Multiple myeloma: an overview of drug therapies and supportive care

SUMMARY

Multiple myeloma is an incurable plasma cell malignancy. Treatment options have evolved significantly in recent years, improving survival and quality of life. Multiple myeloma is increasingly regarded as a chronic illness, particularly for patients with low-risk disease.

For patients fit enough to undergo autologous stem cell transplantation, induction therapy with bortezomib (protease inhibitor), lenalidomide (immunomodulatory drug) and dexamethasone (corticosteroid), followed by transplantation, is the mainstay of treatment. Low-dose lenalidomide is continued after transplantation to help prolong remission. For transplant-ineligible patients, first-line therapy with the monoclonal antibody daratumumab, in combination with lenalidomide and dexamethasone, has significantly improved outcomes.

Novel therapeutic options include bispecific T-cell engagers, which redirect a patient’s immune cells to kill myeloma cells, and chimeric antigen receptor (CAR) T-cell therapy, where a patient’s own T-cells are engineered to target and kill myeloma cells. However, high cost and uncertainty around optimal treatment sequencing remain challenges with the use of these newer treatment options.

Patients receiving treatment for myeloma are at risk of treatment-related toxicities and infection, and have significant ongoing supportive care needs. A multidisciplinary approach involving primary care clinicians (e.g. general practitioners, pharmacists) and the treating haematology specialist is invaluable.

 

Introduction

Multiple myeloma is a malignant plasma cell disorder characterised by the clonal proliferation of plasma cells within the bone marrow, the production of a monoclonal immunoglobulin or free light chains and resultant end-organ damage.¹ It remains incurable but is increasingly treatable with a range of therapies that prolong survival and maintain quality of life.

In Australia, approximately 2500 people are diagnosed each year with multiple myeloma, with a median age of diagnosis of approximately 70 years.² Multiple myeloma is a heterogeneous disease, and many patients experience durable remission prior to requiring subsequent lines of therapy. However, a small proportion of patients will experience rapid relapse, exhausting available therapies in a short space of time.

Although the disease is largely managed by haematologists, primary care clinicians, such as general practitioners (GPs), play an important role in early detection, management of comorbidities, monitoring treatment toxicities, minimising and monitoring infection risk and palliative care. This article reviews current treatments for multiple myeloma, their expected toxicities, emerging therapeutic options and considerations for monitoring and supportive care.

 

Treatment approaches

The goals of myeloma therapy are to control disease, improve quality of life and prolong survival.³ The main treatment strategies include stem cell (bone marrow) transplantation and drugs that either enhance a patient’s immune system or specifically target myeloma cells.

At diagnosis, patients are determined to be either transplant eligible or ineligible based on age and comorbidities. Typically, those under the age of 70 years without significant comorbidities (e.g. renal disease, cardiac disease, poorly controlled diabetes, severe underlying pulmonary disease) are considered fit for autologous stem cell transplantation (ASCT).⁴

Autologous stem cell transplantation (ASCT)

For patients who are transplant eligible, treatment typically begins with 4 to 6 cycles of combination therapy comprising bortezomib (a proteasome inhibitor), lenalidomide (an immunomodulatory drug) and dexamethasone (a corticosteroid). This combination, known as VRd, is used as induction therapy to reduce the burden of myeloma cells. The patient’s own stem cells are then collected, followed by high-dose chemotherapy with melphalan to destroy residual myeloma cells before ASCT. During ASCT, the patient’s stem cells are returned to the body to stimulate blood cell production in the bone marrow. Maintenance therapy with low-dose lenalidomide after transplant is now standard care and helps prolong remission. This regimen results in a 5-year progression-free survival of 58%.⁴

Patients who are ineligible for stem cell transplantation

The anti-CD38 monoclonal antibody daratumumab has recently been made available as first-line therapy for patients who are transplant ineligible, in combination with lenalidomide and dexamethasone (DRd).⁵ This combination provides a 5-year progression-free survival of 52%.⁶

 

Current drug and immune therapies

The different therapies for multiple myeloma work through several mechanisms, as detailed below:

• monoclonal antibodies (e.g. daratumumab) bind to specific proteins on myeloma cells
• proteasome inhibitors (e.g. bortezomib) disrupt protein destruction within myeloma cells, triggering cell death
• immunomodulatory drugs (e.g. lenalidomide) enhance anti-tumour immune responses
• bispecific T-cell engagers (BiTEs; e.g. elranatamab) and chimeric antigen receptor (CAR) T-cell therapy direct a patient’s own T-cells to destroy myeloma cells
• selective inhibitors of nuclear export (e.g. selinexor) block pathways that promote myeloma cell survival.

Access to these treatments in Australia relies heavily on the Pharmaceutical Benefits Scheme (PBS).

Anti-CD38 monoclonal antibodies

Daratumumab is the only approved anti-CD38 monoclonal antibody available in Australia.⁷ By binding to CD38 on myeloma cells, it induces an immune response against the cells, resulting in cell death, primarily through antibody-dependent cell-mediated cytotoxicity. Daratumumab is listed on the PBS in combination with lenalidomide and dexamethasone for first-line treatment of patients who are ineligible for ASCT. For those who have not received daratumumab as first-line therapy, it is PBS-listed for second-line use in combination with bortezomib and dexamethasone (DVd).⁸

Daratumumab is generally well tolerated, with adverse effects largely limited to first-dose infusion reactions,⁶ which occur less frequently with the subcutaneous formulation than with intravenous administration. Because daratumumab binds to CD38 on red blood cells, extended blood grouping must be done prior to commencing treatment in case blood transfusion is required later. Daratumumab can increase infection risk (Table 1), including cytomegalovirus reactivation, particularly when used later in the disease course when a patient is more immunocompromised.

Table 1 Multiple myeloma therapies and common adverse effects

Drug or immune therapy	Drug class	Adverse effect	Management of adverse effects
Daratumumab	Monoclonal antibody	Hypogammaglobulinaemia	Intravenous immunoglobulin
		Increased infection risk	Prophylactic antibiotics Vaccinations Valaciclovir for shingles prophylaxis
Bortezomib	Proteasome inhibitor	Cytopenias	Monitor full blood count Blood transfusion
		Peripheral neuropathy	Dose reduction
		Autonomic neuropathy (e.g. postural hypotension)	Monitor blood pressure Adjust antihypertensive therapy
		Shingles reactivation	Valaciclovir prophylaxis
Carfilzomib	Proteasome inhibitor	Heart failure	Monitor weight Fluid management
		Hypertension	Blood pressure management
		Renal impairment	Monitor renal function
		Venous thromboembolism	Thromboprophylaxis
Lenalidomide, pomalidomide	Immunomodulatory drugs (thalidomide analogues)	Cytopenias	Monitor full blood count Blood transfusion
		Venous thromboembolism	Thromboprophylaxis
Elranatamab	Bispecific T-cell engager	Hypogammaglobulinaemia	Intravenous immunoglobulin
		Increased infection risk	Prophylactic antibiotics Vaccinations Valaciclovir for shingles prophylaxis
CAR T-cell therapy	–	Hypogammaglobulinaemia	Intravenous immunoglobulin
		Increased infection risk	Prophylactic antibiotics Vaccinations Valaciclovir for shingles prophylaxis
Selinexor	Selective inhibitor of nuclear export	Cytopenias	Monitor full blood count Blood transfusion
CAR = chimeric antigen receptor

Proteasome inhibitors

The proteasome’s role is for orderly degradation of cellular proteins that are no longer required. Proteasome inhibition results in cell death, possibly through reduced destruction of pro-apoptotic proteins and increasing protein stress in cells.

Bortezomib was the first PBS-listed proteasome inhibitor for myeloma. It is delivered subcutaneously. Bortezomib has progressively been used earlier in treatment and, in combination with lenalidomide and dexamethasone (VRd), is now first line in the treatment of ASCT-eligible patients.⁹ The main adverse effect of bortezomib is painful peripheral neuropathy, which is reversible and typically abates with dose reduction or cessation (Table 1). Bortezomib can also cause diarrhoea, constipation and blood count abnormalities. In addition, bortezomib can cause autonomic neuropathy, including postural hypotension; therefore, monitoring blood pressure and managing antihypertensive therapy is important. Because bortezomib is a substrate of cytochrome P450 (CYP) 3A4 and P-glycoprotein, caution is required when prescribing macrolides and azoles.

Carfilzomib is a proteasome inhibitor reserved for later lines of treatment.¹⁰ It is delivered intravenously. Unlike bortezomib, carfilzomib does not cause peripheral neuropathy, but it has many significant potential adverse effects, including pulmonary and systemic hypertension, cardiac failure, renal impairment and an increased risk of venous thromboembolism (VTE), which limit its use.

Immunomodulatory drugs

The use of immunomodulatory drugs in myeloma started with thalidomide, which is now rarely prescribed. Currently used immunomodulatory drugs are thalidomide analogues that interact with the cereblon E3 ubiquitin ligase complex, a cellular system that tags unwanted proteins for removal, leading to the degradation of key transcription factors involved in myeloma cell growth and survival.

Lenalidomide is now used in all first-line treatment regimens for myeloma, regardless of transplant eligibility. It is an oral capsule given 3 weeks on, 1 week off. Lenalidomide is also used continuously (i.e. no week off) as maintenance therapy following ASCT. Careful dose adjustments can moderate its adverse effects, which include lethargy, blood count abnormalities, rash, diarrhoea and VTE (Table 1). Typically, aspirin, enoxaparin or a direct-acting oral anticoagulant (used off label) is prescribed as VTE prophylaxis. Lenalidomide is renally excreted, so dose adjustments are required in patients with renal impairment. Given its relationship to thalidomide, lenalidomide is assumed to cause birth defects.

Pomalidomide with dexamethasone, in combination with bortezomib, is used in later lines of treatment in appropriate patients.¹¹ Pomalidomide is better tolerated than lenalidomide but can cause significant cytopenias. Inducers of CYP1A2 will reduce pomalidomide exposure by up to one-third.

Bispecific T-cell engagers

BiTEs, also known as bispecific antibodies, simultaneously bind to a target antigen on myeloma cells with one limb and to T cells with the other limb, bringing the cells into opposition and directing T-cell cytotoxicity against the myeloma cells.

Elranatamab is PBS-listed for fourth-line use as monotherapy. It targets B-cell maturation antigen (BCMA) on myeloma cells. In patients who respond, elranatamab treatment can prolong survival for over 1.5 years.¹² Elranatamab can cause cytokine release syndrome,¹³ characterised by an acute massive release of T-cell cytokines into the circulation, manifesting as fever, hypotension and hypoxia. In severe instances, admission to an intensive care unit may be required. When these inflammatory cytokines affect the central nervous system, immune effector cell–associated neurotoxicity syndrome can occur, although this is rare; clinical manifestations range from confusion to cerebral oedema, seizures and coma.

Several new BiTEs are in clinical trials and showing promising results. These include teclistamab and linvoseltamab, which target BCMA, talquetamab,¹⁴ which targets G protein–coupled receptor class C group 5 member D (GPRC5D), and cevostamab, which targets Fc receptor–homolog 5 (FcRH5).

CAR T-cell therapy

CAR T-cell therapy is a form of personalised medicine. A patient’s T-cells are collected and then engineered to recognise specific targets on myeloma cells, commonly BCMA and, more recently, GPRC5D. CAR T-cell therapy has demonstrated deep and durable responses, even in heavily pre-treated patients.¹⁵ CAR T-cell therapy is approved in Australia as fifth-line therapy.

Major limitations of CAR T-cell therapy include the lag time for creation of the modified T cells (typically 6 to 8 weeks in Australia), cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome and delayed neurotoxicity. In addition, the cost of CAR T-cell therapy is significant, at approximately A$500,000 for a single dose.

Selective inhibitors of nuclear export

Selinexor is a first-in-class selective inhibitor of nuclear export. Selinexor blocks exportin-1, a protein that transports tumour suppressor proteins out of the cell nucleus. This leads to accumulation of tumour suppressor proteins in the nucleus, resulting in cell death. Selinexor can be used in combination with either dexamethasone or bortezomib.¹⁶ Its main adverse effects are severe nausea and vomiting, cytopenias and hyponatraemia.

 

Emerging therapies

Antibody–drug conjugates

Antibody–drug conjugates are antibodies conjugated to a cytotoxic ‘payload’, effectively delivering the chemotherapy to the target cell. Belantamab mafodotin is the most advanced of these drugs and targets BCMA. Studies have demonstrated its efficacy in the treatment of relapsed or refractory multiple myeloma.¹⁷ In Australia, belantamab mafodotin is available through compassionate-use programs for patients at first and second relapse.

Cereblon E3 ligase modulators

Cereblon E3 ligase modulators are the next generation of immunomodulatory drugs, with up to 100-fold greater potency.¹⁸ Cereblon E3 ligase modulators also serve as immune stimulants, potentially affecting T-cell activity.

Iberdomide and mezigdomide are the 2 drugs in this class, but are still in clinical studies.^19,20

B-cell lymphoma 2 inhibitors

The B-cell lymphoma 2 (BCL2) inhibitor venetoclax has shown efficacy in patients with t(11;14) myeloma (a subset of myeloma where there is translocation of chromosomes 11 and 14 resulting in increased sensitivity to BCL2).²¹ It is currently in clinical trials.

 

Monitoring and supportive management in primary care

For patients with multiple myeloma, primary care clinicians (e.g. GPs, nurses, pharmacists) play a crucial role in identifying and managing adverse effects (Table 1), infection prevention, and coordination of multidisciplinary care.³ Key considerations in primary care are listed in Box 1.

Corticosteroid adverse effects

Corticosteroids, often continued long-term, form a mainstay in all treatment lines of multiple myeloma. As such, monitoring of blood glucose concentrations and management of steroid-induced diabetes and acute hypertension may be required. Further, sleep disturbance is common, often necessitating pharmacological intervention and corticosteroid dose reduction in consultation with the treating haematologist.

Cytopenias

Cytopenias related to myeloma therapies may be detected mid-cycle by primary care clinicians and should be reported to the treating specialist.

Infection risk

Infection is a significant cause of morbidity and mortality in myeloma patients. Influenza, COVID-19 and Streptococcus pneumoniae vaccinations are recommended for all patients. Varicella zoster vaccination is reasonable but does not negate the need for prophylactic valaciclovir. Vaccinations are routinely provided after ASCT at most Australian hospitals. Live vaccines should not be given to patients receiving bispecific antibodies or CAR T-cell therapy. Intravenous immunoglobulin therapy should be considered for those with recurrent infections and low residual IgG concentrations, and is required for patients receiving elranatamab.

Antibiotic prophylaxis is not routinely recommended for myeloma patients but may be prescribed by a haematologist in specific cases. Pneumocystis jirovecii pneumonia is an issue with high-dose corticosteroids (greater than or equal to 20 mg dexamethasone weekly) and in the 6 to 12 months after ASCT. Prophylaxis with trimethoprim+sulfamethoxazole 3 times a week can effectively prevent this life-threatening infection.

Shingles (herpes zoster) reactivation is common, particularly in patients on proteasome inhibitors or anti-CD38 monoclonal antibodies. Prophylactic valaciclovir 500 mg daily is typically prescribed by the treating haematologist to reduce this risk.

Hepatitis B prophylaxis with entecavir 500 micrograms daily is required for all patients with prior or chronic hepatitis B infection.

Bone protection and osteonecrosis

Bone protection with zoledronic acid is standard of care for myeloma patients, typically for 2 years. A significant potential adverse effect is osteonecrosis of the jaw, which can be precipitated by dental work, particularly root canals or tooth extractions. Judicious dental care and antibiotics (prescribed by either a haematologist or dentist) are necessary to prevent this complication. Vitamin D should also be prescribed to all myeloma patients as part of bone protection.

 

Conclusion

There has been a rapid expansion in the treatments available for multiple myeloma, which has improved survival and helped maintain quality of life. The greatest challenge is determining the timing of various treatments and identifying who will benefit most. In Australia, many drugs remain in clinical trials, and the future funding of these therapies presents a significant barrier. As myeloma increasingly becomes a chronic disease, monitoring and supportive management by primary care clinicians, in collaboration with the treating haematologist, are critical.

This article was finalised on 7 September 2026.

Conflicts of interest: The author declared no conflicts of interest.

This article is peer reviewed.

 

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