Clinical Pathways Updates in Multiple Myeloma: New and Expected Treatments for Refractory and Resistant Multiple Myeloma

Multiple myeloma (MM) is caused by abnormal plasma cell growth in bone marrow and results in marrow failure, production of an abnormal antibody called M protein that can cause tumors and impair immune function, and bone destruction. MM is relatively rare, representing only 1.8% of all new cancer cases,¹ 18% of all hematologic cancers,² and 2.1% of all cancer deaths¹ in the United States. An estimated 140,779 US people in 2017 were living with MM,¹ and approximately 12,830 people are expected to have died from the disease in 2020.³ An estimated 32,270 new cases were diagnosed in 2019, with a median age at diagnosis of 69 years and with diagnoses most commonly occurring between 65 and 74 years.¹

The number of MM diagnoses increased globally from 1990 to 2016, with aging contributing to 52.9% of cases and population growth contributing to 40.4% of cases.⁴ MM has a 53.9% 5-year survival rate,¹ with the latest available data from the federal Surveillance, Epidemiology, and End Results Program (SEER) showing an upward trend over time.¹ The 5-year relative survival rate for MM when SEER data were first collected between 1975 and 1977 was 24.6%.⁵ This rate increased by approximately 2% every 2 years until 2005. Between 2002 and 2004, the 5-year survival percentage was 42.5%, which increased to 46.4% between 2005 and 2007 and increased even further to 52.4% between 2008 and 2018.⁵

While there is no cure for MM, a number of treatments are in the research and development pipeline. Clinicians are particularly challenged to treat relapsed or refractory MM (RRMM); the goal of treatment in patients with relapse is to alleviate symptoms and prevent progressive organ damage.⁶ First-line treatment options are generally standardized, but with extensive options for subsequent therapy and multiple patient factors to consider, each line of therapy (LOT) becomes more complicated. Drug resistance in MM is greatly influenced by genetics, which contributes to a patient’s predisposition to drug resistance and relapse.⁷ Patients typically experience fewer complete responses (CRs) to each LOT. In a retrospective cohort study utilizing electronic health record data from 10,553 patients at more than 280 US cancer clinics from 2011 to 2019, approximately 65% of patients survived until the end of follow-up.⁸ The overall median survival decreased with each additional LOT patients received. The median overall survival in patients receiving first-line therapy was 60 months, which decreased to 48, 36, 29, and 23 months for the second, third, fourth, and fifth-plus LOTs, respectively.⁸

Initial Treatment

For more than 30 years, autologous stem-cell transplant (ASCT) has remained the standard initial treatment of MM. According to the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario guidelines, patients should be referred to transplant centers to determine their transplant eligibility.⁹ Eligibility for ASCT is affected by age, performance status, and comoribidites.¹⁰ A patient’s performance status is determined by how much the cancer affects the patient’s daily living abilities in terms of caring for themselves, daily activity, and physical ability. Prior to stem-cell transplant, 3 to 4 cycles of induction therapy are recommended.⁹ Induction therapy should include an immunomodulating drug, a proteasome inhibitor (PI), and a corticosteroid.⁹ According to guidelines from the National Comprehensive Cancer Network (NCCN), the preferred regimens for primary induction therapy in transplant-eligible candidates are bortezomib + lenalidomide + dexamethasone (VRd) or bortezomib + cyclophosphamide + dexamethasone (CyBorD) (Table 1). Other options include carfilzomib + lenalidomide + dexamethasone (KRd) and ixazomib + lenalidomide + dexamethasone (IRd).¹¹ For nontransplant candidates, the preferred treatments are VRd, daratumumab + lenalidomide + dexamethasone (D-Rd), lenalidomide + low-dose dexamethasone (Rd), and CyBorD. There are 3 other accepted regimens, as well.¹¹

Maintenance Therapy

Lenalidomide. The NCCN Panel recommends lenalidomide as first-line maintenance therapy, regardless of whether a patient has received ASCT.¹¹ This recommendation was based on the results of 2 randomized phase 3 studies. In the CALGB 100104 trial, patients received either maintenance therapy with lenalidomide or placebo following ASCT. At a median follow-up of 34 months, 37% of the patients who had received lenalidomide experienced disease progression or died compared with 58% of patients who had received placebo.¹² The median time to progression for patients receiving lenalidomide was 46 months compared with 27 months in the placebo group.¹² Data from IFM 2005-02, an international, double-blind, randomized trial, demonstrated that patients who received lenalidomide as consolidation therapy following ASCT and then continued to receive lenalidomide as maintenance therapy had improved responses. At the median follow-up of 30 months, 104 patients treated with lenalidomide experienced disease progression compared with 160 patients in the placebo group.¹³ Patients who received lenalidomide had a mean progression-free survival of 41 months compared with 23 months in the placebo group.¹³

Bortezomib. Bortezomib is another recommended maintenance therapy in both transplant-eligible and transplant-ineligible patients.¹¹ This recommendation is based on the results of the phase 3 UPFRONT study. Patients who were newly diagnosed with MM were treated with bortezomib-based primary regimens and then received maintenance therapy with bortezomib. The study demonstrated improved response rates in all treatment arms with no increase in the incidence of peripheral neuropathy.¹⁴

Ixazomib. Ixazomib is recommended as maintenance therapy in patients who are transplant-eligible. The TOURMALINE-MM3 trial, which studied patients receiving ixazomib or placebo over the course of 2 years and who achieved at least partial response following induction therapy and ASCT, demonstrated improved progression-free survival. The median progression-free survival in patients who received ixazomib was 26.5 months compared with 21.3 months in the placebo group.¹⁵

Treatment After Relapse

While initial therapy is well-defined by current guidelines, additional LOTs following relapse can prove more difficult, since treatment is not as straightforward. Numerous options are available for the treatment of patients with relapsed MM (Table 3), including newly approved medications and medications with newly approved indications by the Food and Drug Administration (FDA) over the past few years. Treatment of patients with relapsed MM should be individualized—physicians need to consider prior treatment, cytogenetic risk, comorbidities, myeloma markers, frailty, and patient preference.⁹ Generally, a triplet regimen, consisting of 2 novel agents (PI, immunomodulatory drug, or monoclonal antibody) in combination with a corticosteroid, is preferred.^9,10 In patients who have not yet undergone ASCT, or who underwent ASCT previously and experienced prolonged remission, ASCT should be considered as salvage therapy.¹⁰ If a patient experiences relapse more than 6 months after stopping initial therapy, the first LOT may be restarted.¹⁰ Of the preferred regimens recommended by the NCCN for previously treated MM, 6 of the 8 are triplet therapy.

New and Expected Treatments

In 2020, 3 new treatments were FDA-approved for MM: a first-in-class drug, a monoclonal antibody, and a new formulation of a previously approved medication. Additionally, new treatment regimens were FDA-approved. In August, the FDA approved carfilzomib + daratumumab + dexamethasone for patients with RRMM who have failed 1 to 3 previous LOTs.

Belantamab mafodotin-blmf. The FDA granted accelerated approval to belantamab mafodotin-blmf (Blenrep) in August 2020 for RRMM patients who received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a PI, and an immunomodulatory agent.¹⁶ The FDA granted this approval based on results of the phase 2 DREAMM 2 trial. Belantamab mafodotin-blmf is the first approved anti–B-cell maturation antigen (BCMA). The drug is available through a Risk Evaluation and Mitigation Strategy program, since it may cause serious changes to the cornea, leading to worsening or loss of vision.¹⁶

Isatuximab-irfc. The combination of isatuximab-irfc (Sarclisa), pomalidomide, and dexamethasone was approved in 2020 for RRMM after 2 or more prior therapies (including lenalidomide and a PI).¹⁷ Isatuximab-irfc is an anti-CD38 monoclonal antibody. Patients who received the combination of isatuximab-irfc, pomalidomide, and dexamethasone experienced a 40% reduction in risk of disease progression or death compared with patients who received only pomalidomide and dexamethasone.¹⁷

Daratumumab and hyaluronidase-fihj. Subcutaneous daratumumab (daratumumab and hyaluronidase-fihj) was granted FDA approval in May 2020 for adults with newly diagnosed or relapsed or refractory MM.¹⁸ Efficacy was evaluated in the COLUMBA trial, an open-label noninferiority trial in which 263 patients were randomly assigned to receive daratumumab and hyaluronidase-fihj (Darzalex Faspro) and 259 patients were randomly assigned to receive intravenous daratumumab (Darzalex). The overall response rate was 41.1% for subcutaneous daratumumab and hyaluronidase-fihj and 37.1% for intravenous daratumumab.¹⁸ On average, the first infusion of daratumumab lasts 7 hours, and infusions thereafter last 3 to 5 hours¹⁹; subcutaneous administration drastically reduces this time of administration.

The MM Treatment Pipeline

Other new treatments, indications, and combinations are on the horizon for treating MM.

Venetoclax. Venetoclax, approved by the FDA for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, and acute myelogenous leukemia, is a BCL-2 inhibitor that induces cell death in MM cells. In the BELLINI trial, RRMM patients received venetoclax plus bortezomib and dexamethasone or placebo plus bortezomib and dexamethasone. The trial was put on partial clinical hold in March 2019 due to safety concerns. The partial clinical hold was removed in July after the trial was modified ensure patient safety.²⁰

Melflufen. This drug is activated by aminopeptidase, an enzyme of which persons with MM have high levels. The FDA granted priority review to melflufen in combination with dexamethasone for the treatment of patients with RRMM who have been treated with at least one PI, one immunomodulatory agent, and one anti-CD38 monoclonal antibody. The targeted date of review is February 28, 2021.²¹ The is based on the not yet posted results of a phase 2 clinical trial evaluating melflufen plus dexamethasone in adults with MM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody.²²

Iberdomide. Iberdomide (formerly CC-220) is being studied in a phase Ib/IIa clinical trial to determine dose, safety, tolerability, and efficacy.²³ Iberdomide is a cereblon E3 ligase modulator and would provide a new immunomodulatory treatment option to patients whose cancer is resistant to lenalidomide and pomalidomide.

Chimeric antigen receptor (CAR) T-cell therapy. The CAR T-cell therapy closest to FDA approval targets BCMA (which is also the target of newly approved belantamab mafodotin-blmf). Researchers are utilizing γ-secretase inhibitors to increase the amount of BCMA produced by MM cells. If the myeloma cells express more BCMA, it will be easier for the CAR T cells to recognize and target the cancer.²⁴ However, not all patients with MM express BCMA. The CD229 (Ly9) receptor has been shown to be a target for CAR T-cell therapy. Results from a small study of 20 patients with MM showed that CD229 was heavily expressed on the surface of MM cells, both in patients who were newly diagnosed and in patients with RRMM.²⁵

Bispecific T-cell engager (BiTE). BiTE antibodies bind to 2 separate CD3 molecule clusters on tumor-specific T cells and a specific antigen on myeloma cells.²⁶ Binding to these 2 epitopes leads to T-cell–dependent destruction of the myeloma cells. Only one BiTE antibody, blinatumomab, has been approved, and it is used to treat relapsed or refractory B-cell acute lymphoblastic leukemia. BiTE antibodies are in early development to target BCMA and CD3 in MM, with 5 phase I clinical trials under way. In 42 MM patients with 4 previous LOTs, 31% responded to treatment with the BiTE antibody AMG 420, with CR in 14.2% of those patients, very good partial response in 5%, and partial response in 5%.²⁶ Based on these results, the FDA granted fast-track status to AMG 420 anti-CD3/BCMA BiTE.²⁶

Measuring Minimal Residual Disease

Minimal residual disease (MRD) is the measurable number of myeloma cells that remain in the bone marrow following MM treatment. In January 2020, the FDA released recommendations regarding the development of MRD tests. Current MM-associated MRD data mostly evaluate newly diagnosed patients after ASCT. The FDA states that, in the development of new drug products that reference MRD, the relationship between MRD and clinical benefit of the drug should reflect all disease settings (RRMM, newly diagnosed MM, nontransplant eligible). MRD should only be measured in patients who have achieved complete remission.²⁷

Use of Imaging

ASCO guidelines recommended the use of whole-body low-dose computed tomography (CT), with fluorodeoxyglucose positron emission tomography (FDG-PET) or magnetic resonance imaging (MRI) as alternatives.⁹ The NCCN recommends either whole-body low-dose CT or FDG-PET/CT for initial diagnosis and whole-body FDG-PET/CT, low-dose CT scan, or whole-body MRI without contrast for advanced imaging.¹¹

Supportive Care

Bone disease. All patients undergoing primary treatment for MM should receive a bisphosphonate or desosumab.¹¹ Additionally, it is recommended that patients receive a baseline dental examination. Treatment with a bisphosphonate or denosumab should be continued for up to 2 years.¹¹ Patients should be monitored for osteonecrosis of the jaw, as well as for renal dysfunction if receiving bisphosphonate therapy. Radiation therapy can be used for palliation in patients with MM, including those with uncontrolled pain, impending pathologic fracture, or impending cord compression.¹¹ Patients with impending or actual long-bone fractures, bony compressions of the spinal cord, or vertebral column instability should receive orthopedic consultation. Vertebroplasty or kyphoplasty should be considered for patients with symptomatic vertebral compression fractures.¹¹

Hypercalcemia. The NCCN panel recommends hydration, bisphosphonates (with zoledronic acid preferred), denosumab, steroids, and/or calcitonin for the management of hypercalcemia.¹¹

Blood hyperviscosity. Plasmapheresis should be utilized as adjunctive therapy in patients with symptomatic blood hyperviscosity.¹¹

Anemia. Erythropoietin can be considered for use in patients with MM with anemia. The NCCN panel recommends utilizing the NCCN Guidelines for Hematopoietic Growth Factors.¹¹

Infection. If a patient with MM is experiencing recurrent serious infections, intravenous immunoglobulin therapy can be considered.¹¹ Patients should receive the pneumococcal conjugate vaccine followed by the pneumococcal polysaccharide vaccine 1 year later.¹¹ If a patient is at high risk for infection at diagnosis, 3 months of antibiotic prophylaxis should be considered.¹¹ Patients receiving high-dose dexamethasone should receive prophylaxis for Pneumocystis jiroveci pneumonia, herpes zoster, and fungal infections. All patients treated with PIs, daratumumab, isatuximab-irfc, or elotuzumab should receive herpes zoster prophylaxis.¹¹ For more in-depth recommendations, the NCCN panel recommends utilizing the NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.¹¹

Kidney dysfunction. Patients with MM and kidney disease should have their serum creatinine, electrolyte, and uric acid levels routinely tested. Patients’ urine should also be monitored for protein.¹¹ Treatment option recommendations change for patients with renal dysfunction. A bortezomib-based regimen is recommended, dexamethasone should be pulsed, and a third drug (cyclophosphamide, thalidomide, anthracycline, or daratumumab) may be considered.¹¹ If a patient will be receiving lenalidomide, there are dose adjustments based on kidney function (Table 4). The NCCN MM guidelines contain in-depth management recommendations.¹¹

Coagulation/thrombosis. Aspirin (dosed at 81-325 mg) is recommended for patients receiving immunomodulator-based therapy.¹¹ Patients who are at high risk for thrombosis should receive therapeutic anticoagulation.¹¹ The NCCN Panel recommends utilizing the NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease.¹¹

Continued Challenges

MM, a challenging cancer manage on its own, has become even more difficult to manage during the COVID-19 pandemic. Coronavirus infection is dangerous for any person but particularly for those with cancer. Patients with MM receive treatment that can cause immunosuppression and increase the risk of infection. Immunomodulatory drugs can cause neutropenia, which also increases the risk of infection. In combination with PIs and corticosteroids, these therapies increase the infection risk even further.²⁸ When possible, utilization of oral-only treatment regimens can decrease the risk of exposure in patients who otherwise would have gone to the hospital or oncology clinic for administration of an intravenous treatment regimen.²⁸

Cost is another concern in the treatment of MM. The annual cost of the 3-drug combinations recommended by the NCCN for RRMM is estimated at $220,000 to $300,000.²⁹ While no cure exists for MM, patients may be able to discontinue treatment if the cancer goes into remission. New therapies have increased the survival rate after relapse, and as a result a large portion of disease costs, resource use, and time occur in the setting of RRMM.³⁰ Patients beginning their fourth or fifth LOT can be financially exhausted.

The 5-year survival rate for MM continues to improve, more drugs are available to treat newly diagnosed patients and patients with RRMM, and promising treatments are in development.   

References

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