Feature

Minimal residual disease status prognostic for PFS in myeloma

Theresa Hahn, PhD
Theresa Hahn

Minimal residual disease status appeared prognostic for PFS at three specific time points for patients with multiple myeloma, according to results of a correlative study.

“Converting to minimal residual disease (MRD) negative ... does not mean [patients] can stop their therapy, but it does convey a significant association with longer survival and long-term PFS,” Theresa Hahn, PhD, professor of oncology at Roswell Park Comprehensive Cancer Center, told HemOnc Today. “Clinicians should routinely incorporate MRD testing ... into patients’ disease assessments at regular intervals. MRD assessments should be done at various points during the patient’s therapy, not just at one time.”

The prospective randomized phase 3 STaMINA trial — results of which were published earlier this year in Journal of Clinical Oncology — assessed multiple interventions for patients with multiple myeloma who underwent autologous hematopoietic stem cell transplant and then received maintenance therapy with the immunomodulating agent lenalidomide (Revlimid, Celgene).

In the correlative PRIMeR study — selected for a Best Abstract Award at this year’s Transplantation and Cellular Therapy Meetings — Hahn and colleagues aimed to determine if MRD status in a patient’s bone marrow at key points of treatment accurately predicted long-term disease control.

Researchers assessed MRD in bone marrow samples by multiparameter flow cytometry at three specified time points: before transplant (baseline), after transplant but before initiation of maintenance therapy (pre-maintenance), and 1 year after HSCT.

The final analysis — based on 883 samples from 437 patients — showed MRD status was prognostic for PFS at all three time points and was prognostic for OS at 1 year after HSCT.

HemOnc Today spoke with Hahn about the study results and their potential implications.

Question: What prompted the PRIMeR study? 

Answer: This is the first study in the United States to look at MRD before and after autologous transplant for myeloma. This was done to see if we could use it as a surrogate endpoint for clinical decision-making, and for prognosis of patients’ long-term PFS and OS.

Q: How did you conduct the study?

A: We approached patients enrolled in the STaMINA trial, which evaluated three different treatment arms for patients with myeloma. Patients received either one autologous transplant, two autologous transplants, or an autologous transplant combined with cycles of consolidation therapy. All patients received maintenance therapy with lenalidomide. We tested patients’ marrow at three time points — before transplant, before maintenance, and 1 year after first transplant. We looked for the presence of MRD as measured by flow cytometry, which looks at the expression of different antigens or proteins on a cell’s surface. We were looking for abnormal cells that would tell us if patients still had myeloma present in their marrow.

Q: What did you find?

A: There were no significant differences between the three different treatment groups. It didn’t matter which therapy the patient received, the rate of no detectable MRD was similar. When we looked at baseline samples and pre-maintenance samples, the same rates of MRD-negative status were present in both. When we looked at the 1-year time point, it initially seemed like the patients who received two autologous transplants had a higher negative rate for MRD, but when we looked at their actual treatment instead of what they were intended to be treated with, that effect went away. Then we assessed long-term PFS and OS using MRD status at those three time points. Patients who tested negative for any residual disease or MRD in their marrow at any of the three time points achieved significantly longer PFS than patients who tested positive. Long-term OS only appeared significantly associated with MRD levels at one time point — 1 year after first transplant. Multivariate analysis adjusted for other significant factors showed MRD status was still a significant predictor of PFS and OS.

Q: Did the results surprise you?

A: We were pleasantly surprised. There was a lot of doubt that we would be able to have samples shipped from around the country overnight and maintain viability to be able to perform the testing. Our study showed we were able to run the samples in about 97% of patients, which was fantastic news and proved our study was feasible. We also were surprised by the 1-year time point. When we originally designed this study, there were published results from a few trials from Europe that showed the pre-maintenance time point was significant for PFS, but no one had reported on the 1-year time point before. We were surprised that, even at a later stage in the patient’s treatment, MRD-negative status was associated with PFS and OS.

Q: Why hadn’t MRD been used to assess prognosis for patients with multiple myeloma prior to this study?

A: It hadn’t been done before in a central laboratory as part of a clinical trial for myeloma largely due to the questionable feasibility of performing flow cytometry centrally for patients across the country. Shipping samples overnight from Seattle to Buffalo might sound a little challenging, but we didn’t have any problems. Much of the worry stemmed from the effort being put into this study and the possibility that we wouldn’t have analyzable results. The other problem is that MRD by flow cytometry has not been standardized for multiple myeloma. A consensus conference published recent guidance for standardizing MRD assessment for myeloma. That helped, but it came out less than 2 years ago. This study was designed about 8 years ago. The flow for MRD assessment was not standardized when we first proposed this study.

Q: Why do you think your study earned the Best Abstract Award?

A: Overcoming the initial doubts surrounding this study definitely helped, especially because we had significant results that were a little surprising. We were not expecting the 1-year time point to be significant, but it was. Further, this is an exciting topic area because there are efforts underway to improve standardization across the country for MRD assessments. Researchers also are trying to incorporate MRD as a surrogate endpoint for clinical trials in multiple myeloma. Because PFS and OS are so long for myeloma, it makes conducting clinical trials difficult, as patients must be followed for a very long time. There are efforts by the FDA and others who want to look at generating data to support using MRD as a surrogate endpoint for trials. This is not finalized yet, but there is a lot of interest in making that happen. – by Joe Gramigna

References:

Hahn T and Pasquini M. Minimal residual disease (MRD) assessment before and after autologous hematopoietic cell transplantation (AutoHCT) and maintenance for multiple myeloma: Results of the prognostic immunophenotyping for myeloma response (PRIMeR) study. Presented at: Transplantation & Cellular Therapy Meetings; Feb. 20-24, 2019; Houston.

Stadtmauer EA, et al. J Clin Oncol. 2019;doi:10.1200/JCO.18.00685.

For more information:

Theresa Hahn, PhD, can be reached at Roswell Park Comprehensive Cancer Center, Medicine/TCT Program, Elm and Carlton streets, Buffalo, NY 14263; email: theresa.hahn@roswellpark.org.

Disclosure: The NIH provided funding for this study. Hahn reports no relevant financial disclosures.

Theresa Hahn, PhD
Theresa Hahn

Minimal residual disease status appeared prognostic for PFS at three specific time points for patients with multiple myeloma, according to results of a correlative study.

“Converting to minimal residual disease (MRD) negative ... does not mean [patients] can stop their therapy, but it does convey a significant association with longer survival and long-term PFS,” Theresa Hahn, PhD, professor of oncology at Roswell Park Comprehensive Cancer Center, told HemOnc Today. “Clinicians should routinely incorporate MRD testing ... into patients’ disease assessments at regular intervals. MRD assessments should be done at various points during the patient’s therapy, not just at one time.”

The prospective randomized phase 3 STaMINA trial — results of which were published earlier this year in Journal of Clinical Oncology — assessed multiple interventions for patients with multiple myeloma who underwent autologous hematopoietic stem cell transplant and then received maintenance therapy with the immunomodulating agent lenalidomide (Revlimid, Celgene).

In the correlative PRIMeR study — selected for a Best Abstract Award at this year’s Transplantation and Cellular Therapy Meetings — Hahn and colleagues aimed to determine if MRD status in a patient’s bone marrow at key points of treatment accurately predicted long-term disease control.

Researchers assessed MRD in bone marrow samples by multiparameter flow cytometry at three specified time points: before transplant (baseline), after transplant but before initiation of maintenance therapy (pre-maintenance), and 1 year after HSCT.

The final analysis — based on 883 samples from 437 patients — showed MRD status was prognostic for PFS at all three time points and was prognostic for OS at 1 year after HSCT.

HemOnc Today spoke with Hahn about the study results and their potential implications.

Question: What prompted the PRIMeR study? 

Answer: This is the first study in the United States to look at MRD before and after autologous transplant for myeloma. This was done to see if we could use it as a surrogate endpoint for clinical decision-making, and for prognosis of patients’ long-term PFS and OS.

Q: How did you conduct the study?

A: We approached patients enrolled in the STaMINA trial, which evaluated three different treatment arms for patients with myeloma. Patients received either one autologous transplant, two autologous transplants, or an autologous transplant combined with cycles of consolidation therapy. All patients received maintenance therapy with lenalidomide. We tested patients’ marrow at three time points — before transplant, before maintenance, and 1 year after first transplant. We looked for the presence of MRD as measured by flow cytometry, which looks at the expression of different antigens or proteins on a cell’s surface. We were looking for abnormal cells that would tell us if patients still had myeloma present in their marrow.

PAGE BREAK

Q: What did you find?

A: There were no significant differences between the three different treatment groups. It didn’t matter which therapy the patient received, the rate of no detectable MRD was similar. When we looked at baseline samples and pre-maintenance samples, the same rates of MRD-negative status were present in both. When we looked at the 1-year time point, it initially seemed like the patients who received two autologous transplants had a higher negative rate for MRD, but when we looked at their actual treatment instead of what they were intended to be treated with, that effect went away. Then we assessed long-term PFS and OS using MRD status at those three time points. Patients who tested negative for any residual disease or MRD in their marrow at any of the three time points achieved significantly longer PFS than patients who tested positive. Long-term OS only appeared significantly associated with MRD levels at one time point — 1 year after first transplant. Multivariate analysis adjusted for other significant factors showed MRD status was still a significant predictor of PFS and OS.

Q: Did the results surprise you?

A: We were pleasantly surprised. There was a lot of doubt that we would be able to have samples shipped from around the country overnight and maintain viability to be able to perform the testing. Our study showed we were able to run the samples in about 97% of patients, which was fantastic news and proved our study was feasible. We also were surprised by the 1-year time point. When we originally designed this study, there were published results from a few trials from Europe that showed the pre-maintenance time point was significant for PFS, but no one had reported on the 1-year time point before. We were surprised that, even at a later stage in the patient’s treatment, MRD-negative status was associated with PFS and OS.

Q: Why hadn’t MRD been used to assess prognosis for patients with multiple myeloma prior to this study?

A: It hadn’t been done before in a central laboratory as part of a clinical trial for myeloma largely due to the questionable feasibility of performing flow cytometry centrally for patients across the country. Shipping samples overnight from Seattle to Buffalo might sound a little challenging, but we didn’t have any problems. Much of the worry stemmed from the effort being put into this study and the possibility that we wouldn’t have analyzable results. The other problem is that MRD by flow cytometry has not been standardized for multiple myeloma. A consensus conference published recent guidance for standardizing MRD assessment for myeloma. That helped, but it came out less than 2 years ago. This study was designed about 8 years ago. The flow for MRD assessment was not standardized when we first proposed this study.

PAGE BREAK

Q: Why do you think your study earned the Best Abstract Award?

A: Overcoming the initial doubts surrounding this study definitely helped, especially because we had significant results that were a little surprising. We were not expecting the 1-year time point to be significant, but it was. Further, this is an exciting topic area because there are efforts underway to improve standardization across the country for MRD assessments. Researchers also are trying to incorporate MRD as a surrogate endpoint for clinical trials in multiple myeloma. Because PFS and OS are so long for myeloma, it makes conducting clinical trials difficult, as patients must be followed for a very long time. There are efforts by the FDA and others who want to look at generating data to support using MRD as a surrogate endpoint for trials. This is not finalized yet, but there is a lot of interest in making that happen. – by Joe Gramigna

References:

Hahn T and Pasquini M. Minimal residual disease (MRD) assessment before and after autologous hematopoietic cell transplantation (AutoHCT) and maintenance for multiple myeloma: Results of the prognostic immunophenotyping for myeloma response (PRIMeR) study. Presented at: Transplantation & Cellular Therapy Meetings; Feb. 20-24, 2019; Houston.

Stadtmauer EA, et al. J Clin Oncol. 2019;doi:10.1200/JCO.18.00685.

For more information:

Theresa Hahn, PhD, can be reached at Roswell Park Comprehensive Cancer Center, Medicine/TCT Program, Elm and Carlton streets, Buffalo, NY 14263; email: theresa.hahn@roswellpark.org.

Disclosure: The NIH provided funding for this study. Hahn reports no relevant financial disclosures.