XPOVIO® (selinexor): A Treatment Approved for Multiple Myeloma as Early as First Relapse

Author: Cristina Gasparetto, MD
Sponsored by: Karyopharm Therapeutics, Inc.
Dr. Gasparetto is a paid consultant for Karyopharm Therapeutics, Inc. and has been compensated.

Multiple myeloma (MM) remains an incurable hematologic cancer due to the clonal nature of the disease.1 With each relapse, cancer cells undergo clonal evolution and acquire new mutations that render them resistant to certain treatments.1 Triplet therapies combining proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (CD38-mAbs) have improved patient outcomes and their use has steadily increased over the past decade.2,3 When patients relapse after exposure to daratumumab (a CD38-mAb), the prognosis becomes unfavorable; even if patients previously responded to PIs or IMiDs, median survival may not reach one year.3 A significant unmet need therefore remains for providing durable disease control for patients with MM.1

For patients with previously-treated MM, the National Comprehensive Cancer Network® (NCCN®) recommends a new triplet regimen should preferably include drugs or drug classes patients have not been exposed to, or not exposed to for at least 6 months.4 For patients with MM who are triple class exposed, a selective inhibitor of nuclear export (SINE) may be a potential treatment class to consider in early relapsed (1-3 prior therapies) MM.4 Once-weekly XPOVIO® (selinexor), is a first-in-class, oral SINE compound approved as early as first relapse in MM that reversibly inhibits exportin 1 (XPO1).5 This action leads to accumulation of tumor suppressor proteins in the nucleus and reductions in several oncoproteins, such as c-myc and cyclin D1, cell cycle arrest, and apoptosis of cancer cells.5 Oral, once weekly selinexor (XPOVIO®) in combination with bortezomib and dexamethasone (XVd) is recommended by the NCCN as a Category 1 therapeutic option in early relapsed (1 to 3 prior therapies) MM.4

The efficacy and safety of XPOVIO was assessed in a phase 3, randomized, open-label trial comparing XPOVIO (100 mg once weekly) in combination with bortezomib (1.3 mg/m2) and dexamethasone (20 mg) with Vd alone in patients exposed to one to three prior lines of therapy.6 Patient disease characteristics were well balanced in both treatment groups and the primary endpoint was progression-free survival (PFS).5,6 Patients in the XVd group demonstrated a median PFS of 13.9 months (95% CI: 11.73-NE) compared with 9.5 months (95% CI: 8.11-10.78) in the Vd group (HR 0.70 [95% CI: 0.53-0.93], P=0.0075).6 In patients treated with XVd, a greater median PFS was consistently observed in certain subgroups compared with patients treated with Vd (Figure 1).6,7 When comparing patients 65 years of age and older to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (28% vs 13%) and a higher incidence of serious adverse reactions (56% vs 47%).5

XPOVIO-Combination-Demonstrated-Sustained-PFSFigure 1. Median PFS in the XVd and Vd treatment groups (primary endpoint) and in select patient subgroups in the XVd trial.

Oral, once-weekly XPOVIO dosage may be adjusted to help mitigate potential adverse reactions (ARs).5 The indicated starting dose of XPOVIO is 100 mg once weekly and the dose may be reduced to 80 mg, 60 mg, or 40 mg based on ARs.5 Dose reductions were permitted in the XVd trial to help mitigate ARs – 65% of patients in the XVd group had a dose reduction and the median dose of XPOVIO in that group was 80 mg once weekly.5,7 Patients in my clinical practice typically get reduced from 100 mg to 60 mg once weekly and experience minimal tolerability issues at 60 mg. In an exploratory post-hoc analysis of the XVd trial, efficacy was maintained with XPOVIO dose reductions (Figure 2).7

Efficacy-Maintained-Even-With-XPOVIO-Dose-ReductionFigure 2. Median PFS in XPOVIO dose-reduced patients in the XVd trial.

XVd was not associated with serious organ toxicities of the cardiac, pulmonary, renal, or hepatic systems.6,7 Warnings and precautions include life-threatening thrombocytopenia and neutropenia, gastrointestinal toxicities, severe life-threatening hyponatremia, serious infection, and life-threatening neurological toxicities.5 The most common adverse reactions (≥20% with a difference between arms of >5% compared to Vd) were fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract, and vomiting (Figure 3).5 The XVd trial protocol required a prophylactic 5-HT3 antagonist to address nausea but allowed for other interventions as required.7 Nausea events were reported in 50% of patients, however, treatment-related nausea associated with XPOVIO diminished over time; 92% of nausea cases were resolved/resolving in the first month of treatment.7 Patients should be counseled on what to expect with XPOVIO therapy and monitored throughout treatment, with more frequent monitoring during the first three months of treatment.5

Figure 3. Adverse reactions reported in the XVd trial.

Below we consider 2 hypothetical patients where XPOVIO may be considered.

Patient A is a 66-year-old woman with relapsed/refractory MM. She was started on lenalidomide, bortezomib, and dexamethasone, and received autologous stem cell transplant (ASCT) followed by lenalidomide maintenance, which she did well on for 16 months. Upon relapsing, she was given daratumumab, pomalidomide with dexamethasone, and after 7 months, imaging confirmed that her MM progressed again. Given her DPd exposure, Patient A (RVd → ASCT → R → DPd) may be a candidate for a class switch to XVd.

Patient B is a 74-year-old man with a history of hypertension and was diagnosed with MM 2 years ago. Because of his hypertension, he was unable to start a PI due to risk of cardiotoxicity and he is ASCT ineligible. His healthcare provider started him on daratumumab, lenalidomide, and dexamethasone (DRd), but after 2 years, he has relapsed. A class switch to XPOVIO could be considered for Patient B as his second-line therapy.

Healthcare providers should consider patients’ individual clinical characteristics when making treatment decisions. Consider switching class with XPOVIO® (selinexor) for patients at relapse, including those who have been exposed to a CD38-mAb–based regimen.5 Based on the results of the XVd trial and considering the clonal nature of MM, switching patients to XPOVIO may be an option to consider.

INDICATIONS
XPOVIO® (selinexor) is a prescription medicine approved:
• in combination with bortezomib and dexamethasone to treat adult patients with multiple myeloma who have received at least one prior therapy.
• in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti‐CD38 monoclonal antibody.

IMPORTANT SAFETY INFORMATION

Thrombocytopenia:
XPOVIO can cause life-threatening thrombocytopenia, potentially leading to hemorrhage. Thrombocytopenia was reported in patients with multiple myeloma.
Thrombocytopenia is the leading cause of dosage modifications. Monitor platelet counts at baseline and throughout treatment. Monitor more frequently during the first 3 months of treatment. Monitor patients for signs and symptoms of bleeding. Interrupt, reduce dose, or permanently discontinue based on severity of adverse reaction.

Neutropenia: XPOVIO can cause life-threatening neutropenia, potentially increasing the risk of infection.
Monitor more frequently during the first 3 months of treatment. Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF). Interrupt, reduce dose, or permanently discontinue based on severity of adverse reaction.

Gastrointestinal Toxicity: XPOVIO can cause severe gastrointestinal toxicities in patients.

Nausea/Vomiting/Diarrhea:
Provide prophylactic antiemetics or treatment as needed.

Anorexia/Weight Loss:
Monitor weight, nutritional status, and volume status at baseline and throughout treatment and provide nutritional support, fluids, and electrolyte repletion as clinically indicated.

Hyponatremia:
XPOVIO can cause severe or life-threatening hyponatremia.
Monitor sodium level at baseline and throughout treatment.

Serious Infection:
XPOVIO can cause serious and fatal infections. Atypical infections reported after taking XPOVIO include, but are not limited to, fungal pneumonia and herpesvirus infection.

Neurological Toxicity:
XPOVIO can cause life-threatening neurological toxicities.
Coadministration of XPOVIO with other products that cause dizziness or mental status changes may increase the risk of neurological toxicity.
Advise patients to refrain from driving and engaging in hazardous occupations or activities until the neurological toxicity fully resolves. Institute fall precautions as appropriate.

Embryo-Fetal Toxicity:
XPOVIO can cause fetal harm when administered to a pregnant woman.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose.

Cataracts: New onset or exacerbation of cataract has occurred during treatment with XPOVIO. The incidence of new onset or worsening cataract requiring clinical intervention was reported.

ADVERSE REACTIONS

The most common adverse reactions (ARs) (≥20%) in patients with multiple myeloma who received XVd were fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract, and vomiting.

Grade 3-4 laboratory abnormalities (≥10%) were thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia.

Fatal ARs occurred in 6% of patients within 30 days of last treatment. Serious ARs occurred in 52% of patients. Treatment discontinuation rate due to ARs was 19%. The most frequent ARs requiring permanent discontinuation in >2% of patients included fatigue, nausea, thrombocytopenia, decreased appetite, peripheral neuropathy and vomiting. Adverse reactions led to XPOVIO dose interruption in 83% of patients and dose reduction in 64% of patients.

USE IN SPECIFIC POPULATIONS

No overall difference in effectiveness of XPOVIO was observed in patients >65 years old when compared with younger patients. Patients ≥65 years old had a higher incidence of discontinuation due to an adverse reaction (AR) and a higher incidence of serious ARs than younger patients.

The effect of end-stage renal disease (CLCR <15 mL/min) or hemodialysis on XPOVIO pharmacokinetics is unknown.

Please see full Prescribing Information.
To report SUSPECTED ADVERSE REACTIONS, contact Karyopharm Therapeutics Inc. at 1-888-209-9326 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

© 2022 Karyopharm Therapeutics Inc. US-XPOV-10/22-00003

References
1. Mikkilineni L, Kochenderfer JN. CAR T cell therapies for patients with multiple myeloma. Nat Rev Clin Oncol. 2021;18(2):71-84. doi:10.1038/s41571-020-0427-6
2. Braunlin M, Belani R, Buchanan J, Wheeling T, Kim C. Trends in the multiple myeloma treatment landscape and survival: a U.S. analysis using 2011-2019 oncology clinic electronic health record data. Leuk Lymphoma. 2021;62(2):377-386. doi:10.1080/10428194.2020.1827253
3. Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266-2275. doi:10.1038/s41375-019-0435-7
4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma V.5.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed October 18, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
5. XPOVIO (selinexor) [prescribing information]. Karyopharm Therapeutics Inc. https://www.karyopharm.com/wp-content/uploads/2019/07/NDA-212306-SN-0071-Prescribing-Information-01July2019.pdf
6. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. The Lancet. 2020;396(10262):1563-1573. doi:10.1016/S0140-6736(20)32292-3
7. Data on File. Karyopharm Therapeutics Inc. 2021. Published online 2021.

FDA Approves TECVAYLI® for Relapsed or Refractory Multiple Myeloma

SUMMARY: The FDA on October 25, 2022, granted accelerated approval to TECVAYLI® (Teclistamab-cqyv), the first bispecific B-Cell Maturation Antigen (BCMA)-directed CD3 T-cell engager, for adult patients with Relapsed or Refractory multiple myeloma who have received at least four prior lines of therapy, including a Proteasome Inhibitor, an Immunomodulatory agent, and an anti-CD38 monoclonal antibody. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2022 remains an incurable disease.

B-Cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and Multiple Myeloma. At the time of writing, there are three BCMA-targeted therapies approved by the FDAfor patients with Relapsed or Refractory multiple myeloma with triple-class exposure. They include CARVYKTI® (Ciltacabtageneautoleucel) and ABECMA® (Idecabtagenevicleucel),which are B-Cell Maturation Antigen (BCMA)-directed genetically modified autologous T cell immunotherapies (CART-Cell therapies), and BLENREP® (Belantamabmafodotin-blmf), which is a B-Cell Maturation Antigen (BCMA)-directed antibody and microtubule inhibitor drug conjugate (Antibody Drug Conjugate). Even though CAR T-cell therapies have resulted in remarkable clinical responses, logistic challenges include at least 2 weeks of hospital stay, long manufacturing times, need for bridging therapy, and high cost of treatment.

TECVAYLI® is a bispecific antibody with dual binding sites, that targets both CD3 expressed on the surface of T cells and BCMA expressed on the surface of myeloma cells, and thereby mediates T-cell activation and lysis of BCMA-expressing myeloma cells. This effect occurs regardless of T-cell–receptor specificity or Major Histocompatibility Complex class I molecules on the surface of myeloma cells. This mechanism of action of TECVAYLI® is distinct from that of other available therapies for this patient group.

The present FDA approval was based on the efficacy and safety results from the pivotal, single-arm, multi-cohort, open-label, multi-center Phase 1/2 portion of MajesTEC-1 study, which enrolled 165 patients, who had Relapsed or Refractory myeloma after at least three therapy lines, including triple-class exposure to an Immunomodulatory drug, a Proteasome Inhibitor, and an anti-CD38 antibody. Patients received TECVAYLI® 1.5 mg/kg subcutaneously once weekly, after receiving step-up doses of 0.06 and 0.3 mg/kg separated by 2- 4 days and completed 2-4 days before the administration of the first full TECVAYLI® dose. Patients were hospitalized and premedicated with Dexamethasone, Acetaminophen, and Diphenhydramine for each step-up dose and for the first full dose of TECVAYLI®. Treatment was continued until disease progression, unacceptable toxicity, or the end of the study. The median age was 64 years, the median time between diagnosis and the first treatment dose was 6 years, 26% had at least one high-risk cytogenetic abnormality defined as del(17p), t(4;14), or t(14;16) among those with available cytogenetic data (N=148), 77.6% had triple-class refractory disease, and patients had received a median of 5 previous lines of therapy. The Primary end point was the Overall Response Rate (ORR), which was defined as a Partial Response or better according to the International Myeloma Working Group criteria, as assessed by an Independent Review Committee. Secondary end points included Duration of Response, Very Good Partial Response (VGPR) or better, Progression Free and Overall Survival, Minimal Residual Disease (MRD) status and Safety.

At a median follow-up of 14.1 months, the Overall Response Rate was 63%, with 39.4% having a Complete Response or better. Close to 60% of patients had a Very Good Partial Response or better. Approximately, 27% of patients had negative results for Minimal Residual Disease in bone marrow (<1 myeloma cell in 100,000 cells), and the MRD-negativity rate among the patients with a Complete Response or better was 46%. The median Duration of Response was 18.4 months, and the median duration of Progression Free Survival was 11.3 months. Common adverse events included Cytokine Release Syndrome (CRS) noted in 72% and were mostly Grade 1 or 2 and fully resolved. None of the patients discontinued TECVAYLI® due to CRS. Other common adverse events included neutropenia, anemia, and thrombocytopenia, as well as immune effector cell–associated neurotoxicity syndrome, but none of the patients discontinued therapy because of neurotoxic events.

It was concluded from this study that TECVAYLI® had substantial clinical activity, with a high rate of deep and durable response in patients with triple-class-exposed Relapsed or Refractory multiple myeloma. Toxic effects were common but were mainly of low grade and reversible. The researchers added that the efficacy of TECVAYLI® compared favorably with other FDA approved treatments that are currently available for later lines in multiple myeloma, including BLENREP® (Belantamabmafodotin-blmf), XPOVIO® (Selinexor), and CAR T-cell therapies.

Teclistamab in Relapsed or Refractory Multiple Myeloma. Moreau P, Garfall AL,van de DonkNW,et al. N Engl J Med 2022; 387:495-505

Overall Survival Benefit with SARCLISA® Plus POMALYST® and Dexamethasone in Relapsed and Refractory Myeloma

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, Multiple Myeloma (MM) in 2022 remains an incurable disease.

CD38 is a transmembrane glycoprotein, abundantly expressed on malignant plasma cells, and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38 and was approved for use in combination with POMALYST® (Pomalidomide) and Dexamethasone in 2017, for the treatment of patients with multiple myeloma, who have received at least two prior therapies including REVLIMID® (Lenalidomide) and a Proteasome Inhibitor. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, DARZALEX® may have a role in immunomodulation by depleting CD38-positive regulator Immune suppressor cells, and thereby expanding T cells, in patients responding to therapy.

SARCLISA® (Isatuximab) is a CD38-targeting monoclonal antibody, similar to DARZALEX®, but unlike DARZALEX®, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, SARCLISA® targets a specific epitope on the CD38 receptor, and this distinction from DARZALEX® allows use of SARCLISA® in cases when DARZALEX® fails. Additionally, SARCLISA® infusions are less cumbersome.

The FDA approval of SARCLISA® in 2020 was based on ICARIA-MM trial, which is an open-label, randomized, multicentre Phase III study in which 307 adult patients with Relapsed and Refractory multiple myeloma who had received at least two previous lines of treatment, including REVLIMID® and a Proteasome Inhibitor were eligible. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. Patients were randomly assigned 1:1 to receive either SARCLISA® along with POMALYST® and low-dose Dexamethasone (N =154) or POMALYST® and low-dose Dexamethasone alone (N = 153). Treatment consisted of 28-day cycles of SARCLISA® 10 mg/kg given IV on days 1, 8, 15, and 22 in the first cycle and days 1 and 15 in subsequent cycles. Both groups received POMALYST® 4 mg orally on days 1 to 21 of each cycle and Dexamethasone 40 mg (20 mg for patients aged 75 years or older) orally or IV on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression or unacceptable toxicity. The Primary endpoint was Progression Free Survival (PFS), determined by an Independent Response Committee, and assessed in the intent-to-treat population.

At a median follow up of 11.6 months, the median PFS was 11.5 months in the SARCLISA® group versus 6.5 months in the control group (HR= 0.596; P=0.001). This PFS improvement represented an approximately 40% reduction in the risk of disease progression or death in the SARCLISA® group and was noted in all poor prognostic patient subgroups, including patients who were refractory to REVLIMID®, a Proteasome Inhibitor or both.

The researchers in this publication reported prespecified updated Overall Survival analysis, at 24 months after the primary analysis (second interim analysis). The median follow-up at data cutoff was 35.3 months. The median Overall Survival was 24.6 months in the SARCLISA® group and 17.7 months in the control group (HR=0.76; P=0.028, not crossing prespecified stopping boundary). Final Overall Survival analysis follow up is ongoing. Updated median PFS was 11.1 months in the SARCLISA® group versus 5.9 months in the control group (HR= 0.60; P<0.0001).

Approximately 60% of patients in the SARCLISA® group and 72% in the control group received subsequent therapy after disease progression. Median time to next treatment was longer in the SARCLISA® group (P<0.0001). Among these patients, 24% received DARZALEX® as subsequent therapy versus 58% in the control group. In a post hoc analysis, median overall survival was 19.9 months among control group patients who received DARZALEX® and 17.4 months among those who did not. Overall, median PFS on subsequent therapy or death was 17.5 months in the SARCLISA® group versus vs 12.9 months in the control group (HR=0.76; P=0.02).

The most common Grade 3 or worse treatment-related adverse events in the SARCLISA® group versus the control group were neutropenia (50% versus 35%), pneumonia (23% versus 21%), and thrombocytopenia (13% versus 12%). No new safety concerns were identified with SARCLISA® plus POMALYST® and Dexamethasone, with longer follow up.

The authors concluded that the addition of SARCLISA® to POMALYST® and Dexamethasone resulted in an approximately 7 month difference in median Overall Survival compared with POMALYST® and Dexamethasone, and is a new standard of care for REVLIMID® and Proteasome Inhibitor-refractory or relapsed multiple myeloma.

Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study. Richardson PG, Perrot A, San-Miguel J, et al. Lancet Oncol. 2022;23(3):416-427. doi:10.1016/S1470-2045(22)00019-5

Late Breaking Abstract – ASCO 2022: RVd Plus Autologous Stem Cell Transplantation and REVLIMID® Maintenance Improves PFS in Multiple Myeloma

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, Multiple Myeloma (MM) in 2022 remains an incurable disease.

In patients with newly diagnosed Myeloma who are eligible for transplant, the optimal use of triplet/quadruplet induction regimens, Autologous Stem Cell Transplantation (ASCT), and REVLIMID® (Lenalidomide)-based maintenance, continues to evolve. In the IFM 2009 French trial, REVLIMID® maintenance treatment was admininstered for one year and after a median follow-up of 89.8 months, the median Progression Free Survival (PFS) was 47.2 months with RVd plus ASCT and 35 months with RVd alone, but there was no Overall Survival (OS) benefit.

DETERMINATION ((Delayed vs Early Transplant with Revlimid Maintenance and Antimyeloma Triple Therapy) trial is a randomized Phase III trial, conducted to determine whether Autologous Stem Cell Transplantation (ASCT) enhances the efficacy of first line triplet induction therapy or whether it should be kept in reserve for select group of patients. In this study, 722 patients with symptomatic newly diagnosed Myeloma were enrolled. All patients received 3 cycles of RVd followed by stem cell mobilization (for possible ASCT if disease progressed). Patients were then randomly assigned to receive 5 additional cycles of RVd (RVd-alone arm, N=357) or Melphalan at 200 mg/m2, followed by ASCT and 2 additional cycles of RVd (RVd+ASCT arm, N=365). Each RVd cycle consisted of REVLIMID® 25 mg orally on days 1-14, VELCADE® (Bortezomib) 1.3 mg/m2 IV or SC on days 1, 4, 8, 11, and Dexamethasone given orally on days 1, 2, 4, 5, 8, 9, 11, 12, given as 21 day cycles. Dexamethasone was dosed at 20 mg/day for first 3 cycles and 10 mg/day for remaining cycles. Both treatment groups then received REVLIMID® maintenance at 10-15 mg orally daily, until disease progression or drug related toxicities. Both treatment groups were well balanced. The median age of enrolled patients was 56 years, approximately 14% of patients had ISS Stage III Multiple Myeloma and 18% had high-risk cytogenetics such as t(4;14), t(14;16), del17p. Approximately 19% of trial participants were African American, which is the highest representation of this subset of patients in any Phase III Myeloma trial. The Primary endpoint was Progression Free Survival (PFS). Secondary end points included Response Rates, Duration of Response (DOR), time to progression, Overall Survival (OS), Quality of Life, and Safety.

At a median follow up of 76 months, the median PFS was 46.2 months in the RVd alone group versus 67.6 months in the RVd plus ASCT group (HR=1.53; P<0.0001). The estimated 5-year PFS rates were 41.5% and 55.6% respectively. The 5 year Overall Survival was similar and not statistically different and was 79.2% and 80.7% respectively. The authors attributed the lack of Overall Survival in the RVd plus ASCT group to the availability of many highly effective treatment options now available after first-line therapy including salvage ASCT, next-generation immunomodulatory drugs, Proteasome Inhibitors, and monoclonal antibodies.

When evaluated by cytogenetic risk, for the standard risk group, the median PFS was 82.3 months in the RVd plus ASCT group versus 53.2 months in the RVd alone group, whereas for patients with high risk cytogenetics, the median PFS was 55.5 versus 17.1 months, respectively. Further, patients with t(4;14) derived more PFS benefit from RVd plus ASCT than those with del(17p). The PFS benefit with RVd plus ASCT was inferior among the African American enrollees and individuals with a Body Mass Index greater than 25 kg/m2.

Even though the Response Rates and quality of responses were similar between the two treatment groups, the Duration of Response was longer in the RVd plus ASCT group at 56.4 months, compared to 39.9 months in the RVd alone group.

More patients in the RVd plus ASCT group achieved MRD (Minimal Residual Disease) negativity compared to RVD alone (54.4% versus 39.8%), despite similar Complete Response Rates in both treatment groups. These MRD negative patients had favorable 5-year PFS, regardless of their treatment assignment. However, RVd plus ASCT improved PFS by 67% among the MRD positive patients.

Grade 3 or greater treatment-related adverse effects including mucositis, fatigue, and infections were less common without ASCT than with, at 78% versus 94% respectively. Secondary malignancies occurred in 10% of the RVd-alone group and 11% of the RVd plus ASCT group. Following RVd plus ASCT, 10 patients developed Myelodysplastic syndrome and/or Acute Myeloid Leukemia, compared with none in the RVd-alone group, and this was statistically significant (P=0.002).

The authors concluded that a combination of REVLIMID®, VELCADE® and Dexamethasone (RVd) plus ASCT as initial therapy followed by REVLIMID® maintenance until progression, demonstrated a significant improvement in PFS compared to RVd alone, followed by REVLIMID® maintenance, in patients with newly diagnosed Multiple Myeloma. There was no Overall Survival advantage observed to date. The researchers added that given the lack of benefit in OS and potential toxicities associated with ASCT, these data provide support for personalized treatment approaches, and helps patients make informed decision to delay transplant. Additionally, the significantly longer PFS for both treatment groups in the DETERMINATION study compared to the IFM 2009 (preplanned comparison), suggests that there is a clear benefit to continuous REVLIMID® maintenance until disease progression.

Lenalidomide, bortezomib, and dexamethasone (RVd) ± autologous stem cell transplantation (ASCT) and R maintenance to progression for newly diagnosed multiple myeloma (NDMM): The phase 3 DETERMINATION trial. Richardson PG, Jacobus SJ, Weller E, et al. J Clin Oncol. 2022;40(suppl 17):LBA4. doi:10.1200/JCO.2022.40.17_suppl.LBA4

DARZALEX® plus KYPROLIS® and Dexamethasone in Relapsed or Refractory Multiple Myeloma

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients are expected to die of the disease. Multiple Myeloma (MM) in 2022 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile or refractory disease have the worst outcomes. The median survival for patients with Myeloma is over 10 years.

REVLIMID® (Lenalidomide) in combination with VELCADE® (Bortezomib) and Dexamethasone is the preferred regimen according to the NCCN guidelines, for both transplant and non-transplant candidates with newly diagnosed Multiple Myeloma, and when given continuously or with maintenance therapy, has improved survival outcomes. Nonetheless, a significant number of patients progress while on these agents or discontinue therapy due to toxicities. There is therefore a need for effective and tolerable regimens for patients who are exposed or refractory to REVLIMID® or VELCADE®.

KYPROLIS® (Carfilzomib) is a second generation selective, epoxyketone Proteasome Inhibitor and unlike VELCADE®, proteasome inhibition with KYPROLIS® is irreversible. DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Dependent Cytotoxicity (CDC) and direct Apoptosis. Additionally, DARZALEX® may play a role in immunomodulation, by depleting CD38-positive regulator immune suppressor cells, and thereby expanding T cells, in patients responding to therapy. Both KYPROLIS® and DARZALEX® are approved as single agents, as well as in combination with other drugs, for the treatment of patients with Relapsed/Refractory Multiple Myeloma. In a Phase I study, KYPROLIS® in combination with Dexamethasone and DARZALEX® demonstrated safety and efficacy in patients Relapsed/Refractory Multiple Myeloma.

The efficacy of KYPROLIS® and DARZALEX® along with Dexamethasone was evaluated in two clinical trials, CANDOR and EQUULEUS. CANDOR is a global, multicenter, open-label, randomized Phase III trial, which included Relapsed/Refractory Multiple Myeloma patients with measurable disease who had received 1-3 prior lines of therapy, with Partial Response or better to one or more lines of therapy. A total of 466 patients were randomly assigned 2:1 to receive triplet of KYPROLIS®, Dexamethasone, and DARZALEX® (KdD)- N=312 or KYPROLIS® and Dexamethasone (Kd) alone- N=154. All patients received KYPROLIS® as a 30 minute IV infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m2 on days 1 and 2 during cycle 1 and 56 mg/m2 thereafter). DARZALEX® 8 mg/kg was administered IV on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 weeks for 4 cycles (cycles 3-6), and every 4 weeks thereafter. All patients received Dexamethasone 40 mg oral or IV weekly (20 mg for patients over 75 years of age). Patients were stratified by disease stage, previous Proteasome Inhibitor or anti-CD38 antibody exposure, and number of previous therapies. The median age was 64 years, 42% and 90% received prior REVLIMID® and VELCADE® (Bortezomib) containing regimens respectively, and a third of patients were refractory to REVLIMID®. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Response Rate (ORR), Minimal Residual Disease (MRD)-negative status, Complete Response (CR) rate at 12 months, Overall Survival (OS), Duration of Response, and Safety.

After a median follow up of 17 months, the study met its Primary endpoint and the median PFS was not reached for the KdD arm and was 15.8 months for the Kd arm (HR=0.63; P=0.0027). This represented a 37% reduction in the risk of progression or death in the KdD group. The PFS benefit of KdD was maintained across prespecified subgroups, particularly among REVLIMID®-exposed and REVLIMID®-refractory patients. The ORR was 84.3% in the KdD group versus 74.7% in the Kd group (P=0.004), with a CR rate or better of 28.5% versus 10.4% respectively. The median time to first response was one month in both treatment groups. Patients treated with KdD achieved deeper responses which was nearly 10 times higher, with a MRD-negative Complete Response rate at 12 months of 12.5% for KdD versus 1.3% for Kd (P<0.0001). The median treatment duration was longer in the KdD group compared to the Kd group (70.1 versus 40.3 wks). The median OS was not reached in either groups, at a median follow up time of 17 months. The FDA in August , 2020, approved KYPROLIS® (Carfilzomib) and DARZALEX® (Daratumumab), in combination with Dexamethasone, for adult patients with Relapsed or Refractory multiple myeloma, who have received one to three lines of therapy.

The analysis in the present publication was a preplanned interim analysis for Overall Survival. However the Overall Survival data were not mature at the time of data cutoff. The authors provided updated PFS and safety data, with 11 months of additional follow up. At a median follow up was 27.8 months, the median PFS was 28.6 months in the KdD group and 15.2 months in the Kd group (HR=0.59; P<0.0001), representing a 41% reduction in the risk of progression or death in the KdD group. Treatment-related Adverse Events were consistent with the primary analysis. Grade 3 or more adverse events occurred in 87% patients in the KdD group and 76% in the Kd group and were most commonly thrombocytopenia (25% versus 16%), hypertension (21% versus 15%) and pneumonia (18% versus 9%), respectively.

The authors concluded that with longer follow up, a combination of KYPROLIS® along with Dexamethasone and DARZALEX® provided a clear and durable Progression Free Survival benefit over KYPROLIS® and Dexamethasone alone, making KdD an emerging standard of care for patients with relapsed or refractory multiple myeloma.

Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study. Usmani SZ, Quach H, Mateos M-V, et al. The Lancet Oncology 2022;23:65-76.

Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, Multiple Myeloma (MM) in 2022 remains an incurable disease.

High Dose Melphalan followed by Autologous Stem Cell Transplantation (HDM/ASCT) remains an important treatment option for transplant eligible patients. REVLIMID® (Lenalidomide) was approved by the FDA in 2017 as maintenance therapy for patients with multiple myeloma following Autologous Stem Cell Transplant (ASCT) and to date is the only drug approved for this indication. Maintenance or Continuous Treatment in patients with newly diagnosed multiple myeloma following induction treatment can result in significantly longer PFS and OS, compared to those patients who receive therapy for a fixed duration of time.

The role of consolidation treatment for newly diagnosed, transplant-eligible patients with multiple myeloma has not been conclusively established and needed prospective evaluation. The present prospective clinical trial was conducted to study the relevance of consolidation therapy using Bortezomib, Lenalidomide, and Dexamethasone (VRD) followed by Lenalidomide maintenance, compared with Lenalidomide maintenance alone, in transplant-eligible newly diagnosed multiple myeloma patients.

The EMN02/HOVON95 trial is an open-label, Phase III study, performed by the European Myeloma Network (EMN) in which 1197 previously untreated transplant-eligible patients with symptomatic Stages I-III Multiple Myeloma were randomly assigned initially to four cycles of Bortezomib, Melphalan, and Prednisone (VMP) or High-Dose Melphalan followed by Autologous Stem Cell Transplantation (HDM/ASCT). Within 2 months after ASCT or last VMP treatment, 878 eligible patients underwent a second randomization to either two 28-day cycles of VRD consolidation treatment, which consisted of Bortezomib 1.3 mg/m2 either IV or SC once daily on days 1, 4, 8, and 11, combined with Lenalidomide 25 mg orally once daily, days 1-21 and Dexamethasone 20 mg orally once daily, on days 1, 2, 4, 5, 8, 9, 11, and 12 (N=451 – Arm B) or no consolidation (N=427 – Arm A). Patients then received Lenalidomide maintenance 10 mg orally once daily on days 1-21 of a 28-day cycle, starting 1-2 months after ASCT or consolidation, and treatment was continued until disease progression or toxicity. The Primary end point was Progression Free Survival (PFS) defined as time from second randomization to disease progression or death. Secondary end points included Partial Response or higher, Overall Survival (OS) from second randomization until death from any cause, and toxicity. Predefined high-risk prognostic subgroups for PFS were cytogenetic abnormalities defined by FISH and included deletion (17p) in 20% or more of enriched plasma cells, t(4;14) in 10% or more of enriched plasma cells, t(14;16) in 10% or more of enriched plasma cells; and amplification 1q. This was in addition to the standard clinical variables such as Hemoglobin level, Serum Creatinine and LDH. Disease assessment was performed before and after consolidation and every 2 months until progression. Bone marrow Minimal Residual Disease (MRD) assessment was performed by multicolor flow cytometry in bone marrow with a detection of 10−4 to 10−5.

At a median follow-up of 74.8 months after the second randomization, the median PFS was significantly prolonged in the VRD consolidation group, compared those who did not receive consolidation treatment (59.3 versus 42.9 months, HR=0.81; P=0.016). This PFS benefit was observed across most predefined subgroups, including Stage, standard-risk cytogenetics, and prior treatment groups. VRD consolidation was however not beneficial in patients with del(17p). Stage III disease and addition of chromosome 1q by FISH at diagnosis were significant adverse prognostic factors for PFS from second randomization. The median duration of maintenance treatment with Lenalidomide was 33 months. Complete Response (CR) or more after consolidation versus no consolidation, and before start of maintenance treatment was 34% versus 18%, respectively (P<0.001). Complete Response or more on protocol including maintenance treatment was 59% with consolidation and 46% without consolidation (P<0.001). Minimal Residual Disease analysis in a subgroup of 226 VRD-consolidated patients with CR or stringent CR or Very Good Partial Response before start of maintenance treatment demonstrated a 74% MRD-negativity rate. Toxicities related to VRD consolidation were acceptable and manageable.

It was concluded from this study that consolidation followed by maintenance treatment after either Bortezomib, Melphalan and Prednisone or High-Dose Melphalan and Autologous Stem Cell Transplantation, significantly improves Progression Free Survival and Overall Response Rate in transplant-eligible and Lenalidomide-naïve newly diagnosed patients with Multiple Myeloma, compared to maintenance treatment alone.

Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma. Sonneveld P, Dimopoulos MA, Beksac M, et al. J Clin Oncol. 2021;39:3613-3622.

Anti-BCMA CAR T-Cell Therapy for Multiple Myeloma

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,920 new cases will be diagnosed in 2021 and 12,410 patients are expected to die of the disease. Multiple Myeloma (MM) in 2021 remains an incurable disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The median survival for patients with myeloma is over 10 years. With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with Relapsed/Refractory myeloma often have disease that is refractory to multiple drugs. There is an urgent unmet medical need for agents with novel mechanisms of action that are safe and effective, for patients with aggressive and resistant disease.

Chimeric Antigen Receptor (CAR) T-cell therapy has been associated with long-term disease control in some hematologic malignancies and showed promising activity in a Phase 1 study involving patients with Relapsed or Refractory myeloma. B-cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and Multiple Myeloma.

Anti-BCMA CAR T-Cell Therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure. These T cells are then stimulated by treating with interleukin 2 (IL-2) and anti-CD3 antibodies in vitro, so that they will actively proliferate and expand to large numbers. These T cells are then genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR), by transducing with a gene encoding the engineered CAR, via a retroviral vector such as lentiviral vector. These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen such as BCMA on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen such as BCMA. The patient undergoes lymphodepletion chemotherapy with Fludarabine and Cytoxan prior to the introduction of the engineered CAR T-cells. By depleting the number of circulating leukocytes, cytokine production is upregulated and reduces competition for resources, which in turn promotes the expansion of the engineered CAR T-cells.
Anti-BCMA-CAR-T-Cell-Therapy-for-Multiple-Myeloma
ABECMA® (Idecabtagene vicleucel) is the first FDA approved cell-based gene therapy for multiple myeloma and was based on results from the pivotal, open-label, single-arm, multicenter, multinational, Phase II study (KarMMa trial), in which the efficacy and safety of ABECMA® was evaluated in adults with Relapsed and Refractory multiple myeloma. In this study, 128 patients with persistent disease after at least three previous regimens including a Proteasome Inhibitor, an immunomodulatory agent, and an anti-CD38 antibody, received ABECMA® target doses of 150×106 to 450×106 CAR-positive (CAR+) T cells, after receiving lymphodepleting chemotherapy. Lymphodepletion therapy consisted of Fludarabine 30 mg/m2 IV and Cyclophosphamide 300 mg/m2 IV given on 3 consecutive days, followed by 2 days of rest before ABECMA® infusion. The median patient age was 61 years and the median time from diagnosis was 6 years. About 51% of patients had a high tumor burden (50% or more bone marrow plasma cells), 39% had extramedullary disease and 35% had a high-risk cytogenetic abnormalities, defined as del(17p), t(4;14), or t(14;16). Patients had received a median of 6 previous antimyeloma regimens and 94% had received previous Autologous Hematopoietic Stem Cell Transplants. The Primary end point was an Overall Response Rate (ORR) as assessed by an Independent Review Committee (IRC) and key Secondary end point was a Complete Response or better (comprising complete and stringent Complete Responses). Other efficacy endpoints include Time to Response, Duration of Response, Progression Free Survival (PFS), Overall Survival (OS), Minimal Residual Disease (MRD) evaluated by Next-Generation Sequencing (NGS) assay, and Safety.

At a median follow up of 13.3 months, the ORR was 73%, and 33% had a complete or stringent Complete Response. Of those with a complete or stringent Complete Response, 79% had MRD-negative status at a sensitivity level of 10−5, corresponding to 26% of the treated population. This benefit was consistently observed in most subgroups examined, including older patients, those who received bridging therapy, and those with aggressive disease features, including high-risk cytogenetics, triple or penta-refractory disease, a high tumor burden, and extramedullary disease. The median time to first response was 1.0 month and the median time to a Complete Response or better was 2.8 months. The estimated median Duration of Response was 10.7 months for all patients and 11.3 months among those receiving the highest target dose. The response duration increased with the depth of response. The median PFS was 8.8 months for all patients and 20.2 months in patients having a complete or stringent Complete Response. Data on Overall Survival are immature. Cellular kinetic analysis confirmed CAR+ T cells in 59% at 6 months and 36% at 12 months after infusion. Common toxicities included neutropenia, anemia and thrombocytopenia. Cytokine Release Syndrome was reported in 84% of patients including 5% Grade 3 or higher events. Neurotoxic effects developed in 18% of patients.

It was concluded that ABECMA® induced deep and durable responses in majority of heavily pretreated patients with Refractory and Relapsed myeloma, and fulfills a highly unmet need for this patient group. It should however be noted that although some subsets of patients may have sustained responses for long periods of time, most patients eventually relapse. This has been attributed to the loss of CAR T-cells, loss of antigen expression on the tumor cell surface, or to impaired activity of T cells in an immunosuppressive microenvironment. Studies are underway to overcome these shortcomings by optimizing CAR design, as well as preventing antigen escape and developing combination therapies.

Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. Munshi NC, Anderson LD, Shah N, et al. N Engl J Med 2021; 384:705-716

Infection Risk in Multiple Myeloma Patients Receiving New Generation Therapies

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,920 new cases will be diagnosed in 2021 and 12,410 patients are expected to die of the disease. Multiple Myeloma (MM) in 2021 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients will eventually relapse, requiring multiple lines of therapy for disease control. The availability of newer agents has transformed Multiple Myeloma into a chronic disease. Patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The median survival for patients with myeloma is over 10 years.

Infection is a leading cause of morbidity and mortality in patients with Multiple Myeloma. In a study of over 3000 newly diagnosed Multiple Myeloma patients, approximately 50% of early deaths (deaths occurring in less than 6 months following diagnosis) were associated with infections (J Clin Oncol. 2005;23:9219-9226). The increased susceptibility to infection in this patient group has been attributed to disease-related deficits in the innate or adaptive immune system, including hypogammaglobulinaemia, qualitative and quantitative abnormalities of dendritic cells, T cells, and Natural Killer cells, as well as renal function impairment, and therapies administered at different stages of the disease. Further, the introduction of new therapeutic agents such as Proteasome Inhibitors (PIs), Immunomodulatory drugs and monoclonal antibodies, with novel mechanisms of action, for first and later lines of therapy, for both Hematopoietic Stem Cell Transplantation eligible and ineligible patients, has significantly improved survival, but has also changed the spectrum of infections in patients with Multiple Myeloma. The epidemiology and risks for infection with the use of new therapeutic agents however remains unclear. The present study was conducted to determine patterns, risks and outcomes of infections in patients with Multiple Myeloma, managed with new therapeutic agents and monoclonal antibodies.

In this study, patients with Multiple Myeloma treated with second generation therapies and other monoclonal antibodies were identified from pharmacy and clinical databases, collected from 2 major tertiary referral centers for Multiple Myeloma management in Australia. Agents considered new generation therapies included Pomalidomide, Carfilzomib, Isatuximab, Daratumumab and Elotuzumab. Following commencement of new generation therapy, 60% of the patient’s had previously received Autologous Stem Cell Transplantation and 93% of the patient’s had Relapsed or Refractory Multiple Myeloma. Patients were then followed for episodes of infection, from the commencement of therapy with any newer agents, until completion of treatment, death or end of study, which ever occurred first. Prophylaxis with antibiotics for bacterial infections was not routinely used, but antiviral prophylaxis with Valaciclovir was used when patients received therapy with Proteasome Inhibitors. Patients received prophylaxis with Trimethoprim/Sulfamethoxazole for Pneumocystis jirovecii pneumonia when steroid doses exceeded 16-20 mg of Prednisone equivalent per day.

Each episode of infection was classified as Microbiologically Defined (MDI) when pathogens were isolated on microbiological testing, Clinically Defined (CDI) when sites of infection were identified but no pathogens were isolated on microbiological testing, and Fever of Unknown Focus (FUF) when patients had febrile episodes with no pathogen or site identified. Univariate and multivariate analyses were performed to determine risk factors for infection.

A total of 148 patients with Multiple Myeloma were followed for a median of 13.2 months, and 345 infection episodes were identified. Of these, 29% (100 out of 345) were defined as Microbiologically Defined Infections, 58% (200 out of 345) were defined as Clinically Defined Infections, and 13% (45 out of 345) were defined as Fever of Unknown Focus. Of those with Microbiologically Defined Infections, 50% of infections were attributed to viruses, whereas 45% were attributed to bacterial infection. Respiratory Syncytial Virus was the most frequently isolated virus accounting for 24% of episodes, followed by Rhinovirus at 16% and Influenza virus at 14%. E. coli was the most frequently isolated bacteria at 20%, followed by Haemophilus influenza at 11%. The most common infection site was the respiratory tract (56.8%), hospital admission occurred in 41.7% of infection episodes, and the 30-day all-cause mortality rate was 5.4%. Treatment with Proteasome Inhibitors resulted in 16.8 times increased risk for infections, combination of IMiD and PI was associated with 13.44 times higher risk, monoclonal antibody combination therapy was associated with 10.44 times higher risk, and more than 4 lines of therapy was associated with 7.72 times higher risk for infections (P<0.05).

It was concluded from this study that majority of infections are caused by viruses, in patients with Multiple Myeloma treated with newer therapeutic agents. Treatment with a Proteasome Inhibitor and more than 4 lines of therapy were associated with higher risk for infection.

Epidemiology and Risks of Infections in Patients With Multiple Myeloma Managed With New Generation Therapies. Lim C, Sinha P, Harrison SJ, et al. Clinical Lymphoma, Myeloma & Leukemia. 2021;21:444-450.