Multiple myeloma is a malignancy characterized by clonal proliferation of terminally differentiated plasma cells within the bone marrow. Although it leads to a host of different issues within the body, overall survival has steadily improved in recent years. “This is largely because of better identification and diagnosis, better methods of treatment, and improved symptom management,” said Josh Epworth, ARNP, of Washington University Medical Center and the Seattle Cancer Care Alliance.
Josh Epworth, ARNP
Edward Libby, MD
At JADPRO Live, the annual conference of the Advanced Practitioner Society for Hematology and Oncology, Mr. Epworth was joined by Edward Libby, MD, Associate Professor of Medical Oncology at the University of Washington and the Seattle Cancer Care Alliance, to discuss reasonable treatment approaches in newly diagnosed patients, the incorporation of the latest-generation agents, and a preview of new treatments that are being met with enthusiasm by the myeloma community.
Presenting Signs and Symptoms
“Multiple myeloma is a disease of peaks and valleys. We want to diagnose it early, before it causes damage, and suppress the disease as best as we can in the first two cycles of the initial regimen of therapy,” Mr. Epworth said.
Nearly all patients respond to their first treatment, but remissions do not last forever. The first two will be the longest, but as the disease evolves, these remissions become shorter and the cancer becomes more aggressive. It is important, therefore, to achieve a robust effect early, Mr. Epworth said. “Also, because this disease is a marathon,” clinicians should have a treatment plan for the full course of the disease, he suggested.
“Multiple myeloma is a disease of peaks and valleys. We want to diagnosis it early, before it causes damage, and suppress the disease as best as we can in those first two treatment cycles.”— Josh Epworth, ARNP
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In the diagnostic workup, the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) on imaging have been updated to recommend (1) whole-body low-dose high-speed computed tomography (CT); (2) positron-emission tomography (PET)/CT; or (3) bone marrow biopsy and magnetic resonance imaging (MRI).1 In all cases, a number of lab tests are necessary, as is a bone marrow biopsy for genetic and morphologic testing. The main biomarker of myeloma is a spike in monoclonal protein (M spike). It is identified by serum protein electrophoresis or urine protein electrophoresis in approximately 85% of patients; in the 15% of patients with no detectable M spike, serum free light chains can be detected and are diagnostic. There is a small proportion of patients with non-secretory meloma who do not exhibit an m-spike and free light chains. In this case, monitoring is more difficult.
Mr. Epworth also explained that the CRAB criteria (increased calcium level, renal dysfunction, anemia, and destructive bone lesions) are no longer the only indicators of a myeloma diagnosis; a “myeloma-defining event” also qualifies. “A myeloma-defining event means there are some markers of an opening act to multiple myeloma; if we don’t act within a short period, we can expect to see damage,” he explained. “Once we see CRAB criteria (in conjunction with a bone marrow biopsy with > 10% abnormal plasma cells) or a myeloma-defining event, that’s the trigger to begin treatment. And once we start treatment, we don’t stop until we come to the end of the patient’s life.”
Initial Treatment
For initial treatment, triplets are now the standard of care, and even four drugs are being used upfront. Lenalidomide/bortezomib/dexamethasone (RVd), on a 21-day cycle, is the gold standard backbone. Issues with RVd include fatigue, rash and diarrhea; the main problem with bortezomib is peripheral neuropathy, although it occurs less often with newer subcutaneous dosing. After four to six cycles of RVd, patients can progress to collection and an auto stem cell transplant followed by maintenance or simply begin maintenance. With RVd, maintenance will typically utilize either lenalidomide at a reduced dose or bortezomib at a reduced frequency. For patients with high-risk cytogenetic factors, carfilzomib on a 28-day cycle may be the preferred proteasome inhibitor. When patients have multiple comorbidities or advanced age and are transplant-ineligible, RVd “lite,” given on a 35-day cycle with a reduced dose of lenalidomide, helps to maintain blood cell counts, Mr. Epworth indicated.
“Although complete response once was the goal, stringent complete response (all evidence of disease eradicated from blood, urine, and bone marrow) is my goal for my patients.”— Edward Libby, MD
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The latest “game changer” in myeloma is the monoclonal antibody daratumumab, which is being combined with an ever-growing list of agents. For instance, the four-drug regimen of daratumumab/bortezomib/melphalan/prednisone is an option for transplant-ineligible patients at Mr. Epworth’s center in Seattle. “We’re seeing a good effect against the disease and good tolerability,” he noted.
“The biggest problem with daratumumab is its 50% rate of infusion reactions during the first two infusions,” noted Mr. Epworth. At least for the first two to four doses, infusions should be done at a center with experience in managing this side effect, he said.
Stem Cell Transplantation
Autologous transplant, however, remains the goal for most patients whenever possible, emphasized Mr. Epworth. “Currently, transplant has the best chance at suppressing the disease. It’s well tolerated and offers a good quality of life once patients move through the first post-transplant period. We tell most of our patients to plan on undergoing a transplant,” he said.
Dr. Libby weighed in on the use of transplant, noting that he has treated patients up to around age 80. There are certainly exceptions, “but older patients can successfully receive a stem cell transplant. The risk of dying from a transplant is not dramatically higher in older patients than in younger patients,” he said. Renal dysfunction is also not an absolute contraindication. He said that 20% to 30% of his transplant patients have significant kidney damage from their disease but safely undergo transplant (as do some patients on dialysis).
“When considering stem cell transplant, know that it is still an option in older patients and in patients with renal dysfunction, but not in patients who are fragile and frail, even if they are 55 years old,” Dr. Libby said. He added that although stem cell transplant remains a “key” backbone therapy, it is no longer the only option we have.”
Measuring Successful Treatment
The success of treatment is largely, though not entirely, measured by blood tests, according to Dr. Libby. M protein (the intact immunoglobulin) is detected with serum protein electrophoresis in most patients; in patients with no detectable M protein, it is determined by serum free light chains. “With those two tests, almost all patients can be monitored with just a blood test. You don’t need a PET scan or a bone marrow biopsy,” he said.
“Depth of response matters. MRD negativity has become a new target in multiple myeloma….”— Edward Libby, MD
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A partial response to treatment is defined as at least a 50% reduction of serum M protein plus reduction in 24-hour urinary M protein by at least 90% or less than 200 mg/24 hours. “I would like to see this after two to three cycles of chemotherapy, to know the patient is responding well to treatment and we can continue it. If you see only a 10% to 20% fall, you need to think about changing the treatment,” according to Dr. Libby. “However, a 50% reduction is not the goal. We want a deeper remission.”
A very good partial response is at least a 90% reduction in serum M protein plus urine M-protein level up to 100 mg/24 hours. “When we see this, we start to feel pretty confident the drugs are working well and the patient is on the right track,” Dr. Libby explained. “The markers reflect what’s going on in the bone marrow. If they are coming down, almost certainly the cells in the bone marrow are dying, and there are fewer cancerous cells producing abnormal proteins.”
A complete response is indicated by complete disappearance of an M-protein spike (or plasmacytoma) and a normalization of free light chains, he continued, noting that patients can have both an M-protein spike and free light chains, but providers should pick one to monitor. Although complete response once was the goal, stringent complete response (all evidence of disease eradicated from blood, urine, and bone marrow) is a step beyond. “This is my goal for my patients,” Dr. Libby said.
Minimal Residual Disease Negativity
However, an even deeper level of response is now recognized: minimal residual disease negativity. Flow cytometry can now detect abnormal cells at a sensitivity of 10-5 to 10-6, and next-generation sequencing can detect 1 in 1,000,000. Studies have consistently shown that patients who achieve minimal residual disease negativity will have much better outcomes.
“Depth of response matters,” Dr. Libby emphasized. “Minimal residual disease negativity has become a new target in multiple myeloma…. It’s probably going to be our new goal when we’re treating multiple myeloma: not just to achieve a complete remission, but to get patients to be minimal residual disease–negative, which means they may have a fairly long remission. Perhaps we can even start to achieve cures in some of these people.” Although minimal residual disease is a useful measure in clinical trials, and it can be ordered in clinical practice, it is not yet clear how it should be applied, he added.
Treatment in the Foreseeable Future
Three new agents in development are generating much excitement. Belantamab mafodotin—the first antibody-drug conjugate in myeloma—contains a monoclonal antibody targeting the B-cell maturation antigen, which most myeloma cells express. Belantamab has generated response rates of 60% in heavily pretreated relapsed or refractory disease and 30% in penta-refractory disease (including daratumumab), without producing neuropathy.
“This is very, very exciting. It’s the kind of data presented for daratumumab to become approved,” noted Dr. Libby. Patients in the daratumumab trials had also failed to respond to all effective treatments, yet daratumumab worked in 30% of them. Belantamab may be approved within months, he proposed.
Bispecific T-cell engagers are early in development for myeloma, but one, blinatumomab, is already approved for acute lymphoblastic leukemia. Bispecific T-cell engagers are composed of two single-chain antibodies with different targets, which attach to the myeloma cell (the target) and pull T cells into the area to engage and kill the myeloma cell. “This is an exciting type of therapy,” Dr. Libby said. “We are hopeful it will be brought to reality in multiple myeloma.”
Finally, chimeric antigen receptor (CAR) T-cell therapy is in development for myeloma by many different companies, with at least one product (bb2121) expected to be approved in 2020. “The response rates in myeloma are ‘jaw dropping.’ The patient may be dying of the large burden of disease, but 1 week later, you cannot find a single cell,” according to Dr. Libby. “The biggest issue has been that CAR T cells don’t last, and remissions have been limited to about 1 year, but it’s still early in the game, and we will figure this out.”
In a small but pivotal study of 33 very heavily pretreated patients, the response rate was 85%, with 45% being complete responses.2 The median progression-free survival was 11.8 months. Cytokine-release syndrome occurred in 75%, yet all but 6% were grade 1 or 2. Neurologic toxicity occurred but was mainly low grade, although one patient had a reversible grade 4 neurologic event.
Next-generation immunomodulatory drugs include iberdomide, a cereblon E3 ligase modulator. In a phase I/II study, approximately 30% of patients responded after becoming refractory to daratumumab and pomalidomide.3
DISCLOSURE: Mr. Epworth and Dr. Libby reported no conflicts of interest.
REFERENCES
1. Kumar SK, Callander NS, Baljevic M, et al: NCCN Practice Guidelines in Oncology for Multiple Myeloma, version 2.2020. Available at https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed December 9, 2019.
2. Raje N, Berdeja J, Lin Y, et al: Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med 380:1726-1737, 2019.
3. Lonial S, van de Donk NWCJ, Popat R, et al: First clinical (phase 1b/2a) study of iberdomide (CC-220), a CELMoD, in combination with dexamethasone in patients with relapsed/refractory multiple myeloma. 2019 ASCO Annual Meeting. Abstract 8006. Presented June 2, 2019.
