Approach to Treatment in Multiple Myeloma

By Manni Mohyuddin, MD, Assistant Professor of Medicine at Huntsman Cancer Institute 

Treatments

In disease management, the initial step is to verify the diagnosis and ensure treatment is indicated. Patients with monoclonal gammopathy of undetermined significance (MGUS) may have concurrent renal failure due to common comorbidities such as diabetes mellitus. Thus, the diagnosis of multiple myeloma (MM) requires close verification in order to avoid patients having MGUS or SMM from inappropriately getting treated.

Once the diagnosis is established, treatment should start promptly, as life expectancy is measured in months without treatment. Treatment for MM is a rapidly evolving field with major advances over the last few decades.

Traditionally, the approach for newly diagnosed patients has been categorized based on whether patients are transplant eligible.

Transplant eligibility involves a thorough assessment based on many factors beyond just numerical age. In general, transplant centers in the United States routinely consider a transplant for eligible patients well into their 70s.

For transplant eligible patients, the initial treatment approach is divided into three phases. The first phase of treatment is referred to as induction therapy. Contemporary induction therapies involve the use of either triplet or quadruplet regimens in an attempt to drive the disease into a deep remission and prevent further organ damage. This is followed by the second phase of consolidation, which involves the use of high dose chemotherapy and autologous stem cell transplant (and sometimes additional courses of multi-drug regimens afterward). The third phase is maintenance, which involves using lower intensity regimens (such as lenalidomide alone) to keep the disease under control. The maintenance phase continues until the patient experiences a relapse, in which case continuous therapy is started again.

For transplant ineligible patients, some regimens are given continuously from induction through progression, whereas other regimens are de-escalated, and certain medications are discontinued after a finite period.

This paradigm of a continuous therapy may change in the future, as response-adapted approaches are being evaluated.

Chemotherapeutic Agents

The primary chemotherapeutic agent utilized in MM is high dose melphalan in concurrence with an autologous stem cell transplantation.

In multiple trials, high-dose melphalan has consistently prolonged progression-free survival (PFS) compared to standard therapies.^{1, 2}

Cyclophosphamide is another chemotherapeutic agent utilized in the treatment of both newly diagnosed and relapsed MM as part of various regimens.^3-5 As lenalidomide requires careful dose adjustments in patients with renal failure, cyclophosphamide is often used in a triplet regimen of bortezomib/cyclophosphamide/dexamethasone in newly diagnosed MM who present with renal failure.⁵

Outside the United States, low-dose melphalan administered over a long period of time is a part of backbone regimens for transplant ineligible patients in regimens such as bortezomib/melphalan/prednisone and daratumumab/bortezomib/melphalan/prednisone.⁶

Corticosteroids

Dexamethasone, a corticosteroid, is part of the backbone for most treatment regimens for MM. It helps to stabilize lysosomal membranes and is cytotoxic to lymphoid cells. Additionally, it helps enhance the efficacy of numerous other agents and can decrease the incidence of side effects of other medications. However, it is associated with numerous side effects, including blood sugar changes, insomnia, mood changes, vision changes, weight gain, and increased appetite.

In modern regimens, the isolated effect of dexamethasone is hard to elucidate. In clinical trials evaluating most regimens, both control and intervention arms have had similar doses of dexamethasone. In some newer studies, efforts are underway to evaluate treatment regimens without dexamethasone (NCT05083169). 

Immunomodulatory Drugs

The immunomodulatory drugs thalidomide, lenalidomide, and pomalidomide represent important backbone therapies for the treatment of MM. Thalidomide was previously withdrawn from the market due to its teratogenicity but was later found to prevent neoangiogenesis in human malignancies and modulate the immune system against MM.

Although thalidomide is not commonly used in the United States due to toxicities such as neuropathy, it remains a widely used agent in Europe.⁷

Lenalidomide is widely used as front-line treatment. The prevailing standard of care in the United States for transplant eligible patients is the triplet of bortezomib/lenalidomide/dexamethasone (VRd), which has been established in large randomized trials.^{8, 9} In a dataset of 1,000 patients who received this regimen for induction followed by transplant, researchers observed an overall survival of 127 months,¹⁰ and response rates consistently exceeding 90%.¹⁰

Pomalidomide is a second-generation immunomodulatory drug that has an established role in the relapsed/refractory space. In combination with dexamethasone, pomalidomide has served as the backbone for numerous regimens that are currently widely used in MM, such as daratumumab/pomalidomide/dexamethasone, isatuximab/pomalidomide/dexamethasone, elotozumab/pomalidomide/dexamethasone, and others. Its safety and toxicity profile is similar to that of lenalidomide.

Lenalidomide also represents the only drug to date that has shown an overall survival advantage when used in the maintenance setting following an autologous transplant. It is widely approved and used as the standard of care in that setting.¹¹

Proteasome Inhibitors

The three proteasome inhibitors approved for use in MM are bortezomib, ixazomib, and carfilzomib. Proteasome inhibitors interfere with cellular mechanisms of protein degradation by blocking the β proteolytic subunits of the 20s proteasome and hence increasing apoptosis of MM cells.

Currently, bortezomib is an established backbone of newly diagnosed treatment regimens. The main side effects associated with bortezomib are thrombocytopenia and peripheral neuropathy, although rates are lower with contemporary once-weekly subcutaneous dosing.¹²

Carfilzomib is a second-generation proteasome inhibitor with established use in the relapsed and refractory setting, based on multiple randomized trials.^{13, 14} However, in the front-line setting, it has not been shown to be superior to bortezomib in two randomized trials.^{8, 15} In non-randomized settings, it has demonstrated improved efficacy in high-risk patients compared to historical controls and patients within those trials that had standard risk MM.¹⁶ Based on that data, carfilzomib is occasionally considered in high-risk patients as part of an induction regimen. Although it has a much lower incidence of peripheral neuropathy compared with bortezomib, it is associated with cardiac and renal toxicities, as well as pulmonary hypertension.

Ixazomib, an oral agent, has consistently demonstrated a much smaller margin of benefit in randomized trials. Long-term follow-up data has not demonstrated an overall survival benefit in the early relapse or maintenance settings.¹⁷ Despite a lower incidence of peripheral neuropathy, it has gastrointestinal side effects and is associated with similar hematological toxicities. Thus, its use is reserved for situations where an oral regimen is strongly preferred.

Monoclonal Antibodies

Monoclonal antibodies have played a transformative role in the management of MM. Daratumumab, an anti-CD38 targeting monoclonal antibody, is a mainstay of therapy for patients with relapsed and refractory MM and increasingly in the newly diagnosed setting.

Daratumumab has shown efficacy in 4 phase III trials, in which it has improved PFS as part of a triplet when compared to a doublet arm.^{14, 18-20} For example, in a trial of 569 patients who received either lenalidomide and dexamethasone alone (Rd) or with daratumumab (D-Rd), D-Rd significantly prolonged PFS (median of 44.5 vs. 17.5 months; hazard ratio= 0.44; 95% CI, 0.35-0.55).¹⁸

In the newly diagnosed setting, daratumumab has been evaluated in multiple trials and has consistently been shown to deepen responses when added to standard therapy. Low cross-over rates upon progression in these trials, however, continue to raise the question of whether up-front daratumumab is better than daratumumab at relapse.²¹

In the MAIA trial, daratumumab/lenalidomide/dexamethasone was compared to lenalidomide/dexamethasone²² for transplant ineligible patients with newly diagnosed MM. In this trial, the expected five-year median PFS for the triplet intervention arm was 52%, setting a new milestone for this disease. Given the results of this trial, daratumumab/lenalidomide/dexamethasone represents a standard of care option for newly diagnosed MM, although no direct comparison exists with bortezomib/lenalidomide/dexamethasone (VRd).

Daratumumab also met demonstrated greater response rates and PFS in two other trials in the newly diagnosed space in the CASSIOPEIA trial. (daratumumab/bortezomib/thalidomide/dexamethasone versus bortezomib/thalidomide/dexamethasone) for transplant eligible patients and the ALCYONE trial (daratumumab/bortezomib/melphalan/prednisone versus bortezomib/melphalan/prednisone).^{6, 7}

In the GRIFFIN trial, daratumumab was added to VRd. The trial met its primary endpoint of stringent complete response at end of consolidation (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068, meeting the prespecified 1-sided alpha of 0.10). Upon extended follow-up, the PFS curves appear to be separating, with a longer PFS for GRIFFIN, but the data remains immature, and the trial was not powered for more durable outcomes such as PFS or OS.²³

In summary, daratumumab is currently an integral part of treatment for relapsed/refractory disease and is increasingly being utilized in front-line treatment as well.

Isatuximab is another CD-38 targeting antibody that binds to a different epitope. Although no head-to-head comparison with daratumumab exists, isatuximab has demonstrated PFS benefits comparable to daratumumab in randomized three versus two trials in the relapsed/refractory space. Two such trials are the IKEMA trial (Isatuximab-Carfilzomib-Dex versus Carfilzomib-Dex)²⁴ and the ICARIA trial (Isatuximab-Pomalidomide-dexamethasone versus Pomalidomide-dexamethasone)²⁵.

Thus, isatuximab represents a reasonable alternative to daratumumab in the relapsed and refractory setting. It is administered intravenously (IV), as opposed to the subcutaneous formulation of daratumumab, so the need for IV access and longer infusion times may be an inconvenience for patients. However, its weight-based dosing and slightly cheaper price allow for cost-savings for health care systems.

Elotuzumab is a monoclonal antibody directed to the surface glycoprotein SLAMF7, which is highly expressed on MM cells. Elotuzumab stimulates NK cell-mediated antibody-dependent cellular cytotoxicity.²⁶ Although this drug lacks single agent activity, it has demonstrated activity and met its endpoint in two randomized trials. In the long-term follow-up of the ELOQUENT-2 trial, the combination of elotozumab-Rd compared to Rd demonstrated a statistically significant 8.7-month improvement in OS (median, 48.3 vs. 39.6 months: hazard ratio, 0.82 [95.4% Cl, 0.68-1.00].²⁷ In the ELOQUENT-3 study, the combination of elotozumab-pomalidomide-dexamethasone compared to pomalidomide-dexamethasone demonstrated a significant improvement in PFS  (10.3 months in the elotuzumab group and 4.7 months in the control group, hazard ratio=0.54, 95% CI=0.34-0.86).²⁸

In the newly diagnosed setting, elotozumab did not meet its primary endpoint in randomized trials.²⁹ Thus, the utility of elotozumab in today’s landscape is limited compared to anti CD-38 targeting monoclonal antibodies.

BCMA Targeting Antibody-Drug Conjugate

Belantamab mafadotin represents the first B-cell maturation antigen (BCMA)-targeting antibody drug conjugate approved for MM. The antibody component is an immunoglobulin directed against BCMA, whereas the small molecule component is MMAF, a microtubule inhibitor.

Its approval in the United States was based on the DREAMM-1 study evaluating its efficacy at various doses. A total of 30 of 97 patients in the 2.5 mg/kg cohort and 34 of 99 patients in the 3.4 mg/kg cohort achieved an overall response. However, the drug was associated with corneal toxicity in addition to hematologic toxicities. Therefore, the drug requires close ophthalmological monitoring due to its corneal toxicity and vision impairment.³⁰

The role of belantamab will be in question as newer BCMA-targeting constructs, such as chimeric antigen receptors (CAR) T-cell therapies and bispecific T-cell engagers, mature.

CAR T-Cell Therapies

Idecabtagene vicleucel (ide-cel) represents the first approved CAR T-cell therapy for patients with MM. It targets the BCMA receptor, which is present in plasma cells with limited expression elsewhere.³¹ Its approval was based on results from a single-arm non-randomized phase II study that enrolled 140 patients, with 128 successfully receiving ide-cel.

Among these 128 patients, 73% experienced a response. However, with a median PFS of 8.8 months, responses were not durable.

The side effect profile of ide-cel was consistent with what has been observed with other CAR T cell products. Cytopenias were observed in the majority of patients, and cytokine release syndrome (CRS) in 84% of patients. CRS was occasionally severe, with 5% of CRS cases being classified as grade 3 or higher. Neurological side effects were seen in 18% of patients, and 3% of patients had grade 3 neurotoxicity.

Other CAR T cell products, such as ciltacabtagene autoleucel (cilta-cel), have demonstrated impressive efficacy with longer responses relative to what was observed with ide-cel. Cilta-cel is expected to be approved by the U.S. Food and Drug Administration for the treatment of MM soon.³²  Numerous other CAR T constructs targeting various receptors are in different stages of development.³³

Selinexor

Selinexor represents a first in class drug with a novel mechanism of action. It is an elective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and, in the process, forces nuclear accumulation and activation of tumor suppressor proteins.³⁴

The approval of selinexor in the United States was based on data from the single arm non-randomized STORM trial.³⁴ In this trial, a total of 123 patients who were heavily pre-treated with daratumumab were recruited. Selinexor was administered at 80 mg twice weekly. A response rate of 26% was observed, with a median duration of response of 4.4 months. Median PFS was 3.7 months, and median overall survival was 8.6 months.

At this dosage, the side effects of selinexor were significant, with fatigue, nausea, decreased appetite, hyponatremia, diarrhea, and thrombocytopenia seen in a significant number of patients.

Selinexor was then evaluated at a lower once weekly dosing in the randomized BOSTON trial. In this trial, the intervention arm of bortezomib/selinexor/dexamethasone was compared to the doublet of bortezomib/dexamethasone. Of note, in the intervention arm bortezomib was given at once weekly dosing, as opposed to the twice weekly dosing in the control arm.³⁵

In this trial, amongst 402 patients, median PFS was 13.9 months with selinexor, bortezomib, and dexamethasone compared to 9.5 months (8.11-10.78) with bortezomib and dexamethasone (hazard ratio 0.70 [95% CI 0.53-0.93]).

Based on these two trials, selinexor is clinically active in MM. However, how to best use this drug remains unclear. The BOSTON trial recruited a few patients with disease that was refractory to lenalidomide. Daratumumab-based therapies have a more established track record of safety and efficacy for earlier relapses. Furthermore, the BOSTON trial recruited these patients well after the control arm of bortezomib/dexamethasone had already shown inferiority to other regimens. The efficacy of selinexor in the context of contemporary regimens is in question.

 

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