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Multiple myeloma: Treatment of third or later relapse

Multiple myeloma: Treatment of third or later relapse
Author:
Jacob P Laubach, MD, MPP
Section Editor:
S Vincent Rajkumar, MD
Deputy Editor:
Rebecca F Connor, MD
Literature review current through: Dec 2022. | This topic last updated: Dec 05, 2022.

INTRODUCTION — There are many treatment options for relapsed or refractory multiple myeloma (MM). Most patients experience serial relapse and will be treated with most available agents at some point during their disease course. The choice of therapy at each relapse is informed by prior therapies used, response to these treatments, comorbidities, and disease aggressiveness.

Treatment of MM in third or later relapse will be discussed here. Many of the regimens used for first or second relapse may also be appropriate if not utilized previously. General principles for the management of relapsed or refractory MM, the management of first or second relapse, administration considerations for common therapies, and the use of autologous and allogeneic hematopoietic cell transplantation are discussed separately.

(See "Multiple myeloma: Overview of management".)

(See "Multiple myeloma: Treatment of first or second relapse".)

(See "Multiple myeloma: Initial treatment".)

(See "Multiple myeloma: Administration considerations for common therapies".)

(See "Multiple myeloma: Use of autologous hematopoietic cell transplantation".)

(See "Multiple myeloma: Use of allogeneic hematopoietic cell transplantation".)

ASSESS DRUG SENSITIVITY — The choice of therapy for relapsed MM must consider prior therapy, response, and likelihood of the disease being sensitive or refractory to prior agents (algorithm 1). In general, refractory disease is defined as progressing on or within 60 days of receiving standard doses of a specific therapy.

As an example, MM progressing on or within 60 days of receiving standard doses of lenalidomide (eg, 25 mg daily) is refractory to lenalidomide. In contrast, disease progression in a patient that previously received lenalidomide but not within the past 60 days or in a patient on a maintenance dose of single-agent lenalidomide (eg, 10 mg daily) is considered lenalidomide sensitive. Lenalidomide-sensitive MM may respond to a regimen that increases the dose of lenalidomide, reintroduces dexamethasone, and/or adds a third agent (eg, a monoclonal antibody or a proteasome inhibitor).

The term penta-refractory disease is used for MM refractory to all of the following:

An anti-CD38 monoclonal antibody (eg, daratumumab, isatuximab)

Lenalidomide

Pomalidomide

Bortezomib

Carfilzomib

Whether a patient has penta-refractory disease represents an important determinant of therapy in third or greater relapse, since the drugs that define penta-refractory MM are some of our most active agents in MM, and the regulatory approval of several other therapies has been limited to this specific population. Our approach is therefore structured according to whether or not the patient has penta-refractory MM.

NON-PENTA-REFRACTORY DISEASE — For most patients with MM in third or greater relapse who maintain sensitivity to these agents, we suggest combination therapy that contains an agent among the following, to which the patient has not already become refractory:

An anti-CD38 monoclonal antibody (eg, daratumumab, isatuximab)

Lenalidomide

Pomalidomide

Bortezomib

Carfilzomib

This recommendation is based on evidence derived from prospective trials evaluating these regimens containing one or more of these agents in patients with relapsed MM who received one to three prior lines of therapy. This approach also ensures patients with disease that is sensitive to these agents derive maximum benefit from them before receiving other agents in subsequent lines of treatment. The trials that have evaluated these combinations are discussed separately. (See "Multiple myeloma: Treatment of first or second relapse".)

The choice of regimen is similar to that in first or second relapse, and it is driven by an understanding of drug sensitivity and expected toxicity (algorithm 2). Accompanying tables provide active drugs by class (table 1), and major toxicities of selected treatment regimens (table 2).  

Daratumumab, pomalidomide, and dexamethasone (DPd) – (See "Multiple myeloma: Treatment of first or second relapse", section on 'Daratumumab, pomalidomide, dexamethasone (DPd)'.)

Isatuximab, pomalidomide, and dexamethasone (IsaPd) – (See "Multiple myeloma: Treatment of first or second relapse", section on 'Isatuximab, pomalidomide, dexamethasone (IsaPd)'.)

Elotuzumab, pomalidomide, and dexamethasone (EPd) – (See "Multiple myeloma: Treatment of first or second relapse", section on 'Elotuzumab, pomalidomide, dexamethasone (EPd)'.)

Carfilzomib, pomalidomide, and dexamethasone (KPd) – (See "Multiple myeloma: Treatment of first or second relapse", section on 'Carfilzomib, pomalidomide, dexamethasone (KPd)'.)

Bortezomib, pomalidomide, and dexamethasone (VPd) – (See "Multiple myeloma: Treatment of first or second relapse", section on 'Bortezomib, pomalidomide, dexamethasone (VPd)'.)

Bortezomib, cyclophosphamide, and dexamethasone (VCd) – (See "Multiple myeloma: Treatment of first or second relapse", section on 'Bortezomib, cyclophosphamide, dexamethasone (VCd)'.)

Daratumumab, carfilzomib, and dexamethasone (DKd) – (See "Multiple myeloma: Treatment of first or second relapse", section on 'Daratumumab, carfilzomib, dexamethasone (DKd)'.)

Isatuximab, carfilzomib, and dexamethasone (IsaKd) – (See "Multiple myeloma: Treatment of first or second relapse", section on 'Isatuximab, carfilzomib, dexamethasone (IsaKd)'.)

Selinexor, bortezomib, and dexamethasone (SVd) – (See "Multiple myeloma: Treatment of first or second relapse", section on 'Selinexor, bortezomib, dexamethasone (SVd)'.)

We consider four-drug regimens for patients with highly aggressive disease.

PENTA-REFRACTORY DISEASE — For patients with penta-refractory disease, we typically offer therapies that target the B cell maturation antigen (BCMA) or alkylator-containing regimens before offering other therapies (algorithm 1). These treatments have largely been studied in prospective, uncontrolled trials.

Targeting BCMA — BCMA is selectively expressed on differentiated plasma cells, including tumor cells in MM, and is thus an important therapeutic target in this disease (algorithm 1). It can be targeted using chimeric antigen receptor (CAR)-T cells or the bispecific BCMA-directed CD3 T-cell engager (BiTE) teclistamab. Use of these agents in relapsed MM is based on single-arm clinical trials evaluating the investigational agent. CAR-T cells must be manufactured for the individual patient, while teclistamab is available as an off-the-shelf treatment. The anti-BCMA antibody drug conjugate belantamab mafodotin has been withdrawn from the market and is only available from the manufacturer for patients who started treatment prior to its withdrawal. At this time, we do not have evidence that MM refractory to one anti-BCMA therapy will respond to another. Until such data are available, we presume that MM refractory to one anti-BCMA therapy is likely refractory to the other.

Chimeric antigen receptor T cells

Clinical use – The use of CAR-T cell therapy is individualized weighing disease tempo, availability of other treatments, and expected toxicity (algorithm 1). While initial studies suggest that CAR-T therapy has substantial activity against relapsed or refractory MM, treatment is associated with significant toxicity, and the manufacturing process is complex and expensive.

Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are BCMA-directed CAR-T therapies approved in the United States (US) for relapsed or refractory MM following at least four lines of systemic therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Ide-cel is also approved in Europe. The prescribing information for ide-cel and cilta-cel carry warnings for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Facilities that dispense this agent require special certification, and staff must be trained to recognize and manage these adverse events.

CAR-T cells are generated from the patient's own T lymphocytes, which are genetically modified (transfected) with a gene that encodes a CAR to direct the patient's T cells against the MM cells. The T cells are genetically modified ex vivo, expanded in a production facility, and then infused back into the patient as therapy. Prior to reinfusion, patients receive a lymphodepleting chemotherapy preparative/conditioning regimen (ie, cyclophosphamide plus fludarabine).

Efficacy – A phase 2 study (KarMMa) evaluated ide-cel in 128 patients with relapsed and refractory MM after at least three prior regimens including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody [1]. The overall and complete response rates were 73 and 33 percent, respectively. Estimated median progression-free survival (PFS) and overall survival (OS) were 8.8 and 19.4 months, respectively.

The anti-BCMA CAR-T product ciltacabtagene autoleucel (cilta-cel) has also been evaluated in a phase 2 study (CARTITUDE-1) [2,3]. Cilta-cel was administered to 97 patients with a median of six prior therapies. The overall and stringent complete response rates were 98 and 83 percent, respectively. PFS at 12 and 27 months were 77 and 55 percent, respectively. OS at 12 and 27 months were 89 and 70 percent, respectively. Deaths were due to adverse events (6 patients), progressive disease (14 patients), and other (10 patients).

A meta-analysis that included data from 950 patients undergoing CAR-T for MM reported a pooled response rate of 78 percent (95% CI 72-84 percent) [4]. Median PFS ranged from 8 to 20 months.

Toxicity – CAR-T therapy can be associated with serious complications, including some fatal neurologic events and CRS, which is a severe systemic response to the activation and proliferation of CAR-T cells characterized by various symptoms including high fever, flu-like symptoms, hypotension, mental status changes.

In the KarMMa trial of ide-cel, all but one patient experienced at least one grade 3 or 4 toxicity, with hematologic toxicity being most common [1]. CRS occurred in 107 patients (84 percent), of which 7 (5 percent) were grade 3 or 4. Severe neurologic toxicities were seen in 3 percent.

In the CARTITUDE-1 trial of cilta-cel, there were six treatment-related deaths [2,3]. CRS occurred in 92 patients (95 percent; 4 percent grade 3 or 4). CAR-T cell neurotoxicity occurred in 21 patients (22 percent; 11 percent grade 3 or 4).

CRS is common and may be life-threatening, but it typically responds to treatment with aggressive supportive care that includes tocilizumab and corticosteroids. In the meta-analysis described above, the pooled grade 3 or 4 or higher CRS rate was 6.4 percent (95% CI 4-9 percent) and the pooled grade 3 or 4 ICANS rate was 3.5 percent (95% CI 2-5 percent) [4]. CRS and ICANS are discussed separately. (See "Cytokine release syndrome (CRS)" and "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

Other adverse events include hypersensitivity reactions, serious infections [5], prolonged cytopenias, prolonged hypogammaglobulinemia, hemophagocytic lymphohistiocytosis/macrophage activation syndrome [6], effects on ability to drive and use machines, second malignancies, Guillain-Barre syndrome, and a delayed-onset progressive movement disorder (ie, progressive parkinsonism). Delayed parkinsonism following BCMA-targeted CAR-T is discussed in more detail separately. (See "Immune effector cell-associated neurotoxicity syndrome (ICANS)", section on 'Delayed parkinsonism'.)

Teclistamab

Clinical useTeclistamab is bispecific monoclonal antibody directed at both BCMA on the tumor and CD3 on patient’s T-cells. It has demonstrated activity in heavily pretreated populations but has not been directly compared with other therapies (algorithm 1) [7-9].

Teclistamab is approved in the US for patients who have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent [10]. The prescribing information for teclistamab carries warnings for cytokine release syndrome (CRS) and neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS). Teclistamab is available through a restricted risk evaluation and mitigation strategy (REMS) program.

Teclistamab is administered as a subcutaneous injection in gradually increasing doses on days 1, 4, and 7, followed by weekly dosing thereafter.  

Specific administration considerations are discussed separately. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Teclistamab'.)

Efficacy – An open-label, single-arm phase 1/2 multicenter trial (MajesTEC-1) evaluated teclistamab in 165 patients with relapsed or refractory MM who had received at least three prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent, and who had not received prior BCMA-targeted therapy [8,9].

After a median follow-up of 14.1 months, the overall response rate was 63 percent, 65 patients (39 percent) had a complete response or better, and 44 patients (27 percent) had no measurable residual disease.

The median duration of response was 18.4 months. Estimated median progression-free survival was 11.3 months (95% CI 8.8 to 17.1 months). Overall survival data was not mature, but the estimated median overall survival was 18.3 months (95% CI 15.1 months to not estimable).  

Toxicity – In addition to warnings about CRS and ICANS, the prescribing information includes warnings about hepatotoxicity, infections, neutropenia, hypersensitivity and other administration reactions, and embryo-fetal toxicity.

In MajesTEC-1, 95 percent experienced at least one grade 3 or 4 toxicity, with hematologic toxicity being most common [9]. CRS occurred in 120 patients (73 percent), all but one of which were grade 1 or 2. Neurologic toxicities were reported in 15 percent, all but one of which were grade 1 or 2.

Other nonhematologic toxicities occurring in 20 to 30 percent of cases included injection-site erythema, gastrointestinal toxicity, fatigue, fever, headache, arthralgia, and cough. Those occurring in 15 to 19 percent included pneumonia, COVID-19, bone pain, and back pain.

Belantamab mafodotin

Clinical useBelantamab mafodotin is being withdrawn from the market beginning November 2022, although it remains accessible through the manufacturer for patients who started treatment prior to its withdrawal [11]. Belantamab mafodotin is an anti-BCMA humanized immunoglobulin G (IgG) antibody conjugated to the microtubular disrupting agent monomethyl auristatin.

Belantamab mafodotin had received accelerated approval in the US for patients who have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent [12]. Full approval was contingent upon confirmed clinical benefit in a phase 3 randomized trial.

Efficacy – Two uncontrolled open-label trials (DREAMM-1 and DREAMM-2) demonstrated positive response data with belantamab mafodotin in relapsed or refractory MM. However, initial results of a randomized phase 3 trial (DREAMM-3) of belantamab mafodotin versus pomalidomide and dexamethasone (Pd) in relapsed or refractory MM have not confirmed clinical benefit, leading to market withdrawal [11].

An open-label randomized trial (DREAMM-2) evaluated two dosing regimens of belantamab mafodotin in 196 patients with MM refractory to a proteasome inhibitor and an immunomodulatory agent, and refractory or intolerant to an anti-CD38 monoclonal antibody, with a median of seven lines of prior therapy (range 3 to 21) [13]. After a median follow-up of approximately six months, the overall response rates (ORR) and median PFS times for the two groups were:

2.5 mg/kg cohort – ORR 31 percent (30 of 97 patients), median PFS 2.9 months (95% CI 2.1-3.7)

3.4 mg/kg cohort – ORR 34 percent (34 of 99 patients), median PFS 4.9 months (95% CI 2.3-6.2)

In a smaller open-label, single-arm trial (DREAMM-1), responses to belantamab mafodotin (3.4 mg/kg) were noted in 21 of 35 patients (60 percent) with MM refractory to an immunomodulatory agent and a proteasome inhibitor [14,15]. The median PFS was 12 months. On subgroup analysis, responses were lower among patients with prior exposure to daratumumab.

Initial results from DREAMM-3 available through a company press release reported numerically longer observed median PFS with belantamab mafodotin versus Pd that did not reach statistical significance (11.2 versus 7 months; HR 1.03, 95% CI 0.72-1.47) [16]. At a median follow-up time of approximately 11 months, median overall survival was similar in the two arms (21.2 versus 21.1 months; HR 1.14, 95% CI 0.77-1.68).

ToxicityBelantamab mafodotin frequently results in changes in the corneal epithelium, resulting in corneal ulceration, visual loss, and symptoms including blurred vision and dry eyes [12]. Most cases reverse with dose reductions or dose holds, and the ongoing use of artificial tears. Patients are advised to use preservative-free lubricant eye drops and to avoid contact lens use. Ophthalmic exams must be conducted at baseline, prior to each dose, and in the event of worsening symptoms. (See "Ocular side effects of systemically administered chemotherapy", section on 'Antibody-drug conjugates'.)

Other common nonhematologic adverse reactions include nausea, pyrexia, infusion-related reactions, and fatigue. Grade 3 or greater thrombocytopenia is seen in approximately one-third of patients treated with a dose of 3.4 mg/kg [13].

Alkylator containing — Regimens containing alkylators, such as cyclophosphamide, melphalan, and bendamustine are active in MM (algorithm 1). It is important to note that patients who have not been treated with standard-dose melphalan- or cyclophosphamide-based chemotherapy can still benefit from these regimens even if they previously received autologous hematopoietic cell transplantation (HCT), which typically employs a single high-dose administration of melphalan [17]. Melphalan-based therapy is discussed separately. (See "Multiple myeloma: Management in resource-limited settings".)

VDT-PACE

Clinical use – The VDT-PACE regimen (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) is an intensive treatment option for patients with penta-refractory disease, usually as a bridge to additional therapies in patients with an adequate performance status (algorithm 1).

Each cycle of VDT-PACE consists of subcutaneous bortezomib (1 mg/m2 body surface area [BSA] on days 1, 4, 8, and 11), oral dexamethasone (40 mg/day on days 1, 2, 3 and 4), and oral thalidomide (200 mg daily at bedtime throughout the cycle) [18]. The remaining drugs are given as continuous intravenous infusions on days 1 through 4, and include cisplatin (10 mg/m2 BSA per day), doxorubicin (10 mg/m2 BSA per day), cyclophosphamide (400 mg/m2 BSA per day), and etoposide (40 mg/m2 BSA per day). Cycles are repeated at four- to six-week intervals as long as neutrophil and platelet counts are recovered and other toxicities have resolved. Growth factor support with filgrastim or pegylated filgrastim is required.

The PACE is administered as a 24-hour infusion to maintain continuously high drug levels to target slowly dividing plasma cell clones and reduce the risk of doxorubicin-related cardiomyopathy. Specific administration considerations are discussed separately. (See "Multiple myeloma: Administration considerations for common therapies".)

Efficacy – Initial data regarding VDT-PACE come from its use in the Total Therapy-3 protocol from the University of Arkansas in which it was given before and after tandem HCT [19,20]. Additional data come from earlier Total Therapy protocols that used DT-PACE without bortezomib along with HCT [21]. In these trials, VTD-PACE had high response rates, but assessment of response duration was confounded by the incorporation of HCT.

Efficacy outside of these protocols comes from small, single-center retrospective studies. As an example, a single-center retrospective analysis of 141 patients with relapsed refractory MM after a median of four prior therapies treated with VDT-PACE or a VDT-PACE-like regimen [18]. An at least partial response (PR) was reported in 54 percent and very good PR (VGPR) or better in 10 percent. Median PFS was 3 months. Separate retrospective analyses of VD-PACE [22], TD-PACE [23,24], and VTD-PACE [25] have reported median PFS up to 11 months.

Toxicity – Treatment with VDT-PACE is often associated with high incidence of therapy-related adverse events including severe cytopenias, neuropathy, and thromboembolic events. In one of the retrospective analyses described above, over half of patients receiving VDT-PACE required readmission for toxicity during cycle 1, including admissions for neutropenic fever (37 percent) and nephrotoxicity (15 percent).

Growth factor support with filgrastim or pegylated filgrastim is required. Prophylactic antimicrobial therapy is strongly recommended until white blood cell (WBC)/absolute neutrophil count (ANC) recovery. Antithrombotic prophylaxis and ulcer prophylaxis are also encouraged.  

DCEP

Clinical use – The DCEP regimen (dexamethasone, cyclophosphamide, etoposide, and cisplatin) is an intensive treatment option for patients with penta-refractory disease, usually as a bridge to additional therapies in patients with an adequate performance status (algorithm 1).

For each cycle of DCEP, treatment is administered on days 1 through 4 and includes a continuous intravenous infusion of cyclophosphamide (400 mg/m2 BSA per day), cisplatin (15 mg/m2 BSA per day), and etoposide (40 mg/m2 BSA per day), along with oral or intravenous dexamethasone (40 mg daily) [26,27]. Cycles are repeated every 28 days as long as neutrophil and platelet counts are recovered and other toxicities have resolved. Specific administration considerations are discussed separately. (See "Multiple myeloma: Administration considerations for common therapies".)

Palliative radiation therapy has been administered safely in conjunction with DCEP [28].  

Efficacy – Data regarding efficacy of DCEP come from small studies. In a single-center prospective trial of DCEP in relapsed or refractory MM, responses were seen in 7 of 12 patients (two complete) and median response duration was 9 months (range 4 to 36 months) [26]. In a retrospective study of DCEP in 52 patients with relapsed or refractory MM, an at least PR was reported in 27 patients (9 VGPR) [25]. Median PFS was 3.8 months (95% CI 2.8-4.9 months).

Toxicity – In the trial described above, the main toxicities associated with DCEP were transient cytopenias that required granulocyte growth factor support [26]. In the retrospective study, there was 6 percent treatment-related mortality [25]. Common adverse events included increased transfusion requirement (62 percent), rehospitalization (29 percent), febrile neutropenia (29 percent), delay in treatment >7 days (33 percent), and venous thromboembolism (6 percent). As with VDT-PACE, growth factor support with filgrastim or pegylated filgrastim is required and prophylactic antimicrobial therapy during WBC/ANC recovery is strongly recommended.

Bendamustine

Clinical use – Off-label bendamustine is used mainly in patients who have exhausted most other treatment options for myeloma but have adequate performance status (algorithm 1).

Bendamustine can be administered as a doublet with a corticosteroid or in three-drug combinations such as bendamustine plus bortezomib and dexamethasone [29]; bendamustine plus lenalidomide and dexamethasone [30-32]; and bendamustine plus pomalidomide and dexamethasone [33].  

Efficacy – Data regarding the off-label use of bendamustine in relapsed MM come from small, single-arm studies. In a dose escalation study of single-agent bendamustine in 31 patients with relapsed MM, ORR was 55 percent with a PFS of 8 months [34]. A retrospective study of bendamustine plus prednisone in multiply relapsed MM reported an ORR of 30 percent with median PFS of 9.3 months [35]. In other studies, responses were reported in 61 percent of patients following bendamustine plus bortezomib and dexamethasone [29], 47 to 89 percent following bendamustine plus lenalidomide and dexamethasone [30-32]; and 61 percent following bendamustine plus pomalidomide and dexamethasone [33].

Toxicity – Most patients treated with bendamustine-containing regimens will have bone marrow suppression with neutropenia and thrombocytopenia [34]. Other toxicities include nausea, vomiting, fatigue, diarrhea, constipation, anorexia, and hyperbilirubinemia. Rare but serious adverse events include severe, potentially fatal skin reactions, second cancers, progressive multifocal leukoencephalopathy, and anaphylaxis. Extravasation injury can occur.

Selinexor — Patients with penta-refractory MM that is also refractory to alkylators and anti-BCMA therapies are encouraged to enroll on clinical trials. Selinexor is an option outside of a clinical trial (algorithm 1).

Clinical use – The oral nuclear export inhibitor selinexor is approved in the US in combination with dexamethasone for the treatment of adults with relapsed refractory MM who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. It is also approved in combination with bortezomib and dexamethasone for all patients with relapsed MM.  

Patients taking selinexor should receive antiemetic prophylaxis and be monitored for the development of thrombocytopenia, neutropenia, and hyponatremia [36,37]. Patients taking selinexor should avoid taking other medications that might cause dizziness or confusion.

The combination of selinexor, bortezomib, and dexamethasone is discussed separately. (See "Multiple myeloma: Treatment of first or second relapse", section on 'Selinexor, bortezomib, dexamethasone (SVd)'.)

Efficacy – A retrospective analysis of single-agent selinexor reported an ORR of 44 percent in plasma cell dyscrasias with t(11;14) [38]. Selinexor has been evaluated in single-arm studies in combination with other drugs in heavily pretreated populations [39-43]. The following two phase 2 trials evaluated selinexor (80 mg) plus dexamethasone (20 mg), each administered twice weekly, in patients with multiply relapsed MM:

STORM Part 1 evaluated this combination in 48 patients refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (ie, quad-refractory) and 31 patients also refractory to an anti-CD38 antibody (ie, penta-refractory) [41]. The ORR was 21 percent and responses were seen in 6 of 17 patients with high-risk cytogenetics. The median duration of response was five months.

STORM Part 2 evaluated this combination in 122 patients with prior exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent, with disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (ie, triple-refractory) [43]. The ORR was 26 percent. The median duration of response was 4.4 months. Quality of life worsened with treatment, as measured using scales for physical well-being, functional well-being, and myeloma-specific measures [44].

Toxicity – In STORM Part 1, the most common grade 3 or higher toxicities were thrombocytopenia (59 percent), anemia (28 percent), neutropenia (23 percent), hyponatremia (22 percent), leukopenia (15 percent), and fatigue (15 percent) [41]. Common less severe toxicities included nausea, vomiting, diarrhea, and infections. All patients received antiemetic prophylaxis with a 5-HT3 receptor antagonist.

In STORM Part 2, toxicity led to treatment interruption or dose modification in 80 percent of patients and permanent treatment discontinuation in 18 percent [43]. There were 12 deaths due to adverse events. Supportive care included granulocyte colony-stimulating factors, thrombopoietin-receptor agonists, nutritional support, appetite stimulants, psychostimulants, and antiemetic agents.

Better outcomes with less toxicity may be achieved with careful attention to supportive care and dose reductions at the onset of toxicity [45].

SPECIAL POPULATIONS

Venetoclax for MM with t(11;14)

Clinical use – Although it is not yet approved for this indication, the BCL-2 inhibitor venetoclax has demonstrated substantial activity in MM with t(11;14), and we thus consider off-label use of venetoclax alone or in combination as a late line of treatment for patients with t(11;14) who have limited treatment options or as an earlier line of treatment in patients with t(11;14) who have highly aggressive disease refractory to initial treatment (algorithm 1). We do not offer venetoclax to other patients with MM, regardless of BCL-2 expression. We do not use BCL-2 expression to guide therapy as it is difficult to measure and testing is not standardized.

Venetoclax can be administered as a single agent, but it is most often given in combination with a proteasome inhibitor (bortezomib or carfilzomib) plus dexamethasone. Trials are evaluating other combinations, including the combination of daratumumab plus bortezomib and dexamethasone [46].

Efficacy and toxicity – A phase 3, placebo controlled trial (BELLINI) evaluated the addition of venetoclax to bortezomib plus dexamethasone in patients with relapsed or refractory MM [47]. While venetoclax deepened responses and improved median progression-free survival (PFS), the trial was stopped early because of an increased risk of death with venetoclax, including eight treatment-emergent fatal infections, which resulted in inferior overall survival (OS; hazard ratio [HR] 2.03, 95% CI 1.04-3.95). The initial trial protocol required herpes simplex virus prophylaxis; a protocol amendment added mandatory antibacterial prophylaxis and PJP pneumonia prophylaxis. In contrast, prespecified subgroup analyses suggested improved PFS without a clear decrease in survival among 35 patients with t(11;14) (PFS HR 0.11, 95% CI 0.02-0.56 and OS HR 0.34, 95% CI 0.03-3.84) and 95 patients with high BCL-2 gene expression (PFS HR 0.50, 95% CI 0.29-0.86 and OS HR 1.45; 95% CI 0.57-3.68). These results suggested that the venetoclax plus bortezomib and dexamethasone regimen is associated with excess morbidity and mortality as compared to bortezomib and dexamethasone in the general population of patients with relapsed or refractory MM, but that the combination is effective in patients with t(11;14) [47-50].

A dose-escalation phase 2 study evaluated venetoclax, carfilzomib, and dexamethasone in 49 patients with relapsed or refractory MM [51]. The overall response rate (ORR) was 80 percent and the complete response (CR) rate was 41 percent. Of the 13 patients with t(11;14), best response was at least a very good partial response (VGPR) in 11 patients, with 7 achieving a CR. There were no dose limiting toxicities. The most common toxicities were diarrhea (65 percent), fatigue (47 percent), and nausea (47 percent). Grade 3 or 4 toxicities included hypertension (16 percent) and pneumonia (12 percent). Other toxicities included other infections, acute kidney injury, congestive heart failure, and hypoxia.

Frail patients — When possible, we prefer three-drug regimens over two-drug regimens. Indeed, many older adults were included in the trials that evaluated three-drug regimens and demonstrated superiority over two-drug regimens. However, two-drug regimens are an acceptable alternative for frail patients who are unable to tolerate three-drug regimens. These are discussed separately. (See "Multiple myeloma: Treatment of first or second relapse", section on 'Frail patients'.)

Anti-CD38 monoclonal antibodies and high-dose steroids are sometimes administered as single agents.

Daratumumab – The anti-CD38 monoclonal antibody daratumumab is approved as a single agent in the United States for patients who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory drug or who are double-refractory to a proteasome inhibitor and an immunomodulatory drug. Specific administration considerations for daratumumab are discussed separately. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Anti-CD38 monoclonal antibodies'.)

Several non-randomized studies have evaluated the efficacy and safety of single-agent daratumumab [52-56]. In a combined analysis of two open-label, multicenter, phase 2 trials (SIRIUS and GEN501), 148 patients with multiply relapsed MM (median of five prior therapies) were treated with daratumumab (16 mg/kg, weekly for eight weeks, then every two weeks for 16 weeks, then monthly until progression) [56]. Treatment was well tolerated. Infusion reactions (mostly mild) were common with the first infusion and uncommon with subsequent infusions. The ORR was 30 percent (7 CR, 13 VGPR, 24 PR) with a median time to first response of one month. The estimated median duration of response and OS rates were 8 and 20 months, respectively. These rates compared favorably to expected outcomes in this population.

Given the increasing use of daratumumab as an earlier line of treatment, including as part of induction therapy in many instances, single-agent daratumumab as treatment of advanced myeloma that is resistant to multiple agents is now less commonly employed.

High-dose steroids – High-dose steroids (eg, intravenous methylprednisolone) can be useful in patients who have organ dysfunction, poor performance status, or low blood counts due to MM.

Resource-poor settings — Access to preferred three-drug regimens is limited in certain areas of the world by age restrictions or resource limitations. Patients in such settings can still benefit from the use of treatment regimens that are based on alkylating agents (eg, melphalan or cyclophosphamide) and/or first generation immunomodulatory agents (eg, thalidomide). Details regarding the use of these regimens and guidance regarding the choice of regimen are provided separately. (See "Multiple myeloma: Management in resource-limited settings".)

Special considerations during the COVID-19 pandemic — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple myeloma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

Basics topics (see "Patient education: Multiple myeloma (The Basics)")

Beyond the Basics topics (see "Patient education: Multiple myeloma symptoms, diagnosis, and staging (Beyond the Basics)" and "Patient education: Multiple myeloma treatment (Beyond the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

General principles – There are many approved treatment combinations for patients with relapsed and/or refractory multiple myeloma (MM). Most patients experience serial relapses over time and will ultimately receive most if not all available agents at some point during their disease course. Accompanying tables provide active drugs by class (table 1) and major toxicities of selected treatment regimens (table 2). General principles for treatment are provided separately. (See "Multiple myeloma: Overview of management", section on 'General principles'.)

Assess drug sensitivity – The choice of therapy for relapsed MM is influenced significantly by prior therapies received, response to those therapies, and likelihood of the disease being refractory to specific agents. In general, refractory disease is defined as progressing on or within 60 days of receiving standard doses of a specific therapy. (See 'Assess drug sensitivity' above.)

The term penta-refractory disease is used for MM refractory to all of the following:

An anti-CD38 monoclonal antibody (eg, daratumumab, isatuximab)

Lenalidomide

Pomalidomide

Bortezomib

Carfilzomib

The drugs that define penta-refractory MM are some of our most active agents in MM, and the regulatory approval of several other therapies has been limited to this specific population. Our approach is therefore structured according to whether or not the patient has penta-refractory MM.

Non-penta-refractory disease – For most patients with MM in third or greater relapse who maintain sensitivity to at least one of the agents listed above, we suggest a regimen that includes these agents rather than therapies used for penta-refractory disease (Grade 2C). The choice of regimen is similar to that in first or second relapse, and it is driven by understanding of drug sensitivity and expected toxicity (algorithm 2). (See 'Non-penta-refractory disease' above.)

Penta-refractory disease – For patients with penta-refractory disease, we suggest therapies that target BCMA or alkylator-containing regimens rather than other therapies (algorithm 1) (Grade 2C). (See 'Targeting BCMA' above and 'Alkylator containing' above.)

Patients with penta-refractory MM that is also refractory to alkylators and anti-BCMA therapies are encouraged to enroll on clinical trials. Combinations that include selinexor are an option outside of a clinical trial. (See 'Selinexor' above.)

The BCL-2 inhibitor venetoclax has demonstrated activity in MM with t(11;14), and we consider off-label use of venetoclax alone or in combination for patients with t(11;14) who have limited alternatives either due to multiply refractory disease or comorbidities. We do not offer venetoclax to other patients with MM, regardless of BCL-2 expression. (See 'Venetoclax for MM with t(11;14)' above.)

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