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Debate: Should All Eligible Myeloma Patients Receive Upfront Transplant?

Fuerst, Mark L.

doi: 10.1097/01.COT.0000528044.08598.5b
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NEW YORK CITY—Even in the era of novel-agent based-therapy, frontline autologous stem cell transplantation (ASCT) is the standard of care for multiple myeloma patients, but the number of therapy choices is growing rapidly for many patients and care needs to be individualized, according to experts who debated the value of upfront ASCT in myeloma at Lymphoma & Myeloma 2017: An International Congress on Hematologic Malignancies.

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Upfront Transplantation

New recommendations for risk-stratified treatment options for standard-risk multiple myeloma patients who are transplant-eligible include early ASCT or bortezomib, lenalidomide, and dexamethasone (VRd) for 8-12 cycles. High-risk patients should receive early ASCT, said Philippe Moreau, MD, Head of the Hematology Department at the University Hospital of Nantes in France.

Some patients who receive carfilzomib, lenalidomide and dexamethasone (KRd) alone for 8 cycles and lenalidomide maintenance for 24 cycles may not go on to stem cell transplant. After almost 3 years of duration, the majority of patients still receive treatment. “Can we tell patients that after 8 cycles of KRd we will assess minimal residual disease (MRD) and if it is still positive then they will receive ASCT? Patients will not buy that strategy. It is not logical. KRd is not an appropriate frontline therapy,” said Moureau.

Progression-free survival (PFS) is better with ASCT by high-risk cytogenetics. Very high-risk patients may need tandem, not single, transplants, he noted.

The IFM DFCI 2009 trial, which included 700 patients less than age 66 years with newly diagnosed, symptomatic multiple myeloma, found a 14-month difference in PFS in favor of ASCT over VRd. PFS was always increased for all subgroups of patients.

Among the prognostic factors in the IFM DFCI 2009 trial, the most important one was MRD-negativity by flow cytometry. “This was more important than cytogenetics or achievement of CR. MRD-negativity has a huge impact before maintenance and is much higher with ASCT upfront. Overall survival (OS) is also impacted by MRD-negativity. The number of patients who reach MRD-negativity is higher with ASCT and, therefore, ASCT should be recommended for all patients,” said Moureau.

To improve MRD-negativity, KRd can be used before ASCT as induction and consolidation. Monoclonal antibodies, such as daratumumab, can also be added in as induction and consolidation to standard therapy to improve results. He noted that adding in a proteasome inhibitor, such as carfilzomib, to immunomodulatory drugs is important in the maintenance phase. Daratumumab maintenance can also follow intensive upfront strategies. Monitoring MRD by flow cytometry or next-generation sequencing can improve assessment of response.

Moureau noted that “inherent in the idea of a cure is the permanent end to the specific instance of the disease. Improved quality of response needs to be maintained carefully to propose a potential cure.”

In conclusion, he said ASCT increases the quality of response, induction with high-dose therapy, consolidation, and maintenance. Evaluating MRD inside and outside of bone marrow is important in defining optimal maintenance and its duration.

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Not Everyone Needs Transplant

One size does not fit all and, therefore, not everyone with myeloma requires an upfront transplant, said James Berenson, MD, Medical and Scientific Director of the Institute for Myeloma and Bone Cancer Research in Los Angeles.

More new combinations involve already approved myeloma drugs, and clinical trials of drugs recently approved and not-yet approved are in the works. “It is becoming clear that patients have many more options today. Patients need to avail themselves of the opportunity to receive different therapies. Reducing that ability with too much prior treatment is detrimental in the long run,” said Berenson.

Clinicians need to establish the goals of therapy for individual myeloma patients. “Patients want the longest life possible with therapy and a disease that has the least impact on their lives. That means overall survival and not simply a delay in disease returning,” he said.

That does not necessarily mean they want the regimen with the highest percentage of CR. “CRs in myeloma are based on paraprotein and are not really molecular CRs, even when MRD is negative. There is very little difference in tumor burden between patients with stable disease and so-called CR,” said Berenson.

The arguments for transplant in myeloma include the highest CR rates, which are associated with a delay in time to progression and prolonged PFS. Older randomized trials show PFS and time to progression and, in some cases, an OS advantage. And no additional therapy is required after transplant.

Now the highest rates of CR are available with a combination of frontline KRd. “Why does CR compare to less than CR delay PFS and time to progression without improvement in OS?” he asked. “These are not true CRs, but are based on M protein becoming undetectable. PCR-based molecular and Fc CRs are only as sensitive as the assay.”

Trials and meta-analyses show there is no consistent advantage in OS for randomized phase III trials even prior to the availability of new drugs, such as IMiDs and proteasome inhibitors. Meta-analyses show a PFS, but not an OS, advantage. In early versus late disease at time of progression, there is no difference from French and U.S. intergroup trials, he pointed out.

“Studies of the timing of transplantation for IMiD-treated myeloma patients show no difference in PFS or OS studies in early versus delayed transplants. Survival from the time of diagnosis shows improvement in PFS, but not OS,” said Berenson.

A recent study of lenalidomide, bortezomib, and dexamethasone (RVD) with or without transplant for myeloma showed a median PFS or 36 months in the RVD-alone group versus 50 months in the transplantation group (N Engl J Med 2017;376(14):1311-1320). OS at 4 years did not differ significantly between the two groups—82 percent in the RVD-alone group versus 81 percent in the transplantation group.

In this study, MRD-negativity was more often observed in the transplantation group (79%) than the RVD-alone group (65%). But the analysis included patients with very good partial responses, who have residual disease, even by paraprotein. “MRD-negativity is a surrogate for patients doing well and is not necessarily related to the treatment itself. To suggest that transplants are necessary because more patients achieve MRD-negativity is a false assumption because overall transplanted patients did not live longer,” said Berenson.

Grade 3 and 4 adverse events were more common with transplantation (97.1%) than with RVD-alone (83.4%). But there were three times the number of treatment-related deaths (six) with transplantation than RVD-alone (two).

In summary, Berenson said “there is no OS advantage of early auto-transplant from any recent randomized trials. The highest CRs are without transplant. And all patients now receive post-transplant maintenance lenalidomide so there is no treatment-free interval.”

Treatment options are rapidly increasing, so compromising a patient's ability to receive these options because of toxicity from high-dose therapy is important to consider. “Also, be careful interpreting results, especially OS, from trials where treatment options are limited. As multiple myeloma patients are living longer, optimizing quality of life becomes of increasing importance,” said Berenson.

“It's no longer about more. It's about being more specific. Transplants are only about more. It's time to focus on more tumor-specific treatments,” he continued. “With so many options, therapies should be tailored to each multiple myeloma patient's disease, co-morbid conditions, and lifestyle. Transplant should not be an option upfront for myeloma in 2017 until we can determine who truly can benefit.”

Mark L. Fuerst is a contributing writer.

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
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