In dealing with coronavirus disease 2019 (COVID-19), some oncologists are modifying conventional treatment regimens to limit patients’ visits to infusion centers and providers’ offices. The ASCO Post asked C. Ola Landgren, MD, PhD, Chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College, New York, how he is managing in regard to the treatment of patients with all stages of myeloma during the COVID-19 pandemic.
C. Ola Landgren, MD, PhD
Newly Diagnosed Myeloma: Tailor to Goals of Care
How do you approach a newly diagnosed patient today?
For patients who are truly newly diagnosed, it is important first to discuss the goals of care. For the young, otherwise healthy patient, we like to offer the most effective possible therapy, and it’s important to tailor that to the patient’s goals. We give the patient options, but they need to take into account COVID-19. Does the patient want to start on a regimen that is all oral or go forward immediately with combination regimens? If you have a young patient with a high disease burden, remember it’s not just about how to manage it now, but also about the next steps.
Before the COVID-19 pandemic, transplant was often recommended for newly diagnosed patients. How about now?
We do not want to do upfront stem cell collection or stem cell transplant at this time, with the exception of the very rare patient with aggressive disease and no other good options. These patients are unusual in the current era because of the effective drugs we now have. But we do need to factor several aspects into our decision-making: if we use an all-oral therapy to avoid visits for infusions/injections, the efficacy is lower and data suggest that progression-free and overall survival are shorter with such drugs as compared to modern combinations that include infusions/injections.
My default recommendation for a fit, otherwise healthy person who has been diagnosed with multiple myeloma in the current era of COVID-19 is to start with a modern, effective combination regimen and then to step down to all-oral maintenance therapy. For a frail person or a person with several comorbidities, my default recommendation would be to start with an all-oral regimen.
Start With Weekly Regimens
You’ve said that modern, effective combinations should be chosen instead of transplant. What are your first choices?
Fortunately, we have treatments we can give weekly. One regimen is carfilzomib, lenalidomide, and dexamethasone (KRd), which we are using as the default combination therapy for fit, newly
diagnosed patients with multiple myeloma at our center. Overall, in our hands, compared to all the other options, the weekly KRd regimen is superior in terms of efficacy, and it is also safe in the setting of newly diagnosed patients with multiple myeloma who are otherwise fit. Importantly, the weekly KRd regimen does not cause peripheral neuropathy or chronic pain and tingling; these side effects you commonly see in patients treated with the older bortezomib, lenalidomide, and dexamethasone (VRd) regimen. As patients with multiple myeloma are living longer and longer, it is increasingly important to avoid debilitating side effects like peripheral neuropathy and chronic pain and tingling in fingers and toes.
We give once-weekly carfilzomib on day 1 (20 mg/m2), day 8 (56 mg/m2), and day 15 (56 mg/m2) for the first cycle, with the fourth week off. In subsequent cycles, we give carfilzomib at 56 mg/m2 on days 1, 8, and 15. Patients also receive dexamethasone at 40 mg on the same days as carfilzomib and lenalidomide at 25 mg for 3 weeks on (ie, days 1–21) with 1 week off. The duration of each cycle is 28 days. Of note, we give 20 mg of dexamethasone (instead of 40 mg) if the patient is older than 60 years, and we decrease the dose for any patient who suffers from side effects such as sleeping problems or mood swings.
To be practical, we typically treat younger, otherwise fit patients with six cycles of KRd—a weekly infusion for 3 weeks on, 1 week off—which is a total of 18 doses. That’s 18 visits, using hand hygiene and social distancing as much as possible. We think that’s a good way to control disease and to justify not giving a more toxic therapy, such as a stem cell transplant.
“We do not want to do upfront stem cell collection or stem cell transplant at this time, with the exception of the very rare patient with aggressive disease and no other good options.”— C. Ola Landgren, MD, PhD
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Other options beyond KRd are the older combination therapies, including the aforementioned VRd regimen, as well as bortezomib, cyclophosphamide, and dexamethasone (CyBorD). We reserve CyBorD for patients with renal failure, and we consider VRd for patients with underlying cardiac disease. For both VRd and CyBorD, we give subcutaneous bortezomib once a week.
Daratumumab is increasingly being used in this setting. Are you modifying its dosing?
The DRd (daratumumab, lenalidomide, dexamethasone) regimen is U.S. Food and Drug Administration–approved for nontransplant patients and, in my experience, is a great alternative to VRd. DRd does not cause peripheral neuropathy and chronic pain and tingling, which commonly occur in patients receiving bortezomib. Indeed, DRd is quite effective and well tolerated.
During the COVID-19 pandemic, the only modification I would consider with DRd is to switch sooner to monthly daratumumab infusions than the label states. For example, give four to eight weekly doses and then consider monthly dosing. I would refer to such a dosing schedule as “DRd-light.” It’s designed to limit the number of infusions and visits, which is reasonable during the COVID-19 outbreak.
What are you using for maintenance therapy, and how are you following patients?
After combination therapy has been completed, we use an all-oral maintenance regimen. In accordance with the guidelines of the National Comprehensive Cancer Network® (NCCN®), we use single-agent lenalidomide at 10 mg on days 1 to 21 of a 28-day cycle.
We limit visits for blood testing; typically, we do blood draws once every 3 months. For follow-up visits during the COVID-19 era, our default is telemedicine.
Relapsed/Refractory Myeloma: Emphasize Safety
What are your first choices for treating a patient with relapsed or refractory disease?
Just as for primary therapy, we want to tailor treatment according to the goals of care and give the patient options. But we also want to avoid any therapy that causes cytopenia and the need for transfusions, since we currently have a shortage of blood and platelets. If you’re considering “old school chemotherapy” or even a second transplant, I think it may be better to choose alternatives.
We suggest daratumumab, carfilzomib, or bortezomib in combination with pomalidomide, lenalidomide, or cyclophosphamide (plus dexamethasone). Established combinations using these drugs include KRd; carfilzomib, pomalidomide, and dexamethasone (KPd); DRd; daratumumab, pomalidomide, and dexamethasone (DPd); carfilzomib, cyclophosphamide, and dexamethasone (KCyD); bortezomib, pomalidomide, and dexamethasone (VPd); and others.
Does the dosing schedule change?
In the relapsed/refractory setting, similar to the primary treatment setting, consider less-frequent dosing schedules. For instance, give bortezomib and carfilzomib once a week; for daratumumab, the current label says to give it once a week for eight doses, then once every other week for eight doses, then monthly, but you may be able to give it less often. You can also use “DRd-light” to limit the number of infusions and visits, giving four to eight weekly doses of daratumumab, then considering monthly dosing.
How has your follow-up protocol changed?
For all patients on active therapy—for newly diagnosed, relapsed, or refractory disease—we recommend limiting extra visits for blood testing. Instead, do blood testing on the last day of the cycle, recognizing you won’t know the full effect of the treatment at that point, but you will be limiting unnecessary visits. As in newly diagnosed patients, we avoid unnecessary biopsies and imaging and use telemedicine for follow-up.
Finally, do you recommend any changes in protocol for managing patients with smoldering myeloma or monoclonal gammopathy of unknown significance (MGUS)?
As there is no approved treatment for these conditions, the use of any drugs in this setting is experimental and not supported by the NCCN Guidelines®. Thus, it’s all about monitoring and making sure patients do not have evidence of disease progression.
Our practical advice is to limit visits for blood testing, bone marrow biopsies, and the use of imaging. If these procedures are scheduled for any time soon, delay them for a few months, unless there is a strong clinical reason for performing them now.
As for the patient who does develop a new symptom, this would be rare, especially with MGUS. Even with smoldering myeloma, disease progression usually occurs slowly over a longer period, so this would also be unusual. For this patient, you could consider blood testing as a first step and a telemedicine visit for follow-up.
DISCLOSURE: Dr. Landgren has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Medscape, and Onyx; has served in a consulting or advisory role for Bristol-Myers Squibb, Celgene, and Onyx; has received research funding from Amgen, Celgene, Janssen, and Takeda; and has been reimbursed for travel, accommodations, or other expenses by Celgene, Millennium, and Onyx.