Expert Highlights Evolving Approaches for Newly Diagnosed Multiple Myeloma

Prashant Kapoor, MD

Risk stratification for patients with newly diagnosed multiple myeloma is an essential component of the treatment plan, explains expert Prashant Kapoor, MD.

By using the revised International Myeloma Working Group (IMWG) criteria, physicians are able to determine if a patient has smoldering myeloma or active multiple myeloma, high-risk or standard-risk disease, and what molecular abnormalities they may harbor—which can be key to determining what treatments will garner responses, he adds.

OncLive: Your talk focused on the clinical approach for patients with newly diagnosed multiple myeloma. What did you highlight?

Kapoor, assistant professor of medicine and of oncology, Mayo Clinic, discussed the various approaches for treating patients with newly diagnosed multiple myeloma in an interview during the 2017 OncLive^® State of the Science Summit on Hematologic Malignancies. In detail, he lectured on the importance of minimal residual disease (MRD) negativity, using IMWG criteria, and pivotal data that have truly changed the landscape.Kapoor: I started with the revised IMWG classification for multiple myeloma. These are in addition to the original CRAB criteria that we typically use to treat patients. Now, we have 3 additional criteria for starting therapy.

One of them is a patient with smoldering myeloma who has more than 60% plasma cells in the marrow, so extreme plasmacytosis is 1 criteria. The other 2 that have been added as myeloma-defining events are 1 focal lesion on the MRI, and involved versus uninvolved free light chain ratio of more than 100 typically in presence of at least 10 mg/dL of the involved free light chain.

These 3 additional criteria are new indications for treatment of myeloma. In essence, it’s the ultra high-risk patients with smoldering myeloma who have a risk of about 40% per year of transforming to active multiple myeloma—in whom we are now essentially asking clinicians to initiate therapy sooner than we typically did in the past.

What are the first steps you take with a patient who has newly diagnosed disease?

What is important to note about staging patients with myeloma?

One of the reasons for starting therapy sooner is, nowadays, the treatments are much better tolerated, and they have much better efficacy in contrast to the medications that we had available about a decade ago. When we see a patient in the clinic, 1 of the first steps we do is typically risk stratify patients with myeloma. We want to know whether these patients are high risk or standard risk. The vast majority of patients actually have standard-risk myeloma. The risk stratification is based on certain chromosomal abnormalities. It is important to risk stratify because it not only helps in prognosticating patients, but it also gives us an idea as to how we should treat and approach them, particularly the ones that are transplant eligible. I did talk about the IMWG, which has recently introduced a new staging system for risk stratification of myeloma. They have piggybacked on the original simple prognostic tool they used, and that was the International Staging System (ISS) introduced first in 2005. Now, more recently, they have integrated some of the cytogenetic abnormalities, in addition to LDH, and these biomarkers that we are now using are commonly used in the community. One can easily stage these patients and risk stratify them. They are not only very good prognostic tools, but we hope that in the future, we will be able to use these staging systems to guide our therapy, as well.

It is also important to emphasize one of the meta-analyses that was conducted very recently. There is a new response criteria that has been introduced by the IMWG, which is MRD-negative state, whether it is MRD state by a next-generation flow cytometry, or it is next-generation sequencing that we use to assess MRD. There is an MRD-imaging response criteria and that combines the PET scan with MRD, either by next-generation sequencing or next-generation flow cytometry.

How has the paradigm for newly diagnosed multiple myeloma evolved?

Then, there was a new category called sustained MRD-negative state in which the patients have achieved MRD-negative state for at least 1 year. Then, there is imaging plus MRD-negative response category, which involves the use of PET scan. Some of these categories have been created because, with the use of novel agents, especially in combination, we have been able to achieve deeper response states. The first step in approaching patients with newly diagnosed myeloma, after their risk stratification, [is to] look at whether these patients are autologous stem cell transplant (ASCT) eligible or not. If they are, then they go through an induction therapy phase followed by ASCT, which could be considered a consolidation phase, followed by a maintenance phase, as well.

For the transplant-ineligible category, the move is now to focus more on induction therapy followed by continuous therapy until disease progression. There are some other criteria that we use in selecting therapy. These are host factors such as the medical comorbidities and disease-related factors, such as how aggressive the disease is, and also therapy-related factors.

How have patient outcomes improved with the addition of some of these new therapeutic regimens?

How convenient is it for the patient to come to the clinic to get certain therapies, and are they able to tolerate certain therapies or not? It is complex decision making, and it involves not only physicians’ judgment in choosing the appropriate therapy, but we like to take patient preferences into account, as well. For the transplant-ineligible population, we had only melphalan/prednisone—and that was found to be just as good as many of the combination chemotherapies. This was noted on an important meta-analysis; subsequently, we conducted a meta-analysis that showed that the addition of thalidomide led to an improvement in not only progression-free survival (PFS), but OS as well.

Later on, the first trial conducted by the IFM group actually showed that melphalan/prednisone/thalidomide is actually inferior to the lenalidomide (Revlimid)/dexamethasone combination. More recently, we have this SWOG trial that showed that the addition of bortezomib (Velcade) to lenalidomide/dexamethasone is superior to lenalidomide/dexamethasone alone, not only in terms of PFS, but also OS.

What pivotal data could propel the field of multiple myeloma forward?

In a step-wise fashion, we have combined 2 novel agents along with a steroid—and the results that we see today are much better than about a decade ago. I also spoke about the IFM 2009 trial in which the results were published in the New England Journal of Medicine. The study was a phase III randomized controlled trial, in which 1 arm received upfront transplant after induction with bortezomib/lenalidomide/dexamethasone and the other arm received bortezomib/lenalidomide/dexamethasone for a total of 8 cycles followed by lenalidomide maintenance. The transplant arm also got 2 cycles of consolidation with lenalidomide/bortezomib/dexamethasone followed by lenalidomide maintenance for 1 year. There is a companion study that is currently ongoing in the United States. The Dana-Farber Cancer Institute’s study allows use of lenalidomide until progression. The results of this IFM 2009 trial showed that the transplant arm led to a better PFS. There was an improvement of approximately 14 months in median PFS, and there was an improvement in the MRD-negative state of approximately 14% with the integration of transplant to the novel agents. The 4-year OS, however, was equivalent in the 2 arms.

What should community oncologists know about treating their newly diagnosed patients with myeloma?

One of the important factors to highlight from this study is that the patients in the non-upfront transplant arm were allowed to undergo transplant at a later time point and about 80% of the patients in the initial non-transplant arm underwent delayed autologous stem cell transplant at the time of first progression. Some of the main points I would like a community oncologist to take home are to use the new IMWG definition of multiple myeloma when they see a newly diagnosed patient with myeloma. I would also emphasize the importance of knowing the new response categories, as MRD-negative states can be achieved with the use of newer therapies.

They need to remember to refer patients not only for clinical trials, but also for transplant early on in the disease—even if patients do not want to undergo stem cell transplant upfront. This is because it is important for the community physicians to realize that we would at least want to collect stem cells in patients who are eligible for ASCT. I also emphasize the importance of newer imaging modalities that can be used, particularly in patients with smoldering myeloma to find out whether the disease is truly smoldering myeloma or an active myeloma.