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Expert Guidance on Therapeutic Strategies for Multiple Myeloma

Charise Gleason, MSN, NP-BC, AOCNP
Sagar Lonial, MD
Kathryn Maples, PharmD, BCOP
Released: May 1, 2020

Treatment Options for Patients With Relapsed/Refractory MM

Patient Case: Early Relapsed MM

Charise Gleason, MSN, NP-BC, AOCNP:
Our next case was a 52-year-old man who was diagnosed with standard risk MM. He was treated with 4 cycles of VRd for induction followed by ASCT and lenalidomide maintenance. Unfortunately, he relapsed within 1 year of his transplant while receiving maintenance therapy.

Sagar Lonial, MD:
The first question is why did this patient relapse so early in his treatment? By our current diagnostic criteria, he was a standard-risk patient. This makes me wonder if he had an IgL lambda translocation, which, as noted in a recent article by Barwick and colleagues,[26] confers a worse outcome with IMiDs. In this study, patients with standard risk and hyperdiploidy who had a poor outcome were found to have an IgL lambda translocation.

Nevertheless, options for patients who experience an early relapse after frontline therapy should include different agents than those used for initial treatment, such as Dara or carfilzomib, both of which partner well with pomalidomide. Based on results of the phase III CANDOR trial, the combination of Dara-Kd would be another option for this early high-risk relapsing patient. In addition, clinical trials are evaluating the role of CAR T-cells in this high-risk early relapse setting as well.

Charise Gleason, MSN, NP-BC, AOCNP:
At first relapse and in subsequent relapses, clinicians should also consider restaging each patient. Performing a bone marrow biopsy to reassess cytogenetics will help identify any important changes to the disease trajectory. We typically also repeat PET/CT imaging at this point as well.

Sagar Lonial, MD:
Yes, I agree. If we enter this patient scenario into our Interactive Treatment Decision Tool that is associated with this activity, 4 out of 5 experts would recommend Dara-Pd for this type of patient. Other treatment recommendations include a regimen with Dara plus a PI/dexamethasone combination. Both pomalidomide or PI-based combinations with Dara are reasonable options for patients who are progressing on lenalidomide maintenance therapy.

Now, let’s discuss some of the data informing treatment decisions. 

Pomalidomide-Based Salvage Therapy for R/R MM

Sagar Lonial, MD:
As shown in this table, various pomalidomide-based regimens are available as salvage therapy for patients with R/R MM based on numerous clinical trials. Pomalidomide is a good option as a backbone for therapy for patients who are refractory to lenalidomide. Partners in these combinations include bortezomib, dexamethasone, carfilzomib, Dara, ixazomib, and elotuzumab. Several key studies of pomalidomide-based regimens are described below.

Phase II Trial of Daratumumab/Pomalidomide/Dexamethasone for R/R MM

Sagar Lonial, MD:
In this phase II study, patients with R/R MM who had received ≥ 2 previous lines of therapy were treated with the combination of Dara-Pd.[27] The primary endpoint of this study was safety, and ORR and MRD status by next-generation sequencing were secondary endpoints. The safety profile was as expected for each of these agents. The ORR was 60% and Dara-Pd resulted a median PFS of 8.8 months and the median OS was 17.5 months.

Phase III ICARIA-MM Trial: Isatuximab/Pomalidomide/Dexamethasone in R/R MM

Sagar Lonial, MD:
Like Dara, isatuximab is an anti-CD38 monoclonal antibody that has been shown to have activity in MM. The randomized, multicenter, open-label phase III ICARIA-MM trial assessed the efficacy of isatuximab plus Pd in patients who had received ≥ 2 previous lines of treatment, including lenalidomide and a PI.[28] Patients were randomized to receive either isatuximab plus Pd or Pd alone, and the primary endpoint of the trial was PFS.

Patients who received isatuximab plus Pd had a median PFS of 11.5 months vs 6.5 months with Pd alone (HR: 0.596; P = .001). Similar HRs were observed for patients who were lenalidomide refractory (HR: 0.59), lenalidomide refractory in most recent line of therapy (HR: 0.50), and lenalidomide and PI refractory (HR: 0.58). In addition, patients achieved an ORR of 60% with isatuximab plus Pd vs 35% with Pd and 32% achieved VGPR of better with isatuximab plus Pd vs < 9% with Pd. The median OS has not yet been reached with either arm, but early data show a trend toward an improvement in OS with the addition of isatuximab (HR: 0.687; P = .0631), with an estimated 12-month OS rate of 72% vs 63%, respectively.

These data suggest that isatuximab is a new option for patients with R/R MM, and the FDA approved isatuximab in combination with Pd for patients with R/R MM who had received ≥ 2 previous lines of treatment, including lenalidomide and a PI.

ELOQUENT-3: Elotuzumab/Pomalidomide/Dexamethasone in R/R MM

Sagar Lonial, MD:
In the phase II ELOQUENT-3 trial, the combination of elotuzumab plus Pd (EPd) extended PFS compared with Pd alone in patients with R/R MM that was refractory and/or relapsed following lenalidomide and a PI.[29] In this study, the median PFS was 10.3 months with EPd vs 4.7 with Pd alone (HR: 0.54; P = .008) and the median OS was not reached but HR for OS was 0.62, favoring EPd.

Phase I Trial of Carfilzomib/Pomalidomide/Dexamethasone in R/R MM

Sagar Lonial, MD:
A phase I study was conducted to evaluate the combination of carfilzomib/Pd (KPd) in patients with R/R MM who were refractory to their most recent therapy (N = 32).[30] Results showed a 50% ORR (no CRs) and a median PFS of 7.2 months.

Phase III CANDOR Trial: Daratumumab/Carfilzomib/Dexamethasone in R/R MM

Sagar Lonial, MD:
The phase III CANDOR trial evaluated the addition of Dara to Kd in patients with R/R MM treated with 1-3 previous therapies with ≥ PR to ≥ 1 previous therapy (N = 466).[31] Dara-Kd resulted in an ORR of 84% vs 75% with Kd. The median PFS was not reached with Dara-Kd vs 15.8 months with Kd alone (HR: 0.63). Median OS was not reached in either arm, and at a median follow-up of approximately 17 months the survival curves appeared very similar (HR: 0.75).

The significant PFS benefit, with a 37% reduction in risk of progression or death, suggest that this regimen should be considered a treatment option for patients with R/R MM.

MM-Developing Regimens Using Genomics (MyDRUG): Targeted Agent Basket Trial in R/R MM

Sagar Lonial, MD:
Clinicians should always consider clinical trial enrollment for their patients with MM. For example, Kumar and the Multiple Myeloma Research Consortium[32] are leading the phase I/II MyDRUG basket trial, which is designed to test targeted agents in patients with early R/R MM with specific genetic abnormalities or mutations. In this nonrandomized trial (planned N = 228), all patients will receive backbone therapy with ixazomib/Pd and undergo whole genome sequencing to determine which targeted therapy will be added to the ixazomib/Pd backbone. Patients with a CDK2 alteration will receive abemaciclib, those with an IDH2 mutation will receive enasidenib, those with a RAF/RAS mutation receive cobimetinib, a FGFR3 mutation means erdafitinib, patients with the t(11;14) translocation will receive venetoclax, and patients with nonactionable genetic abnormalities will receive Dara. The primary endpoint is ORR, and this study will help to determine if these targeted agents are of use in the early relapse setting instead of in later lines of therapy when those mutations are less likely to be driver mutations.

Patient Case: Heavily Pretreated Patient With Relapsed MM

Sagar Lonial, MD:
Seeing patients cycle through a number of their different lines of therapy is becoming a more common but no less challenging situation. As mentioned previously, repeating imaging and cytogenetic testing can also be important. For example, retesting may allow us to identify patients with previously unidentified t(11;14) translocations who could potentially benefit from venetoclax-based therapy.

Charise Gleason, MSN, NP-BC, AOCNP:
In addition to cytogenetics, the type of relapse (ie, a biochemical relapse vs a clinical relapse) can also affect the choice of treatment. For patients with biochemical relapses, clinicians should monitor their patients’ laboratory values to determine the rate of relapse as well as monitor for emergence of clinical symptoms. If a patient presents with clinical symptoms such as anemia or bone pain, symptoms should be treated first and close monitoring is essential.

Sagar Lonial, MD:
Yes, and monitoring patients with a biochemical relapse should also include imaging to ensure that any occult bone disease is not missed. Of note, skeletal surveys have mostly been replaced by more advanced imaging: Low-dose whole body CT scan, PET scan, and whole-body MRI are becoming the standard imaging modalities in MM.

Kathryn Maples, PharmD, BCOP:
Let’s discuss our next patient case example: This is a 71‑year‑old man with a history of R/R MM and he has had many previous lines of therapy. His initial induction therapy with VRd followed by ASCT and lenalidomide maintenance. At first relapse, he received KPd and was also retested and found to have a t(11;14) translocation. After his next relapse, he received venetoclax/dexamethasone and remained in VGPR for 11 months before progressing. His fourth line of therapy was Dara-Pd followed by, most recently, KCd. However, carfilzomib was eventually changed to ixazomib due to cardiac complications. Now, this patient is presenting with progression of disease again.

Sagar Lonial, MD:
For a patient like this, treatment is becoming increasingly challenging due to decreasing performance status and worsening blood counts. As patients relapse, each line of therapy should contain a new class of drugs or a new agent from available classes of agents.

Options for relapse disease includes other PIs such as carfilzomib, newer IMiDs such as pomalidomide or iberdomide (investigational) as well as selinexor or elotuzumab. There are also ongoing trials with investigational agents such as venetoclax and BCMA-targeted agents such as the antibody–drug conjugate belantamab mafodotin, CAR T-cell therapy, and bispecific T-cell engagers (BiTE).

This patient is now refractory to lenalidomide, pomalidomide, carfilzomib, Dara, cyclophosphamide, and venetoclax. If we enter this patient scenario into our Interactive Treatment Decision Tool that is associated with this activity, all 5 experts would recommend either a selinexor-based therapy or enrollment on a clinical trial. Recommended clinical trials include those with BCMA-targeted agents or other novel classes of therapy.

Let’s talk through the data for some of these newer agents.

Venetoclax for Patients With t(11;14) R/R MM

Sagar Lonial, MD:
This patient has a t(11;14) translocation and received venetoclax-based therapy as third-line therapy. Venetoclax, a selective oral inhibitor of BCL-2, is a targeted therapy in development for patients with MM and has been most effective in patients with the t(11;14) translocation. In March 2019, a clinical hold was put on venetoclax use for patients with MM due to safety concerns. The hold was lifted in June 2019 and now we have additional data that continue to support its safety and efficacy in patients with refractory MM, particularly those patients with a t(11;14) translocation.

The clinical hold was due to reports from the phase III BELLINI study with venetoclax plus bortezomib/dexamethasone (Vd) vs Vd alone in which unselected patients who received venetoclax had a higher rate of infections and early deaths due to infection vs those who received Vd alone. However, in a subgroup analysis of BELLINI at ASH 2019, data showed that patients without t(11;14) translocations did not benefit from the addition of venetoclax and OS favored placebo in this population.[33] Furthermore, patients with a t(11;14) translocation did benefit from the combination of venetoclax with Vd and did not have a survival decrement. These patients with t(11;14) translocations had a higher response rate, longer median PFS, and no significant impact on OS.

A phase I/II study, which was also presented at ASH 2019, analyzed the efficacy of venetoclax plus dexamethasone in patients with R/R MM and t(11;14).[34] Patients in this study were heavily pretreated. The phase I portion included patients who were previously treated with an IMiD and a PI, and the phase II portion included patients who were also previously exposed to Dara.

In the phase I expansion cohort (where 20% of patients were refractory to Dara), the ORR was 60%, and in the phase II cohort (where 87% of patients were refractory to Dara), the ORR was 48%. The median time to progression was 12.4 months in the phase I cohort and 10.8 months in the phase II cohort. The median duration of response was not reached in phase II, nor was median OS, but at 12 months, the duration of response was 61 months and 50% of patients remained alive. Although some infections were observed (grade ≥ 3 sepsis in 5% to 10% of patients and grade ≥ 3 pneumonia in 3% to 5% of patients depending on phase of study), only 1 patient died due to infection during the first month of treatment.

I think these data are interesting and may reflect a role for venetoclax-based therapy in patients with t(11;14) who have already experienced disease progression after available treatment options and require additional therapy.

Selinexor-Based Therapy in R/R MM

Sagar Lonial, MD:
Another option for heavily pretreated patients is a selinexor-based therapy. Selinexor is a first-in-class, oral selective inhibitor of nuclear export that inhibits XPO1 and activates tumor suppressor proteins.[35] Selinexor/dexamethasone was recently approved by the FDA for patients with R/R MM after ≥ 4 previous lines of therapy whose disease is refractory to ≥ 2 PIs, ≥ 2 IMiDs, and anti-CD38 monoclonal antibodies.

The STORM trial is a multicenter, single-arm phase II trial evaluating the efficacy and safety of selinexor and low-dose dexamethasone in 122 heavily pretreated patients with penta-exposed, triple-class refractory MM. Patients had been previously treated with bortezomib, carfilzomib, lenalidomide, pomalidomide, Dara, an alkylating agent, and glucocorticoid, with disease documented to be refractory to ≥ 1 PI, ≥ 1 IMiD, Dara, a glucocorticoid, and last therapy. Selinexor and dexamethasone were given in 28-day cycles until disease progression. The primary endpoint was ORR, and secondary endpoints included duration of response, clinical benefit rate, OS, PFS, and safety.

When combined with dexamethasone in this trial, selinexor showed a 26.2% ORR in 122 patients with R/R MM, including a 25.3% rate in those whose disease was penta-refractory.[36,37] In this study, median PFS was nearly 4 months, with median OS of 8.6 months in the intention-to-treat population, but 15.6 months in patients with a minimal response or better.

The main adverse events associated with selinexor were gastrointestinal and hematologic toxicities. The most common all-grade treatment-related gastrointestinal adverse events included nausea (72%), anorexia (56%), vomiting (38%), and diarrhea (46%). However, these only rarely occurred as grade 3 events, affecting 10%, 5%, 3%, and 7% of patients, respectively. Likewise fatigue was seen in 73% of patients but was grade 3 in only 25%. The other nonhematologic event of concern was hyponatremia, which was seen in 37% of patients and was grade 3 in 21%. Only 2 grade 4 nonhematologic events were seen—pneumonia and hyponatremia—and 2 patients died from treatment-related pneumonia.

Hematologic events included thrombocytopenia in 73% (grade 3 in 25%, grade 4 in 33%), anemia in 67% (grade 3 in 43% plus 1 grade 4 event), neutropenia in 40% (grade 3 in 18%, grade 4 in 3%), and leukopenia in 33% (grade 3 in 14%).

In my opinion, it can be challenging to follow the FDA-approved label of selinexor 80 mg in combination with dexamethasone on Days 1 and 3 of each week. When we use selinexor, we recommend a lower dose of selinexor and combine it with a PI, most commonly carfilzomib, and dexamethasone. The phase I/II STOMP trial showed promising results with selinexor combined with Vd.

Kathryn Maples, PharmD, BCOP:
One of the biggest challenges in heavily pretreated patients is the need for individualized supportive care because they typically have more disease burden, have more comorbidities, and have had multiple adverse events at this point in care. With selinexor, we use olanzapine as an antinausea agent and an appetite stimulant and have found it very helpful. We counsel our patients to start olanzapine a few nights before beginning therapy with selinexor and then continue on olanzapine throughout therapy. We also use ondansetron and prochlorperazine as alternatives and as needed for additional support.

BCMA-Targeted Agents: Antibody Drug Conjugates

Sagar Lonial, MD:
In recent years, BCMA—a member of the TNF receptor family of proteins—has been identified as a therapeutically relevant target in MM. BCMA is expressed specifically on plasma cells and MM cells but not in other blood cells or tissues. MM cells have higher expression of BCMA than normal plasma cells, and BCMA expression increases with disease progression to advanced MM. In early clinical trials of BCMA-targeted agents in patients with heavily pretreated MM, multiple approaches have uniformly demonstrated robust and durable responses. These include CAR T-cell therapies, bispecific monoclonal antibodies, BiTE, and antibody–drug conjugates.

Belantamab mafodotin is a humanized, afucosylated, IgG1 BCMA-targeted antibody–drug conjugate that neutralizes soluble BCMA.[35,38,39] Once internalized into MM cells, it releases the linked cytotoxic agent monomethyl auristatin F, which causes cell death. In preclinical studies, belantamab mafodotin demonstrated selective and potent activity against MM cells.

The phase I DREAMM-1 trial evaluated single-agent belantamab mafodotin in 35 patients with R/R MM.[39] The ORR was 60%, including 2 stringent CRs, 3 CRs, 14 VGPRs, and 2 PRs. Of note, more than one half of the patients experienced a 100% reduction in their M-protein or FLC levels from baseline. The median PFS was 12.0 months with a median duration of response of 14.3 months. In patients without previous Dara treatment, median PFS was 15.7 months vs 6.8 months in those with previous Dara treatment. In patients with previous Dara use and MM refractory to IMiDs and PIs, median PFS was 6.2 months.

DREAMM-2 was an open-label, 2-arm phase II trial providing additional data after the DREAMM-1 trial in patients with R/R MM after ≥ 3 lines of therapy whose disease was refractory to IMiDs and PIs and refractory or intolerant to anti-CD38 monoclonal antibodies (N = 196).[40] In DREAMM-2, patients were randomized to receive 1 of 2 doses of belantamab mafodotin—2.5 mg/kg or 3.4 mg/kg—and included a primary endpoint of ORR in all randomized patients. The ORR was 31% in the 2.5-mg/kg cohort and 34% in the 3.4-mg/kg cohort with approximately 20% achieving VGPR or better with 3% achieving stringent CR/CR. With a median follow-up of approximately 6.5 months, the duration of response was not reached for either cohort. The median PFS was 2.9 months in the 2.5-mg/kg cohort and 4.9 months in the 3.4-mg/kg cohort, and median OS has not yet been reached.

Belantamab mafodotin is currently under investigation in several trials enrolling patients with R/R MM, including the phase II DREAMM-4 trial as well as the phase I/II DREAMM-5 and DREAMM-6 trials. In addition to belantamab mafodotin, the BCMA-targeted antibody–drug conjugates MEDI2228 and CC-99712 are under phase I clinical investigation.

Charise Gleason, MSN, NP-BC, AOCNP:
The most common nonhematologic adverse event associated with belantamab mafodotin was ocular toxicity comprising blurred vision (52%), photophobia (29%), dry eye (27%), and eye pain (12%). Patients who receive belantamab mafodotin need regular eye examinations to monitor for ocular toxicities. Other common adverse events associated with belantamab mafodotin included thrombocytopenia, cough, anemia, diarrhea, and hypokalemia.

Overall, patients in later lines of therapy require more supportive care, and it can be very patient specific and treatment specific. Many of these patients in later lines of therapy, depending on treatment options, may need growth factor support. For patients receiving belantamab mafodotin, clinicians will also have to be mindful of any ocular toxicity and use eye drops and/or eye steroid drops as needed.

BCMA-Targeted Bispecific T-Cell Engagers in R/R MM

Sagar Lonial, MD:
BCMA-targeted BiTE are another “off-the-shelf” approach to targeting BCMA in MM. A BiTE molecule has 2 arms that link to an antigen on tumor cells on one arm and a cell-surface receptor on T-cells on the other arm. This results in activation of the T-cells and engaging them with tumor cells. The most mature data using this approach in MM are from AMG 420 (formerly BI 836909), a BiTE with a short half-life that targets BCMA on MM cells and CD3 on T-cells. AMG 420 has been granted Fast Track designation by the FDA.

In a first-in-human phase I trial, 42 patients with R/R MM who had received ≥ 2 previous lines of therapy, including a PI and IMiD, were enrolled to receive up to 10 cycles of AMG 420.[41] Of the patients treated at the maximum tolerated dose of 400 μg/day, 70% had a response and 50% achieved an MRD-negative CR. Across all doses, the response rate was 31%, with 14% achieving an MRD-negative CR. The median duration of response was 9.0 months with 400 μg/day and 8.4 months at all doses, but the responses were very rapid, with 11 out of 13 responders experiencing response within the first cycle.

Overall, AMG 420 has been well tolerated; however, cytokine-release syndrome did occur in 38% of patients (most grade 1/2) and serious infections were reported in 33% of patients. There were 2 deaths from infection (adenovirus and aspergillus/influenza), but they were considered unrelated to treatment.

We need longer-term data to better determine the durability of these responses, but these results are certainly promising. Compared with T-cell therapy, BiTE constructs have the advantage of being used “off the shelf” for patients and do not require waiting for the CAR T-cells to be manufactured. The disadvantage with this particular construct is that it needs to be administered as a continuous infusion. Other BiTE molecules, including some with longer half-lives, are in early stages of development and we are awaiting results of additional trials.

BCMA-Targeted CAR T-Cell Therapy in R/R MM: CARTITUDE-1

Sagar Lonial, MD:
Clinical trials with BCMA-targeted CAR T-cell therapy has also shown promise for patients with R/R MM. The phase Ib/II CARTITUDE‑1 trial was conducted in the United States and examined the CAR T-cell construct JNJ-4528 in 29 patients with heavily pretreated R/R MM.[42] JNJ-4528 contains 2 BCMA-targeting single-domain antibodies designed to confer more avidity for the antigen and a 4-1BB costimulatory domain.

This study was conducted to confirm the exciting data that were initially reported in Chinese patients in the LEGEND-2 study, with LCAR-B38M, an identical CAR to JNJ-4528. Patients in the CARTITUDE-1 study had a median of 5 previous lines of therapy, 86% of the patients had received a previous ASCT, and 86% of patients were triple refractory to PIs, IMiDs, and anti-CD38 agents. In addition, 14% of patients had extramedullary disease.

The safety profile reported in this study was as expected for this population. Although grade 3 cytokine-release syndrome was observed in only 7% of patients, the vast majority—93%—of patients developed some level of cytokine-release syndrome. Tocilizumab was required in 76% of patients and anakinra was required in 21% of patients. Neurotoxicity occurred in 3 patients, and one of these patients had grade ≥ 3 neurotoxicity at the same time as grade 3 cytokine-release syndrome.

All 29 patients responded to treatment, with 69% of them achieving CR or better. In addition, all 17 patients analyzed achieved MRD negativity, with more than one half of them (n = 9) at the level of 10-6. Although follow-up at the time of the report was still very short at a median of only 6 months, 27 of the 29 patients included in the study remained progression free. When examining CAR T-cell expansion and persistence, we can see that the median time to peak expansion was 13 days post infusion, with a preferential expansion of the CD8+ central memory phenotype cells. The detection of CD3+ CAR T-cells did not correlate with continued deepening of the response.

BCMA-Targeted CAR T-Cell Therapy in R/R MM: Idecabtagene Vicleucel (bb2121)

Sagar Lonial, MD:
In addition to current trials with LCAR-B38M/JNJ-4528, additional CAR T-cell therapies are also under investigation. For example, idecabtagen vicleucel (bb2121) is currently in clinical trials and has been submitted for FDA approval.

The phase I CRB-401 trial of idecabtagene vicleucel enrolled patients with R/R MM.[43] In the dose escalation cohort, patients with BCMA expression of ≥ 50% that had received ≥ 3 previous lines of therapy including a PI and an IMiD or were double refractory to PI and IMiDs were included. In a dose expansion cohort, patients had received prior daratumumab and were refractory to their last therapy but there was no specific BCMA expression requirements. The ORR at doses ≥ 150 × 106 CAR T-cells was 90%, with 50% achieving stringent CR or CR. ORR was similar regardless of BCMA expression: with ORR of 100% with low BCMA expression and 91% with high BCMA expression. The median PFS in patients receiving ≥ 150 × 106 CAR T-cells was 11.8 months. Similar to other CAR T-cell therapies, CRS occurred in 76% of patients receiving idecabtagene vicleucel, but only 6% were grade 3 and none were grade 4. Neurotoxicity occurres in 42% of patients, with 3% with grade 4 severity.

The phase II KarMMA trial in patients with RR MM after ≥ 3 prior therapies, including an IMiD, a PI, and an anti-CD38 antibody is ongoing and reports have suggested that this trial has met it’s primary endpoint of ORR. As clinical trials of CAR T-cell therapies continue to mature, we will be able to see more data regarding their use for our patients with myeloma.

Novel IMiD Iberdomide Plus Dexamethasone in R/R MM

Sagar Lonial, MD:
Another MM therapy that I think shows promise is iberdomide (formerly CC-220). Broadly speaking, iberdomide belongs to the class of drugs referred to as IMiDs, which include lenalidomide and pomalidomide. Iberdomide is a small molecule inhibitor of cereblon E3 ligase modulator and binds cereblon with higher affinity than either lenalidomide or pomalidomide. An initial dose-escalation phase Ib/IIa study of iberdomide was conducted in 66 patients with MM and at least 2 previous lines of therapy including lenalidomide and/or pomalidomide as well as a PI.[44]

Early results suggest a promising adverse event profile. This regimen was associated with some hematologic toxicity, notably neutropenia (grade 3 in 15.2%; grade 4 in 13.6%) and infections (any grade in 47%; grade 3/4 in 25.7%). In addition to appearing to be well tolerated, it is an oral agent, which will be attractive to patients.

Although the ORR was only approximately 32% in this heavily pretreated patient population, a fair number of patients (n = 48) achieved disease control (defined as stable disease or better), suggesting a different mechanism of action than the other IMiDs. There is great interest in moving this agent forward into earlier lines of treatment, and with its relatively mild adverse event profile, it should be feasible to combine with other MM agents in triplet or quadruplet combinations. Questions on long-term efficacy, how to sequence this therapy with the other IMiDs, and the best combinations with iberdomide will hopefully be addressed in additional clinical trials.

Alkylating Agents in R/R MM

Sagar Lonial, MD:
I wish this was a less common scenario but, unfortunately, I often see patients that have cycled through many different drugs, with treatment becoming increasingly challenging due to decreasing performance status and worsening blood counts. In the absence of a clinical trial, there are few options for heavily pretreated patients who relapse on all currently available agents. For patients who have only seen alkylators once early on in their disease course, an intense alkylator-based chemotherapy regimen like DCEP or VDT-PACE may be of benefit. The other option is to choose a PI plus oral cyclophosphamide and dexamethasone.

Patient Case Discussion: Heavily Pretreated Patients With R/R MM

Sagar Lonial, MD:
Patients with heavily pretreated R/R MM are challenging not just from the disease biology perspective but also from the physical perspective: Are they well enough to take more treatment? Some of them have had ≥ 5 lines of therapy. Finding optimal treatment for these patients while incorporating supportive care into their regimen is important.

Charise Gleason, MSN, NP-BC, AOCNP:
The role of a second transplant is worth mentioning. For patients like the fourth case patient, who has been through so many lines of therapy, if they had a long response from their first ASCT, we might consider a second ASCT if they could tolerate it. However, patients with multiple previous lines of therapy have diminished bone marrow function, so we may give a low dose of melphalan chemotherapy to restore their hemopoietic function.

Sagar Lonial, MD:
The key for these patients is for their clinic to have access to ongoing clinical trials, as some of the currently most effective agents are not necessarily available in the community oncology setting or to refer these patients to institutions who do have access.

MM Educational Tools

Kathryn Maples, PharmD, BCOP:
To close out our discussion, I would like to talk about the different educational tools we use in our clinic to help patients cope with the adverse events and stay adherent to their treatment regimen. These include regimen-specific (and institution-specific) handouts showing the days treatment is given and key adverse events to look for. I always give the patients those handouts and also use Chemocare.com for medication-specific handouts.

Charise Gleason, MSN, NP-BC, AOCNP:
We also provide patients with educational handouts. And, as reinforcement, when they are starting a new regimen, we ask for a nurse to follow up with them to see how they are doing once treatment has begun. We also help guide our patients to reputable Web sites for their information, so we recommend the International Myeloma Foundation, Multiple Myeloma Research Consortium, and Leukemia and Lymphoma Society. We also encourage participation in their local support group, which many of us also participate in. Our institution has a peer support program as well for patients.

Sagar Lonial, MD:
Yes, having multiple resources available to patients helps reduce their burden to remember everything discussed during office visits. Resources for clinicians who treat many different types of patients per month can also be helpful when making treatment decisions.

Clinical Care Options has developed a treatment decision support tool for MM, which can be found at www.clinicaloptions.com/myelomatool. This resource provides individualized management recommendations for specific patient cases from myself and 4 other MM experts.

Provided by the Annenberg Center for Health Sciences at Eisenhower

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