with HDT/ASCT versus SDT alone
  • Comparison of single HDT/ASCT (HDT1) versus tandem HDT/ASCT (HDT2) for purposes of a network meta-analysis only

Overall, four randomized controlled trials with a total of 2,421 patients were selected for the conventional meta-analysis, with the median follow-up for each trial ranging from 26 to 52 months.

One additional study was added for a network meta-analysis that compared HDT2 with HDT1 alone versus HDT1 followed by consolidation with bortezomib, lenalidomide, and dexamethasone.

The combined odds for complete response were 1.27 (95% CI, 0.97-1.65) with HDT/ASCT compared with SDT.

Of the two studies that reported treatment-related mortality (TRM), TRM with HDT/ASCT was minimal (<1) and compatible with SDT.

All four studies selected for the conventional meta-analysis reported PFS, with a combined HR of 0.55 (95% CI, 0.41-0.74) — “indicating a statistically significant PFS benefit with HDT/ASCT.”

Meta-regression showed that longer follow-up was associated with greater PFS (HR/mo 0.98; 95% CI, 0.96-0.99) and overall survival (OS) (HR/mo, 0.90; 95% CI, 0.84-0.96).

The investigators wrote that a possible explanation of this finding is that the HR increases over time, suggesting, for example, that the proportional hazard assumption is not valid. “Thus, future studies should plan for non-proportional hazards and not rely on Cox regression for analyses, as well as allow for longer follow-up for OS.”

For PFS, tandem HDT/ASCT had the superior HR (0.49; 95% CI, 0.37-0.65), followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone (HR. 0.53; 95% CI, 0.37-0.76) and then single HDT/ASCT alone (HR, 0.68; 95% CI, 0.53-0.87) compared with SDT. None of the HDT/ASCT-based approaches had a statistically significant effect on OS.

There could be several causes for the lack of OS benefit shown in the selected studies, the researchers wrote. For example, one reason could be the crossover or use of HDT/ASCT at relapse. “Unidirectional crossover from the control or placebo arm of cancer trials to the experimental drug (but not vice versa) is thought to explain why some cancer drugs that improve PFS fail to improve OS.”

Yet, despite this lack of demonstrable OS benefit, “HDT/ASCT remains the preferred up-front treatment option,” the investigators concluded. “A significant PFS, low TRM, and potential high [minimal residual disease]-negative rates conferred by HDT/ASCT in the context of best available non-transplant therapies are enough to justify this approach for patients with newly diagnosed MM.”

Limitations of the analysis, Dhakal et al said, included the limited number of selected studies, the delivery of heterogeneous treatments, and unreported outcomes (such as the fact that one study did not include OS). In addition, while previous studies have demonstrated that HDT was associated with improved quality of life in the pre-novel agent era, more recent studies have presented no such data.

“Further studies looking at quality of life, patient-reported outcomes, and pharmacoeconomics are recommended, because maintenance and post-transplant therapy are now standard.”

Dhakal reported financial relationships with Millennium Takeda and Celgene. Other coauthors reported financial relationships with those two companies as well as Sanofi, Prothena, Merck, Amgen, Skyline, Onyx, Janssen, Array BioPharma, Pharmacyclics, and Bristol-Myers Squibb.

  • Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner
2018-01-05T13:30:00-0500
Take Posttest Comments

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Medpage Today

MM: High-Dose Chemo with SCT Associated with Longer PFS

Autologous stem cell transplant remains preferred therapy for eligible patients

MedpageToday

  • register today

    Earn Free CME Credits by reading the latest medical news in your specialty.

    sign up

  • by Contributing Writer, MedPage Today

Action Points

  • Note that this meta-analysis of four phase III randomized trials found good evidence that high-dose melphalan plus autologous bone marrow transplant is superior to conventional dosing in terms of progression-free survival.
  • The survival benefit seemed to increase over time, suggesting that some initial toxicity may mask the true benefit of this approach.

The use of high-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) in patients with multiple myeloma (MM) is associated with longer progression free survival (PFS) and minimal toxic effects, compared with use of standard-dose therapy (SDT), according to investigators.

The results of the systematic review and meta-analysis of phase III randomized controlled trials evaluating the role of HDT/ASCT, the team wrote, show that ASCT remains the preferred therapy in transplant-eligible patients with MM.

Results of the systematic review and meta-analysis, led by Binod Dhakal, MD, of Medical College of Wisconsin, were published online in JAMA Oncology.

He and his colleagues note that the role of HDT/ASCT in MM patients has long been debated, considering the "unprecedented efficacy" of novel agents. Consequently, the researchers performed this analysis of the relevant phase III randomized clinical trials to "establish the role of HDT/ASCT compared to SDT in the context of novel agents."

Studies meeting the following criteria were included in the analysis:

  • Phase III randomized controlled trials
  • Enrolled and reported outcomes for patients with newly diagnosed MM undergoing HDT/ASCT
  • Comparison of combination chemotherapy with novel agents followed by consolidation with HDT/ASCT versus SDT alone
  • Comparison of single HDT/ASCT (HDT1) versus tandem HDT/ASCT (HDT2) for purposes of a network meta-analysis only

Overall, four randomized controlled trials with a total of 2,421 patients were selected for the conventional meta-analysis, with the median follow-up for each trial ranging from 26 to 52 months.

One additional study was added for a network meta-analysis that compared HDT2 with HDT1 alone versus HDT1 followed by consolidation with bortezomib, lenalidomide, and dexamethasone.

The combined odds for complete response were 1.27 (95% CI, 0.97-1.65) with HDT/ASCT compared with SDT.

Of the two studies that reported treatment-related mortality (TRM), TRM with HDT/ASCT was minimal (<1) and compatible with SDT.

All four studies selected for the conventional meta-analysis reported PFS, with a combined HR of 0.55 (95% CI, 0.41-0.74) -- "indicating a statistically significant PFS benefit with HDT/ASCT."

Meta-regression showed that longer follow-up was associated with greater PFS (HR/mo 0.98; 95% CI, 0.96-0.99) and overall survival (OS) (HR/mo, 0.90; 95% CI, 0.84-0.96).

The investigators wrote that a possible explanation of this finding is that the HR increases over time, suggesting, for example, that the proportional hazard assumption is not valid. "Thus, future studies should plan for non-proportional hazards and not rely on Cox regression for analyses, as well as allow for longer follow-up for OS."

For PFS, tandem HDT/ASCT had the superior HR (0.49; 95% CI, 0.37-0.65), followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone (HR. 0.53; 95% CI, 0.37-0.76) and then single HDT/ASCT alone (HR, 0.68; 95% CI, 0.53-0.87) compared with SDT. None of the HDT/ASCT-based approaches had a statistically significant effect on OS.

There could be several causes for the lack of OS benefit shown in the selected studies, the researchers wrote. For example, one reason could be the crossover or use of HDT/ASCT at relapse. "Unidirectional crossover from the control or placebo arm of cancer trials to the experimental drug (but not vice versa) is thought to explain why some cancer drugs that improve PFS fail to improve OS."

Yet, despite this lack of demonstrable OS benefit, "HDT/ASCT remains the preferred up-front treatment option," the investigators concluded. "A significant PFS, low TRM, and potential high [minimal residual disease]-negative rates conferred by HDT/ASCT in the context of best available non-transplant therapies are enough to justify this approach for patients with newly diagnosed MM."

Limitations of the analysis, Dhakal et al said, included the limited number of selected studies, the delivery of heterogeneous treatments, and unreported outcomes (such as the fact that one study did not include OS). In addition, while previous studies have demonstrated that HDT was associated with improved quality of life in the pre-novel agent era, more recent studies have presented no such data.

"Further studies looking at quality of life, patient-reported outcomes, and pharmacoeconomics are recommended, because maintenance and post-transplant therapy are now standard."

Dhakal reported financial relationships with Millennium Takeda and Celgene. Other coauthors reported financial relationships with those two companies as well as Sanofi, Prothena, Merck, Amgen, Skyline, Onyx, Janssen, Array BioPharma, Pharmacyclics, and Bristol-Myers Squibb.

  • Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner
2018-01-05T13:30:00-0500
Take Posttest Comments

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.



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