ASCO 2020: High-Risk Disease Progress Continues Despite Uncertainties

“Despite the improvements across the board that we’ve seen in myeloma patients, high-risk disease continues to represent a more complicated arena.”

Treatment strategies for myeloma high-risk disease are becoming more refined, yet individualized approaches to benefit today’s patients remain elusive according to Mount Sinai Hospital’s Dr. Joshua Richter’s ASCO 2020 oral presentation "Pearls" for Newly Diagnosed High-Risk Multiple Myeloma: Finding the Right "Jam."

Developing Better Ways to Stratify Risk

Improved methods of risk stratification—determining which patients benefit from specific options in the menu of possible therapy options—will be key to determine consensus-driven definitions to “standardize and better classify patients” and to “allow [researchers and physicians] to cross-compare” patients.  Among the issues needing more study and clarification are stem cell transplant eligibility, how to interpret minimal residual disease (MRD) negativity if it is achieved, whether to be more aggressive during induction, consolidation, or maintenance phases of treatment, and optimizing the use of monoclonal antibodies like daratumumab.

Myeloma diagnoses are still “defin[ed] in terms of transplant-eligible and -ineligible.”  While the current standard of treatment for all patients favors transplant if they are eligible, high-risk patients “inherently have a predilection for a worse outcome [because they tend to be] transplant-ineligible.”

But for those who are eligible, tandem autologous stem-cell transplants have “varying degrees of success…some patients with high-risk disease still…have further tumor burden reduction…that leads to deeper remissions and hopefully abrogates the diminished outcomes.”  On the other hand, “allogeneic stem cell transplants” are still “very controversial…especially with CAR T-cells and other technologies” in development.

Noting that high-risk patients tend to fall into the MRD-positive category, Dr. Richter emphasized that MRD “has provided a method for further defining both response, prognosis, and potentially a guide for intervention.”

While “the achievement of MRD-negativity in high-risk patients…may…justify more aggressive induction and transplant approaches [it] may not be enough by itself.”  Even if remission is achieved in high-risk patients, that does not mean “we can take our collective foot off the gas pedal,” aggressive measures may need to be continued and evidence of year-long MRD-negativity might be an indication that therapy can be lessened or stopped.

When to Be More Aggressive? 

Another key challenge for treating high-risk patients includes determining which will benefit from being more aggressive in either the induction, consolidation, or maintenance phases of therapy.

“Ultimately, we still don’t know the ideal induction regimen for patients with high-risk disease.”  Despite “more aggressive combinations” of more aggressive “induction regimens” using up to four drug combinations and “a variety of maintenance strategies” survival rates for high-risk patients remain lower as compared to standard-risk patients.

“Another way potentially of controlling or offsetting high-risk disease is with a more aggressive maintenance strategy [with] multi-agent chemotherapy [such as] combined bortezomib, lenalidomide, and dexamethasone (VRd) [which have demonstrated] particularly good outcomes in some of the worst” cases of high-risk disease.

Bortezomib has a long history of effectiveness in high-risk disease according to studies done by the University of Arkansas and the European study groups IFM (France) and HOVON (the Netherlands).  “Pomalidomide has shown efficacy in offsetting this risk, particularly” in patients with the -17p genetic marker.  Additionally, carfilzomib “has shown significant activity in upfront, relapsed and refractory [patients], even over bortezomib-based therapies.”

An open “question is: is the pathway to improve outcomes by combining a monoclonal antibody with some of our best three-drug regimens to achieve a four-drug regimen?”  For example, adding daratumumab to three-drug combinations seems to have a better outcome for more high-risk disease patients than adding it two-drug combinations, but more studies will be needed to verify this.

Risk Adapted Study Approaches

Dr. Richter closed by mentioning an ongoing study by Emory University’s Winship Cancer Institute which “found that with more long-term follow up, the medial overall survival for patients with high-risk disease was 78.2 months [which suggests] a risk-adapted approach” for each individual patient to determine if the best time to be aggressive at either the induction, consolidation, or maintenance phases of high-risk disease treatment.

“I think the big question we all want to know is, which patients specifically with the heterogeneous definitions of high-risk disease will really benefit from these more aggressive approaches?”

Ever since Dr. Bart Barlogie demonstrated 22 years ago that thalidomide was the first drug ever that directly affected myeloma, arguably more progress has been made in this type of cancer than any other.  For confirmation, look no further that this year’s annual American Society of Clinical Oncology (ASCO) meeting, which mostly highlights solid tumors.

More on Myeloma at ASCO and EHA 2020

Myeloma abstracts and oral presentations, like Dr. Richter’s, received an unprecedented amount of attention and prominence as compared to past meetings, yet another sign of the unprecedented advances being made in myeloma research and treatment.

Additional Myeloma Crowd reports on ASCO 2020 include: Are Myeloma Patients Getting the Right Vaccinations?, An Update on COVID-19 and Cancer Patient Outcomes, KRd vs. VRd for Newly Diagnosed Multiple Myeloma, and Mass Spectrometry in MRD Assessment.

To listen to or read the transcript of Dr. Paul Richardson's Myeloma Crowd Radio's overview of ASCO 2020 myeloma presentations, click here.

To listen to or read the transcript of Dr. Richter’s recent Myeloma Crowd Radio interview on what myeloma patients should know about COVID-19, click here.

A 90 minute Myeloma Crowd Round Table Interactive Webcast on the upcoming European Hematology Association annual meeting featuring three European myeloma experts will take place on Saturday, June 20 at noon EDT.  Please register here if you are interested in viewing or want to ask questions.