Hem/Onc Pharmacotherapy Specialist Quick Reference Guide
Based on NCCN Guidelines Version 5.2026  |  January 2026

OVERVIEW & EPIDEMIOLOGY

Multiple Myeloma (MM) is a malignant plasma cell disorder characterized by clonal proliferation of plasma cells in the bone marrow, production of monoclonal immunoglobulin (M-protein), and end-organ damage.

Key Epidemiology Facts

• ~35,000 new cases/year in the US; median age ~65–70 years
• 2nd most common hematologic malignancy after non-Hodgkin lymphoma
• Black/African American individuals have TWICE the incidence of all other races/ethnicities and earlier age at diagnosis
• Black/African Americans present with more severe symptoms: increased anemia, higher calcium, worse renal dysfunction, more extramedullary disease
• Black/African Americans more likely to have chr 14 translocations [t(11;14), t(14;16), t(14;20)]; LESS likely to have del17p, gain/amp 1q

💎 Pearl: Duffy-null phenotype (~67% of Black/African Americans) causes lower baseline ANC — do NOT use rigid reference ranges that may lead to inappropriate dose delays or reductions. This is physiologically insignificant regarding myeloma treatment. Duffy-null phenotype is a genetic RBC/chemokine receptor phenotype.

SIGNS & SYMPTOMS (CRAB/SLiM Criteria)

CRAB — Myeloma-Defining End-Organ Damage

Acronym	Criterion	Definition/Threshold
C	HyperCalcemia	Serum Ca >0.25 mmol/L (>1 mg/dL) above ULN OR Serum Ca >2.75 mmol/L (>11 mg/dL)
R	Renal Insufficiency	CrCl <40 mL/min OR Serum creatinine >177 µmol/L (>2 mg/dL)
A	Anemia	Hgb >20 g/L below LLN OR Hgb <100 g/L
B	Bone Lesions	≥1 osteolytic lesion on skeletal radiography, CT, or PET-CT

Biomarkers of Malignancy (SLiM Criteria — for NDMM without CRAB)

• S — Sixty percent (≥60%) clonal bone marrow plasma cells (BMPC)
• Li — Light chain ratio: involved:uninvolved FLC ratio ≥100
• M — More than 1 focal lesion on MRI studies (>1 cm)

Other Signs & Symptoms

• Bone pain (most common): back pain, rib pain, pathologic fractures
• Fatigue, weakness, dyspnea from anemia
• Recurrent infections (pneumonia, sinusitis) — hypogammaglobulinemia (low normal immunoglobulins/antibodies in the blood due to the malignant plasma cell clone produces one monoclonal immunoglobulin — the M-protein — while suppressing normal plasma cells; therefore, high “total protein” or high M-spike, but their functional normal antibodies are low)
• Peripheral neuropathy (especially with amyloidosis or thalidomide/bortezomib)
• Hyperviscosity: headache, visual changes, bleeding, confusion
• Spinal cord compression — neurologic emergency
• Weight loss, night sweats, fever (uncommon — rule out other hematologic malignancies)

⚠ ~80% of MM patients have bone disease and up to 33% have renal compromise at diagnosis — aggressive supportive care is critical to avoid early complications.

DISEASE DEFINITIONS (MYEL-A)

⚠ If BMPCs ≥10% in a solitary plasmacytoma → treat as active (symptomatic) MM and initiate systemic therapy. Also consider FISH testing on plasmacytoma biopsy if clonal cells absent/inadequate in marrow.

Smoldering MM Risk Stratification (for Progression to Active MM)

High-risk SMM defined as ≥2 of the following risk factors (Lakshman/Mateos criteria):

• BMPCs >20%
• M-protein >2 g/dL
• Serum FLC ratio (FLCr) >20

💎 Pearl: Patients with rising SMM parameters are considered high-risk and should be closely monitored at 3-month intervals. High-risk SMM patients may be candidates for select interventions (daratumumab cat 1, lenalidomide cat 2B).

INITIAL DIAGNOSTIC WORKUP (MYEL-1)

Essential Workup

Category	Tests
History & Physical	Frailty assessment in older adults; H&P exam
CBC/Blood	CBC with differential and platelet count; peripheral blood smear
Chemistry (for staging)	BUN/Cr, electrolytes, LFTs, albumin, calcium, uric acid, LDH (essential for staging), beta-2 microglobulin (essential for staging)
Renal Function	Creatinine clearance (calculated or measured directly)
Protein Studies	Serum quantitative immunoglobulins, SPEP, SIFE; 24-h urine total protein, UPEP, UIFE; Serum free light chain (FLC) assay
Cardiac	NT-proBNP or BNP (if NT-proBNP not available)
Imaging	Whole-body FDG-PET/CT (preferred) or whole-body low-dose CT
Bone Marrow	Unilateral BM aspirate and biopsy with IHC and/or multi-parameter flow cytometry
FISH Panel	del(13), del(17p13), t(4;14), t(11;14), t(14;16), t(14;20), 1q21 gain/amplification, 1p deletion — CD138+ selected sample STRONGLY recommended
Molecular	NGS to assess for TP53 mutation (NEW in v1.2026)

Useful in Certain Circumstances

• Whole-body MRI without contrast (if FDG-PET/CT or low-dose CT negative → to discern SMM from MM)
• Tissue biopsy to confirm suspected plasmacytoma
• Echocardiogram (cardiac evaluation for amyloidosis)
• Evaluation for light chain amyloidosis if appropriate
• Obtain baseline clonotype identification at diagnosis OR store aspirate sample for future MRD testing by NGS
• Serum viscosity (if hyperviscosity suspected)
• Hepatitis B, Hepatitis C, HIV screening as required
• Assess for circulating plasma cells as clinically indicated
• Renal biopsy if albuminuria or abnormal renal function (NEW v1.2026)

💎 Pearl: LDH and beta-2 microglobulin are ESSENTIAL for R-ISS staging — do not skip these. FISH panel requires CD138+ selected sample for optimal yield.

⚠ Daratumumab and isatuximab-irfc interfere with serologic testing → false-positive indirect Coombs test. TYPE AND SCREEN of RBC must be performed BEFORE initiating these agents.

STAGING & RISK STRATIFICATION (MYEL-B)

International Staging System (ISS)

ISS Stage	Criteria
Stage I	Serum beta-2 microglobulin <3.5 mg/L AND serum albumin ≥3.5 g/dL
Stage II	Not Stage I or Stage III
Stage III	Serum beta-2 microglobulin ≥5.5 mg/L

Revised ISS (R-ISS) — Most Clinically Used

R-ISS Stage	Criteria
Stage I	ISS Stage I + standard-risk chromosomal abnormalities by FISH + LDH ≤ ULN
Stage II	Not R-ISS Stage I or III
Stage III	ISS Stage III + either high-risk chromosomal abnormalities [del(17p), t(4;14), t(14;16)] by FISH OR LDH > ULN

R2-ISS (Second Revision) — Point-Based System

Each risk factor assigned points based on impact on OS (only validated for NDMM):

Risk Factor	Points	Risk Category
ISS Stage II	+1	Low risk: 0 pts
ISS Stage III	+1.5	Low-intermediate: 0.5–1 pts
del(17p)	+1	Intermediate-high: 1.5–2.5 pts
t(4;14)	+1	High risk: 3–5 pts
1q+ (gain or amplification)	+0.5
LDH > ULN	+1

IMS-IMWG Definition of High-Risk MM (2025)

High-Risk requires any of:

• del(17p) (>20% of plasma cells) AND/OR TP53 mutation
• One of these translocations co-occurring with 1q+ AND/OR del(1p32): t(4;14), t(14;16), t(14;20)
• Monoallelic del(1p32) along with 1q+ OR biallelic del(1p32)
• High beta-2M (>5.5 mg/dL) with normal creatinine (<1.2 mg/dL)

Cytogenetics — High-Risk Factors (MYEL-B 2 of 2)

Patients with ≥2 of these cytogenetic abnormalities are considered VERY HIGH RISK:

Newly Diagnosed MM	Relapsed MM — Additional Risk Factors
R-ISS III	Disease relapse within 2 yrs of initial therapy (if transplant + maintenance used)
Extramedullary disease	Relapse within 18 months if non-transplant-based treatment
Circulating plasma cells	Acquisition of 1q gain/amplification and/or del(17p)/TP53 mutation at relapse
del(1p32)	Extramedullary disease at relapse and/or circulating plasma cells
t(4;14), t(14;16), t(14;20)
del(17p)/monosomy 17/TP53 mutation
1q21 gain/amplification (≥3 copies; ≥4 copies = amplification)
MYC translocation
High-risk gene expression profile; markers of high proliferation

💎 Pearl: 1q21 amplification = ≥4 copies by FISH; 1q21 gain = 3 copies. Sole 1q21 abnormality NOT considered a marker for high risk of progression/relapse. Two or more cytogenetic abnormalities = very high risk.

💎 Pearl: Two-drug maintenance is RECOMMENDED for high-risk MM patients.

DIFFERENTIAL DIAGNOSIS

Condition	Distinguishing Features	Key Differentiator from MM
MGUS	M-protein <3 g/dL, BMPCs <10%, no CRAB	No end-organ damage; observation only
Smoldering MM	M-protein ≥3 g/dL or BMPCs 10–59%, no CRAB	No myeloma-defining events required for SMM
Waldenstrom Macroglobulinemia	IgM M-protein, lymphoplasmacytic lymphoma, hyperviscosity	IgM paraprotein; MYD88 L265P mutation; BM lymphoplasmacytic infiltrate
Primary Amyloidosis (AL)	Organ dysfunction from amyloid deposition (kidneys, heart, liver)	Biopsy shows amyloid deposits; NT-proBNP elevated
Metastatic Bone Disease	Lytic lesions without M-protein	No M-protein; primary solid tumor found
Plasmablastic Lymphoma	EBV-related; aggressive B-cell lymphoma	No BM plasma cells; EBV-positive
CLL/SLL	Lymphocytosis, lymphadenopathy	Flow cytometry; no M-protein spike
Reactive Plasmacytosis	Increased plasma cells from infection/inflammation	BMPCs <10%; no M-protein; polyclonal immunoglobulins

IMAGING PRINCIPLES (MYEL-C)

Initial Diagnostic Workup

• Whole-body FDG-PET/CT (PREFERRED) OR whole-body low-dose CT — standard for initial workup
• If PET/CT or low-dose CT NEGATIVE → consider whole-body MRI without contrast to discern SMM from MM
• Skeletal survey acceptable in certain circumstances only

Solitary Plasmacytoma Imaging

• Extraosseous plasmacytoma: Whole-body FDG-PET/CT is FIRST choice (initial AND follow-up)
• Osseous plasmacytoma: Whole-body MRI preferred; FDG-PET/CT if MRI not available
• Yearly follow-up imaging for at least 5 years with same technique used at diagnosis
• Risk of progression to MM: 14–38% within first 3 years

Follow-up of MM & SMM

• Advanced whole-body imaging (FDG-PET/CT, low-dose CT, MRI without contrast) annually or as clinically indicated
• Use same imaging technique throughout follow-up for comparison
• Residual focal lesions on PET/CT or MRI = adverse prognostic significance
• Patients without measurable M-protein or FLC → follow with imaging at regular intervals
• Whole-body FDG-PET/CT recommended ~Day 100 after autologous HCT (new footnote, v1.2026)

💎 Pearl: DEXA scans are NOT useful to assess myeloma bone disease. Use PET/CT or low-dose CT instead.

RESPONSE CRITERIA — IMWG (MYEL-E)

Response Category	Criteria
Sustained MRD-Negative	MRD-negative by NGF or NGS + imaging, confirmed ≥1 year apart
Imaging + MRD-Negative	MRD-negative by NGF/NGS + disappearance of all FDG-PET/CT uptake or <mediastinal blood pool SUV
Stringent CR (sCR)	CR + normal FLC ratio + absence of clonal cells in BM biopsy by IHC (κ/λ ratio ≤4:1 or ≥1:2, counting ≥100 plasma cells)
Complete Response (CR)	Negative immunofixation in serum AND urine + disappearance of soft tissue plasmacytomas + <5% plasma cells in BM aspirate
VGPR	M-protein detectable by immunofixation but NOT on electrophoresis OR ≥90% reduction in serum M-protein + urine M-protein <100 mg/24h
PR	≥50% reduction of serum M-protein + ≥90% reduction in 24-h urinary M-protein or to <200 mg/24h
Minimal Response (MR)	≥25% but ≤49% reduction of serum M-protein + 50–89% reduction in 24-h urine M-protein
Stable Disease (SD)	Not meeting criteria for CR, VGPR, PR, MR, or PD
Progressive Disease (PD)	≥25% increase from lowest confirmed value in serum M-protein (absolute ≥0.5 g/dL) OR urine M-protein (absolute ≥200 mg/24h) OR new/enlarging lesions OR ≥50% increase in circulating plasma cells

MRD Testing Notes

• Flow MRD-negative: absence of aberrant clonal PCs by NGF with sensitivity ≥1 in 10⁵ nucleated cells
• Sequencing MRD-negative: absence of clonal PCs by NGS with sensitivity ≥1 in 10⁵ nucleated cells
• MRD testing initiated only at time of suspected complete response
• All response categories require 2 consecutive assessments before starting new therapy (except MRD — no confirmation needed)

💎 Pearl: IgG kappa monoclonal antibodies (daratumumab, isatuximab) can produce FALSE-POSITIVE immunofixation or M-protein — the therapeutic antibody band can be mistaken for the patient’s M-protein. Use special interference testing or mass spectrometry to differentiate.

PHARMACOTHERAPY — PRIMARY THERAPY (MYEL-G)

⚠ QUADRUPLET regimen is PREFERRED for ALL newly diagnosed MM patients (HCT-eligible and ineligible). Based on functional status, may start with 2- or 3-drug regimen with additional drugs added as PS improves.

Clinical Pearl — MOA Quick Reference

• PIs (bortezomib, carfilzomib, ixazomib): block protein degradation → ER stress → apoptosis. SC bortezomib = less neuropathy.
• IMiDs (lenalidomide, pomalidomide): target cereblon → degrade Ikaros/Aiolos → anti-proliferative + immune stimulation. REMS mandatory.
• Anti-CD38 (daratumumab, isatuximab): 4 mechanisms — ADCC, CDC, ADCP, T-cell activation. Must type & screen BEFORE use.
• BsAbs (teclistamab, elranatamab, talquetamab, linvoseltamab): redirect patient T cells to kill myeloma. Step-up dosing mandatory.
• CAR-T (cilta-cel, ide-cel): patient T cells engineered to express BCMA-targeting receptor. Manufacturing takes 4–6 weeks.
• Venetoclax: BCL-2 inhibitor — ONLY active in t(11;14) MM where BCL-2 is overexpressed. TLS protocol required.

💎 Pearl: Talquetamab targets GPRC5D — not BCMA. Unique AEs: skin/nail toxicity, dysgeusia. Can be used as bridge to BCMA CAR-T per NCCN v5.2026.

A. Primary Therapy — HCT Candidates (MYEL-G 1 of 5)

PREFERRED (Category 1)

Regimen	Category	Key Trial / Notes
Daratumumab/Bortezomib/Lenalidomide/Dexamethasone (Dara-VRd)	1	PERSEUS trial: PFS rate 84.3% vs 67.7% (VRd) at 47.5 mo; 58% reduction in risk of progression/death
Isatuximab-irfc/Bortezomib/Lenalidomide/Dexamethasone (Isa-VRd)	1	GMMG-HD7: deeper MRD negativity (50% vs 36% after induction); PFS HR 0.70 at 4-yr follow-up

Other Recommended

Regimen	Category	Notes
Bortezomib/Lenalidomide/Dexamethasone (VRd)	1	SWOG S0777: PFS 43 vs 30 mo; OS 75 vs 64 mo vs Rd
Carfilzomib/Lenalidomide/Dexamethasone (KRd)	2A	ENDURANCE: similar PFS to VRd; less neuropathy but more cardiac/pulmonary/renal toxicity
Daratumumab/Carfilzomib/Lenalidomide/Dexamethasone (Dara-KRd)	2A	MASTER trial: MRD <10⁻⁵ in 81% (no HRCA); 36-mo PFS 88% (no HRCA)
Isatuximab-irfc/Carfilzomib/Lenalidomide/Dexamethasone (Isa-KRd)	2A	IsKia trial: MRD neg 77% vs 67% (KRd) after consolidation

Useful in Certain Circumstances

• Bortezomib/Cyclophosphamide/Dexamethasone (CyBorD) — renal insufficiency, no access to PI/lenalidomide
• Carfilzomib/Cyclophosphamide/Dexamethasone — renal insufficiency and/or peripheral neuropathy
• Daratumumab/Bortezomib/Cyclophosphamide/Dexamethasone — renal insufficiency; no access to dara-VRd
• VTD-PACE (Dara/Bortezomib/Thalidomide/Cisplatin/Doxorubicin/Cyclophosphamide/Etoposide) — aggressive MM, extramedullary disease, plasma cell leukemia

B. Maintenance Therapy Post-HCT (MYEL-G 1 of 5)

Regimen	Category	Notes
Lenalidomide (PREFERRED)	1	Increased risk of secondary cancers (especially with lenalidomide post-transplant) — discuss risk/benefit with patient
Carfilzomib/Lenalidomide	2A	Other recommended option
Daratumumab/Lenalidomide	2A	Used in PERSEUS trial maintenance; consider in dara-VRd responders
Bortezomib ± Lenalidomide	2A	Useful in certain circumstances; preferred for high-risk MM (2-drug maintenance)
Daratumumab	2A	Useful in certain circumstances (new in v1.2026)
Ixazomib	2B	All-oral option; convenient for patients unable to travel

⚠ Two-drug maintenance is recommended for HIGH-RISK MM. Consider dara + lenalidomide or bortezomib + lenalidomide.

C. Primary Therapy — HCT-Deferred or Non-HCT Candidates (MYEL-G 2 of 5)

In general, continue primary therapy UNTIL PROGRESSION with de-escalation as needed.

PREFERRED

Regimen	Category	Key Trial / Notes
Daratumumab/Lenalidomide/Dexamethasone (DRd)	1	MAIA: median PFS 61.9 mo vs 34.4 mo (Rd); OS benefit demonstrated
Dara-VRd (patients <80 yr, not frail)	1	CEPHEUS: MRD neg 60.9% vs 39.4%; PFS HR 0.57
Isa-VRd (patients <80 yr, not frail)	1	IMROZ: PFS 63.2% vs 45.2% at 5 yr; 40% reduction in risk of progression/death

Other Recommended

• Carfilzomib/Lenalidomide/Dexamethasone (KRd) — Category 2A
• Bortezomib/Lenalidomide/Dexamethasone (VRd) — Category 1
• Isatuximab-irfc/Lenalidomide/Dexamethasone (Isa-Rd) — Category 2A (good option if peripheral neuropathy)

Useful in Certain Circumstances

• Lenalidomide/Low-dose Dexamethasone (Rd) — Category 1; for frail/elderly; FIRST trial
• VRd-lite — Category 2A; for frail patients (lenalidomide 15 mg days 1–21; bortezomib 1.3 mg/m² weekly SC; dex 20 mg day of and day after bortz)
• Bortezomib/Cyclophosphamide/Dexamethasone — renal insufficiency; no access to PI/Rd
• Ixazomib/Lenalidomide/Dexamethasone — all-oral; for patients with logistical constraints; TOURMALINE-MM2 (did not meet primary endpoint)
• Daratumumab/Cyclophosphamide/Bortezomib/Dexamethasone — renal insufficiency/AKI

💎 Pearl: Strongly consider collecting and storing stem cells for future HCT in non-HCT candidates receiving primary therapy — within first 6 cycles, before prolonged lenalidomide or daratumumab exposure.

RELAPSED/REFRACTORY MM — THERAPY (MYEL-G 3–5 of 5)

⚠ For RRMM: use drugs/drug classes NOT previously exposed to, or not exposed to for at least 6 months. Agents/regimens may be reconsidered if relapse ≥6 months after stopping therapy.

A. After 1–3 Prior Therapies — Preferred Regimens

Anti-CD38 Refractory

Regimen	Category	Notes
Carfilzomib/Lenalidomide/Dexamethasone (KRd)	1	ASPIRE trial
Carfilzomib/Pomalidomide/Dexamethasone	2A
Pomalidomide/Bortezomib/Dexamethasone (PVd)	1
Elotuzumab/Pomalidomide/Dexamethasone (after 2 prior, incl Len + PI)	2A
Ixazomib/Pomalidomide/Dexamethasone (after 2 prior IMiD+PI, PD within 60d)	2A

Bortezomib-Refractory

Regimen	Category	Notes
KRd	1
Daratumumab/Carfilzomib/Dexamethasone (DKd)	1	CANDOR trial
Daratumumab/Lenalidomide/Dexamethasone (DRd)	1	POLLUX trial
Isatuximab-irfc/Carfilzomib/Dexamethasone (IsaKd)	1	IKEMA trial
Daratumumab/Pomalidomide/Dexamethasone (DPd) — after 1 prior (Len+PI)	1	APOLLO/EQUULEUS trial
Daratumumab/Teclistamab-cqyv — after 1 prior (Len+PI)	1	NEW in v5.2026; BsAb combination
Isatuximab-irfc/Pomalidomide/Dex (after 2 prior Len+PI)	1	IKEMA data

Lenalidomide-Refractory

Regimen	Category	Notes
Daratumumab/Bortezomib/Dexamethasone (DVd)	1	CASTOR trial
Daratumumab/Carfilzomib/Dexamethasone (DKd)	1
Isatuximab-irfc/Carfilzomib/Dexamethasone	1
Pomalidomide/Bortezomib/Dexamethasone	1
Daratumumab/Pomalidomide/Dex (after 1 prior Len+PI)	1
Daratumumab/Teclistamab-cqyv (after 1 prior Len+PI)	1	NEW in v5.2026
Isatuximab-irfc/Pomalidomide/Dex (after 2 prior Len+PI)	1

CAR T-Cell Therapy (After 1–3 Prior Lines)

Agent	Category	Indication
Ciltacabtagene autoleucel (Cilta-cel, CARVYKTI)	1	After ≥1 prior line including IMiD + PI, AND refractory to lenalidomide
Idecabtagene vicleucel (Ide-cel, ABECMA)	1	After ≥2 prior lines including IMiD + anti-CD38 mAb + PI

10B. After ≥3 Prior Lines of Therapy — Preferred

CAR T-Cell Therapy (Preferred)

• Ciltacabtagene autoleucel OR Idecabtagene vicleucel

Bispecific Antibodies (BsAb) — After ≥4 Prior Lines (anti-CD38 + PI + IMiD)

Agent (Brand)	Target	Notes
Elranatamab-bcmm (Elrexfio)	BCMA × CD3
Linvoseltamab-gcpt (Lynozyfic)	BCMA × CD3	NEW in v2.2026
Talquetamab-tgvs (Talvey)	GPRC5D × CD3	May be used as bridge to BCMA CAR-T (new footnote v5.2026)
Teclistamab-cqyv (Tecvayli)	BCMA × CD3	Prophylactic tocilizumab may be considered prior to 1st dose to reduce CRS risk

Other Recommended (After ≥3 Prior Lines)

• High-dose or fractionated cyclophosphamide
• Selinexor/Dexamethasone — after ≥4 prior lines, refractory to ≥2 PIs, ≥2 IMiDs, anti-CD38 mAb

Useful in Certain Circumstances (After ≥3 Prior Lines)

• Belantamab mafodotin-blmf (as available through expanded access program; v5.2026)
• Bendamustine (alone or + bortezomib/carfilzomib/lenalidomide with dex) — NOTE: bendamustine and alkylating agents can impair T-cell collection for CAR T
• Talquetamab + Teclistamab combination

Other Recommended — After 1–3 Prior Lines

• Elotuzumab/Lenalidomide/Dexamethasone (cat 1); Ixazomib/Lenalidomide/Dexamethasone (cat 1)
• Selinexor/Bortezomib/Dexamethasone (cat 1) — XVd; Bortezomib/Cyclophosphamide/Dexamethasone
• Venetoclax/Dexamethasone ± Daratumumab or PI — ONLY for t(11;14) patients
• Belantamab mafodotin-blmf/Bortezomib/Dexamethasone (cat 1) — after 2 prior therapies including IMiD and PI (v3.2026)

💎 Pearl: Patients can receive more than one BCMA-targeted therapy. However, optimal sequencing of sequential BCMA-directed therapies is unknown; immediate follow-on BCMA therapy after relapse may be associated with lower response rates.

⚠ Alkylating agents (bendamustine, cyclophosphamide) can impair the ability to collect T cells for CAR T-cell therapy. Plan carefully before using these agents in potential CAR T candidates.

11. KEY CLINICAL TRIALS — BRIEF SUMMARY

Trial	Population	Intervention	Comparator	Key Results
PERSEUS	NDMM, HCT-eligible (n=709)	Dara-VRd → ASCT → Dara-R maintenance	VRd → ASCT → R maintenance	PFS 84.3% vs 67.7% at 47.5 mo; HR 0.42; MRD neg 75% vs 48%
GRIFFIN	NDMM, HCT-eligible	Dara-VRd	VRd	sCR 67% vs 48%; 4-yr PFS 87.2% vs 70%
GMMG-HD7	NDMM, HCT-eligible (n=660)	Isa-VRd (3 cycles) → HCT	VRd (3 cycles) → HCT	MRD neg 50% vs 36% post-induction; PFS HR 0.70 at 4 yr
MAIA	NDMM, HCT-ineligible (n=737)	DRd (continuous)	Rd (continuous)	Median PFS 61.9 mo vs 34.4 mo; OS benefit confirmed
CEPHEUS	NDMM, HCT-deferred or not planned, <80 yr, not frail (n=395)	Dara-VRd → Dara-R maintenance	VRd → R maintenance	MRD neg 60.9% vs 39.4%; PFS HR 0.57
IMROZ	NDMM, HCT-ineligible, ≤80 yr (n=446)	Isa-VRd (4 cycles) → Isa-Rd continuous	VRd → Rd continuous	PFS 63.2% vs 45.2% at 5 yr; HR 0.60; CR+ 74.7% vs 64.1%
SWOG S0777	NDMM (n=525), no intent to transplant immediately	VRd × 6 cycles → Rd maintenance	Rd × 6 cycles → Rd maintenance	PFS 43 vs 30 mo; OS 75 vs 64 mo
ENDURANCE	NDMM (n=1053) — excluded t(4;14) and other HR	KRd	VRd	Similar PFS; less neuropathy with KRd but more cardiac/renal/pulmonary toxicity
POLLUX	RRMM (1–3 prior), n=569	DRd	Rd	PFS HR 0.37; ORR 92% vs 76%
CASTOR	RRMM (1–3 prior), n=498	DVd	Vd	PFS HR 0.31; ORR 83% vs 63%
CANDOR	RRMM (1–3 prior), n=466	DKd	Kd	Median PFS 28.6 vs 15.2 mo; HR 0.59
IKEMA	RRMM (1–3 prior), n=302	IsaKd	Kd	PFS HR 0.53; MRD neg 29.6% vs 13.0%
APOLLO	RRMM (1–3 prior), n=304	DPd	Pd	PFS HR 0.63; ORR 69% vs 46%
MAJESTIC-1 / MajesTEC-1	RRMM (≥3 prior), n=165	Teclistamab 1.5 mg/kg SC QW	Single arm	ORR 63%; median PFS 11.3 mo; most common AE: CRS 72%

12. DRUG DOSING, ADJUSTMENTS & PHARMACIST REFERENCE

12A. Drug Class Overview & Key Dosing

Drug (Brand)	Class	Standard Dose	Route	Key Monitoring / Dose Adj
BORTEZOMIB (Velcade)	PI (1st gen)	1.3 mg/m² D1,8,15,22 (weekly preferred) or D1,4,8,11 (twice-weekly)	SC (preferred) or IV	Peripheral neuropathy (grade ≥2 → dose reduce or hold); CBC; LFTs; hold if platelets <25k
CARFILZOMIB (Kyprolis)	PI (2nd gen)	Weekly: 70 mg/m² D1,8,15 (28-day); or 20→27 mg/m² D1,2,8,9,15,16 (twice-weekly)	IV	Cardiac (HTN, CHF, MI — monitor BP each infusion); pulmonary; renal; CBC; Cycle 1 Day 1: 20 mg/m² only (ramp up)
IXAZOMIB (Ninlaro)	PI (oral, 3rd gen)	4 mg PO D1,8,15 of 28-day cycle	PO	GI (N/V/D); peripheral neuropathy; rash; avoid high-fat meals (take ≥1h before or 2h after food)
LENALIDOMIDE (Revlimid)	IMiD (2nd gen)	Induction: 25 mg PO D1–21 of 28-day cycle; Maintenance: 10–15 mg PO D1–21	PO	CBC, SCr (REMS required — RiskMAP); VTE prophylaxis MANDATORY; renal dose adjust (see below); secondary malignancy risk
POMALIDOMIDE (Pomalyst)	IMiD (3rd gen)	4 mg PO D1–21 of 28-day cycle	PO	Myelosuppression; VTE prophylaxis; REMS program; no renal dose adjustment needed (unlike lenalidomide); hold if ANC <0.5 or platelets <25k
THALIDOMIDE (Thalomid)	IMiD (1st gen)	50–200 mg PO QHS	PO	Sedation, constipation, DVT, peripheral neuropathy; REMS; teratogenic; VTE prophylaxis
DARATUMUMAB (Darzalex)	Anti-CD38 mAb	16 mg/kg IV weekly × 8, then biweekly × 8, then monthly	IV	Infusion reactions (pre-medicate: dex + acetaminophen + antihistamine); false+ indirect Coombs; type & screen BEFORE starting; VZV prophylaxis; hypogammaglobulinemia
DARATUMUMAB SC (Darzalex Faspro)	Anti-CD38 mAb	1800 mg SC flat dose (with hyaluronidase); Q-weekly/biweekly/monthly	SC	Same AEs as IV but FEWER infusion reactions; ~5 min administration; different dosing than IV formulation; caution in significant thrombocytopenia
ISATUXIMAB-IRFC (Sarclisa)	Anti-CD38 mAb	10 mg/kg IV on D1,8,15,22 (cycle 1), then D1,15 (cycles 2+)	IV	Infusion reactions (pre-medicate); false+ indirect Coombs; type & screen BEFORE starting; different dosing schedule than daratumumab
ELOTUZUMAB (Empliciti)	Anti-SLAMF7 mAb	10 mg/kg IV D1,8,15,22 (cycles 1–2); 10 mg/kg D1,15 (cycles 3+) OR 20 mg/kg D1 Q4W	IV	Infusion reactions; pre-medicate (dex+antihistamine+H2 blocker+acetaminophen); lymphopenia; does NOT interfere with SPEP/immunofixation
DEXAMETHASONE	Corticosteroid	40 mg PO/IV weekly (standard); 20 mg weekly for older/frail patients	PO / IV	Hyperglycemia (monitor glucose); infection risk; fluid retention; GI (take with food); mood changes; consider taper in elderly; REDUCE TO 20 mg/weekly in older adults and discontinue at earliest possible timepoint
TECLISTAMAB-CQYV (Tecvayli)	BsAb BCMA×CD3	Step-up: 0.06 mg/kg SC D1, 0.3 mg/kg SC D4, then 1.5 mg/kg SC QW	SC	CRS (most common 72%, grade 3-4 ~1%); ICANS; infections (levofloxacin + PJP prophylaxis); cytopenias; consider prophylactic tocilizumab prior to 1st dose
ELRANATAMAB-BCMM (Elrexfio)	BsAb BCMA×CD3	Step-up: 12 mg SC D1, 32 mg SC D4, then 76 mg SC QW × 24 wks, then Q2W if ≥PR	SC	CRS; ICANS; infections; consider step-up dosing hospitalization for monitoring
TALQUETAMAB-TGVS (Talvey)	BsAb GPRC5D×CD3	Step-up: 0.01 mg/kg SC D1, 0.06 mg/kg D4, then 0.4 mg/kg QW or 0.8 mg/kg Q2W	SC	CRS; skin toxicity (rash, nail changes, dryness — unique to GPRC5D target); dysgeusia; weight loss; cytokine release
LINVOSELTAMAB-GCPT (Lynozyfic)	BsAb BCMA×CD3	Step-up dosing; 200 mg SC QW × 24 wks then Q4W if ≥VGPR	SC	CRS; infections; cytopenias; NEW in v2.2026
CILTACABTAGENE autoleucel (CARVYKTI)	CAR T (BCMA)	One-time infusion: 0.5–1.0 × 10⁶ CAR+ T cells/kg IV	IV	CRS (within 7 days); ICANS; prolonged cytopenias; infections; REMS; manufacturing time 4–6 wks; leukapheresis required
IDECABTAGENE vicleucel (ABECMA)	CAR T (BCMA)	One-time infusion: 300–460 × 10⁶ CAR+ T cells IV	IV	CRS; ICANS; prolonged cytopenias; secondary T-cell malignancy risk (boxed warning); REMS
SELINEXOR (Xpovio)	XPO1 inhibitor	80 mg PO BIW (with bortezomib); or 100 mg PO weekly (with dex)	PO	Nausea/vomiting (use ondansetron or olanzapine prophylactically); anorexia; weight loss; hyponatremia; thrombocytopenia; fatigue
VENETOCLAX (Venclexta)	BCL-2 inhibitor	400 mg PO daily (ramp up per protocol) with PI/dex	PO	ONLY for t(11;14) patients; tumor lysis syndrome (TLS) prophylaxis mandatory; ramp-up dosing; avoid strong CYP3A4 inhibitors
BELANTAMAB MAFODOTIN-BLMF (Blenrep)	ADC (BCMA)	2.5 mg/kg IV Q21 days (in combination with bortezomib/dex)	IV	Corneal epithelial changes/keratopathy (eye exam REQUIRED before each dose — REMS); blurred vision; dry eyes; thrombocytopenia; BCMA ADC

12B. Lenalidomide Renal Dose Adjustments (MYEL-L)

⚠ Lenalidomide is primarily renally cleared — MUST dose-adjust for renal impairment using Cockcroft-Gault CrCl.

Renal Function (CG CrCl)	Lenalidomide Dose	Notes
Normal (≥60 mL/min)	25 mg D1–21 of 28-day cycle	Full dose
Moderate (≥30 to <60 mL/min)	10 mg every 24 hours	Reduce dose
Severe (<30 mL/min, not on dialysis)	15 mg every 48 hours	Further reduction
ESRD (<30 mL/min, requiring dialysis)	5 mg once daily; on dialysis days — administer AFTER dialysis	Dose after HD session

12C. Bone-Modifying Agent Dosing in Renal Impairment (MYEL-L)

Renal Impairment	Pamidronate (Aredia)	Zoledronic Acid (Zometa)	Denosumab (Xgeva)
None (normal)	90 mg IV Q3–4 wks	4 mg IV Q1–3 months	120 mg SC Q4 wks
Mild/Moderate	Standard dose (but use with caution — focal segmental glomerulosclerosis risk)	Reduce dose (per package insert)	120 mg SC Q4 wks
Severe (CrCl <30 mL/min)	60–90 mg (caution)	NOT RECOMMENDED	120 mg SC Q4 wks (monitor Ca²⁺ closely — risk of severe hypocalcemia)

⚠ Zoledronic acid is NOT recommended in severe renal impairment. Denosumab is PREFERRED in renal insufficiency but carries risk of severe hypocalcemia — monitor calcium levels closely. Do NOT forget vitamin D supplementation.

12D. Considerations for Myeloma Therapy — General (MYEL-F)

• Subcutaneous bortezomib is the PREFERRED method of administration (less neurotoxicity than IV)
• Weekly bortezomib PREFERRED over twice-weekly (similar efficacy, less grade 3/4 toxicity, less neuropathy)
• Carfilzomib: weekly (PREFERRED) or twice-weekly; note Cycle 1 Day 1 ramp-up dose required (20 mg/m²)
• Daratumumab IV or SC (Darzalex Faspro 1800 mg flat dose) may be used in any dara-containing regimen
• Reduce dexamethasone to 20 mg weekly in older/frail patients; discontinue at earliest possible timepoint
• Consider biosimilars as appropriate substitutes for any recommended systemic biologic therapy
• Limit myelotoxic agents (alkylators, nitrosoureas) in potential HCT candidates to preserve stem cell reserve
• Harvest stem cells within first 6 cycles BEFORE prolonged lenalidomide or daratumumab exposure

💎 Pearl: Subcutaneous bortezomib SIGNIFICANTLY reduces peripheral neuropathy risk versus IV — MMY-3021 trial. Always use SC route unless contraindicated.

💎 Pearl: Ixazomib may be substituted for bortezomib or carfilzomib in select patients for logistical reasons (all-oral), intolerance, or patient preference — discuss on case-by-case basis.

13. SUPPORTIVE CARE (MYEL-I)

13A. Bone Disease

⚠ ALL patients receiving primary myeloma therapy should receive bone-targeting treatment (bisphosphonates [cat 1] or denosumab) — do not skip this.

• Baseline dental exam STRONGLY RECOMMENDED before starting bone-targeting therapy
• Assess vitamin D status (supplement if deficient)
• Monitor renal function with bisphosphonate therapy
• Monitor for osteonecrosis of the jaw (ONJ) — dental hygiene counseling essential
• Continue bone-targeting treatment for up to 2 years; beyond 2 years based on clinical judgment
• Monthly vs. Q3 months dosing frequency depends on individual patient criteria, response, and agent used
• If denosumab discontinued → give maintenance denosumab Q6 months OR single dose bisphosphonate to prevent rebound osteoporosis
• DEXA scans are NOT useful to assess myeloma bone disease
• Consider vertebroplasty or kyphoplasty for symptomatic vertebral compression fractures
• Orthopedic consultation for impending or actual long-bone fractures or spinal cord compression/instability

13B. Hypercalcemia Management

• IV hydration (first-line, urgent)
• Bisphosphonates: zoledronic acid 4 mg IV PREFERRED (onset 2–4 days)
• Denosumab 120 mg SC (alternative, especially in renal impairment)
• Calcitonin 4–8 units/kg IM/SC Q6–12h (fastest onset, tolerance develops within 48–72h)
• Corticosteroids (dexamethasone/prednisone) — useful in myeloma-related hypercalcemia
• Furosemide (only after adequate hydration; helps excretion)

13C. Hyperviscosity

• Plasmapheresis as ADJUNCTIVE therapy for symptomatic hyperviscosity — initiate systemic therapy concurrently
• Most commonly with IgM myeloma (Waldenström) but can occur in IgA, IgG3 subtypes

13D. Anemia

• See NCCN Guidelines for Hematopoietic Growth Factors
• Consider erythropoiesis-stimulating agents (ESAs) — INCREASED VTE RISK with ESAs in MM patients on IMiD-based therapy
• Transfusion support as needed

13E. Peripheral Neuropathy (Treatment-Related)

Bortezomib-induced neuropathy grading guide:

Grade	Description	Bortezomib Dose Modification
Grade 1	Asymptomatic, loss of reflexes, paresthesia — no pain	Continue without modification; consider switch to SC
Grade 2	Moderate symptoms, limiting instrumental ADL	Reduce bortezomib by 1 dose level (1.3→1.0→0.7 mg/m²)
Grade 3	Severe symptoms, limiting self-care ADL	Hold until resolved ≤Grade 1, restart at reduced dose
Grade 4	Life-threatening, urgent intervention indicated	DISCONTINUE bortezomib

14. INFECTION PROPHYLAXIS & MANAGEMENT (MYEL-J)

14A. Bacterial Infection Prophylaxis

Intervention	Dose	Indication & Duration
Levofloxacin	500 mg PO daily (alt: Cefdinir 300 mg PO BID or Augmentin 875 mg PO BID)	CAR-T or BsAb: start when ANC <500 or per clinician discretion → until neutrophil recovery; AutoHCT: same; NDMM (newly diagnosed): consider for 12 weeks after diagnosis
Immunoglobulin (IVIG) replacement	Per IgG level	CAR-T: regular IVIG based on clinical context; BsAb: consider for duration of therapy; Other: IgG <400 mg/dL AND/OR recurrent life-threatening infections
Pneumococcal vaccination	1 dose PCV20 OR PCV15 then PPSV23 ≥1 yr later (CDC)	Revaccination 3–6 months after CAR-T or AutoHCT; update status before BsAb therapy

⚠ To estimate NORMAL IgG in IgG myeloma patients: subtract the M-spike value from total IgG. If the corrected IgG <400 mg/dL (not polyclonal), replacement can be considered.

14B. Viral Prophylaxis

Infection	Agent & Dose	Duration
HSV/VZV (Shingles)	Acyclovir 400–800 mg PO BID OR Valacyclovir 500 mg PO QD–BID	CAR-T: minimum 1 year; indefinite preferred. BsAb: indefinite. AutoHCT: 1 year post-HCT. PI or mAb regimens: while on therapy + 3 months after OR per institutional practice
COVID-19	Vaccination per CDC	Stay up to date with current recommendations; consult NCCN guidelines for cancer-related infections
Influenza	Annual influenza vaccination	Per CDC for immunosuppressed patients
RSV	Single dose bivalent vaccine	For MM patients ≥60 years old
CMV	Monitor viral load by PCR only if symptomatic or high risk	See NCCN guidelines for treatment indication

14C. Fungal Prophylaxis

Infection	Agent & Dose	Duration
PJP (Pneumocystis jirovecii)	TMP-SMX (preferred) or pentamidine or atovaquone	CAR-T and BsAb: start with therapy and continue ≥6 months after infusion OR until CD4 ≥200/mm³ (whichever is longer); Other: when dexamethasone equivalent >40 mg/day for 4 days/week
Yeast	Fluconazole 400 mg PO daily	CAR-T and BsAb (high-risk): when ANC <500 or per clinician discretion → until neutrophil recovery
Mold	Anti-mold azole (voriconazole/posaconazole)	High-risk patients: consider ongoing prophylaxis; CAR-T and BsAb high-risk patients

💎 Pearl: High-risk for infection: patients on CAR-T or BsAb receiving >1 dose of tocilizumab; use of anakinra or siltuximab for CRS/ICANS; prolonged/high-dose steroids (>3 days of dex 10 mg/day in 7-day period or methylprednisolone >1 g/day).

15. VTE PROPHYLAXIS & MANAGEMENT (MYEL-K)

15A. Risk Stratification Scores

IMPEDE Score

Risk Factor	Points	Category
Previous VTE	+5
IMiD (any)	+4
Pelvic/hip/femur fracture	+4
Dexamethasone >160 mg/month	+4
Doxorubicin or multiagent chemo	+3
Central venous catheter / tunneled central line	+2
Dexamethasone ≤160 mg/month	+2
Obesity (BMI ≥25)	+1
ESA use	+1
Asian/Pacific Islander race	-3	Protective
Existing prophylactic LMWH or aspirin	-3	Protective
Existing therapeutic LMWH or warfarin	-4	Protective
THRESHOLD: ≤3 pts → LOW RISK → Aspirin 81–325 mg daily
THRESHOLD: ≥4 pts → HIGH RISK → LMWH or DOAC or warfarin

SAVED Score

Variable	Points	Category
Surgery within 90 days	+2
VTE history	+3
Age ≥80 years	+1
Dexamethasone standard dose (120–160 mg/cycle)	+1
Dexamethasone high dose (>160 mg/cycle)	+2
Asian race	-3	Protective
THRESHOLD: <2 pts → LOW RISK → Aspirin 81–325 mg daily
THRESHOLD: ≥2 pts → HIGH RISK → LMWH or DOAC or warfarin

15B. VTE Prophylaxis Recommendations

Risk Level	Prophylaxis Options	Duration
LOW RISK (≤3 IMPEDE or <2 SAVED)	Aspirin 81–325 mg once daily	Indefinite while on myeloma therapy
HIGH RISK (≥4 IMPEDE or ≥2 SAVED)	LMWH (enoxaparin 40 mg SC daily) OR Rivaroxaban 10 mg daily OR Apixaban 2.5 mg BID OR Fondaparinux 2.5 mg daily OR Warfarin (INR 2–3)	3–6 months then aspirin (longer if persistent risk factors) OR indefinite while on IMiD

Key VTE Principles

• Highest VTE risk in FIRST 6 MONTHS after new MM diagnosis
• For any patient developing VTE on IMiD-based therapy → continue therapeutic-dose anticoagulation for AS LONG AS IMiD therapy is indicated
• Full-dose anticoagulation CONTRAINDICATED with platelets <50,000/µL; prophylactic may be appropriate if platelets as low as 25,000/µL in high-VTE-risk patients
• Patients already on therapeutic anticoagulation for other reasons (e.g., AFib) → CONTINUE current anticoagulation
• Carfilzomib + IMiD combination → higher VTE risk; consider DOAC or LMWH over aspirin

💎 Pearl: Warfarin at INR 2–3 is NOT directly comparable to DOAC or LMWH at prophylactic doses with respect to bleeding and thrombotic risks. Prefer DOACs or LMWH where possible.

16. CRITICAL PHARMACIST WATCHOUTS

16A. REMS Programs — MANDATORY Enrollment

Drug	REMS Name	Key Requirement
Lenalidomide (Revlimid)	RevASSIST	Mandatory contraception (2 methods); monthly pregnancy test; dispensed ≤28-day supply; males also enrolled
Pomalidomide (Pomalyst)	Pomalidomide REMS	Same as lenalidomide — mandatory contraception and pregnancy testing
Thalidomide (Thalomid)	THALOMID REMS (S.T.E.P.S.)	STRONGEST teratogen — mandatory contraception; dispensed ≤28 days; no blood/sperm donation
Belantamab mafodotin (Blenrep)	BLENREP REMS	Eye exam (slit-lamp) REQUIRED before each dose; patients wear hydrating eye drops; prescribers certified; dispensed to certified healthcare facilities only
Cilta-cel (CARVYKTI)	CARVYKTI REMS	Only certified treatment facilities; patient wallet card; monitor for CRS, ICANS; secondary T-cell malignancy
Ide-cel (ABECMA)	ABECMA REMS	Only certified treatment facilities; monitor for CRS, ICANS; secondary T-cell malignancy

16B. Drug-Drug Interactions of Note

Drug	Interaction	Clinical Action
Lenalidomide/Pomalidomide	AVOID combined with strong CYP1A2 inhibitors (e.g., fluvoxamine)	Increased IMiD exposure
Ixazomib (Ninlaro)	Avoid strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin)	Significantly reduces ixazomib exposure; loss of efficacy
Venetoclax	Strong CYP3A4 inhibitors (azoles, clarithromycin): increase venetoclax levels; CYP3A4 inducers: decrease levels	Dose reduce if unavoidable CYP3A4 inhibitor; avoid grapefruit; follow ramp-up protocol to minimize TLS
Dexamethasone + CYP3A substrates	Dexamethasone is a moderate CYP3A4 inducer	May reduce exposure of CYP3A4 substrates (e.g., some statins, certain antifungals)
Selinexor	Inhibits XPO1 — affects nuclear export of many proteins; serotonergic risk	Avoid coadministration with serotonergic agents if possible; monitor closely
Daratumumab / Isatuximab	Interfere with blood bank testing	Type & screen BEFORE starting; notify blood bank; inform patient
Any IMiD + ESA	Synergistic VTE risk	Aggressive VTE prophylaxis mandatory; prefer therapeutic anticoagulation
Bortezomib + green tea extract (EGCG)	EGCG inhibits bortezomib activity in vitro	Counsel patients to AVOID green tea supplements while on bortezomib

16C. Common Adverse Effects Management

AE	Causative Agent(s)	Management
Peripheral neuropathy	Bortezomib (most), thalidomide	Switch IV → SC bortezomib; dose reduce per grade; neurontin or duloxetine for symptomatic relief
Infusion reactions	Daratumumab, isatuximab, elotuzumab	Pre-medicate: dexamethasone + antihistamine + acetaminophen; slow infusion rate; have epinephrine available
CRS	CAR-T, bispecific antibodies	Grade 1: antipyretics/fluids; Grade 2–3: tocilizumab 8 mg/kg IV; Grade 4: dexamethasone + tocilizumab; ensure stepwise dosing for BsAbs
Cytopenia	All myeloma therapies	Monitor CBC; dose hold/reduction per protocol; G-CSF per NCCN guidelines for hematopoietic growth factors
Hyperglycemia	Dexamethasone	Insulin management; counsel on glucose monitoring; reduce/eliminate dex dose when possible
ONJ (Osteonecrosis of jaw)	Bisphosphonates, denosumab	Dental exam BEFORE therapy; avoid invasive dental procedures while on therapy; report jaw pain
Hypocalcemia	Denosumab	Supplement calcium + vitamin D; severe in renal impairment (CrCl <30 mL/min); monitor ionized calcium
Skin/nail changes, dysgeusia	Talquetamab (GPRC5D-targeted)	Unique to GPRC5D target; moisturizers for skin; dietary counseling for taste changes; supportive care
Keratopathy/Corneal changes	Belantamab mafodotin	Mandatory eye exams (slit-lamp) before EVERY dose; dose hold/reduce based on grade; lubricating eye drops
TLS	Venetoclax	Ramp-up dosing per protocol; hydration; uric acid monitoring; allopurinol prophylaxis; avoid in high-burden disease without adequate monitoring
Secondary malignancies	Lenalidomide maintenance post-HCT	Discuss risk/benefit with patient; increased risk of hematologic secondary cancers; balance against PFS benefit

17. DRUG CLASS REFERENCE TABLE — MM THERAPEUTICS

Drug (Brand)	Class/MOA	Clinical Pearls / Key Side Effects / Counseling
Bortezomib (Velcade)	PI — reversible 26S proteasome inhibitor → accumulation of misfolded proteins → apoptosis	SC preferred (less neuropathy); weekly preferred; give herpes prophylaxis; monitor CBC, LFTs; hold if Grade ≥2 PN; green tea/EGCG supplements inhibit activity
Carfilzomib (Kyprolis)	PI — IRREVERSIBLE proteasome inhibitor; more selective for β5 subunit	Cycle 1 Day 1 ramp-up to 20 mg/m²; monitor BP each visit; cardiac, pulmonary, renal toxicity; hold for acute kidney injury; hydrate before infusion
Ixazomib (Ninlaro)	PI — oral, reversible; first oral PI	Take on empty stomach (≥1h before or 2h after food); GI toxicity common; peripheral neuropathy; avoid strong CYP3A4 inducers; logistical convenience
Lenalidomide (Revlimid)	IMiD — targets cereblon E3 ubiquitin ligase → degrades Ikaros/Aiolos → anti-myeloma + immunomodulatory	REMS mandatory; renal dose-adjust REQUIRED; VTE prophylaxis MANDATORY; secondary malignancy risk; embryo-fetal toxicity; monitor CBC, SCr, LFTs; 28-day supply max
Pomalidomide (Pomalyst)	IMiD (3rd gen) — more potent cereblon modulator than lenalidomide	REMS mandatory; NO renal adjustment needed; VTE prophylaxis; myelosuppression; used in lenalidomide-refractory patients
Thalidomide (Thalomid)	IMiD (1st gen) — anti-angiogenic, immunomodulatory	MOST teratogenic — S.T.E.P.S. REMS; profound sedation (take at night); constipation; DVT; peripheral neuropathy; no longer commonly used as primary therapy
Daratumumab (Darzalex / Darzalex Faspro)	Anti-CD38 IgG1κ mAb → CDC, ADCC, ADCP, T-cell activation	Pre-medicate (dex+antihistamine+APAP); type & screen BEFORE use; false+ indirect Coombs; SC formulation (1800 mg flat) preferred for convenience; VZV prophylaxis; IVIG for hypogammaglobulinemia; false+ IFE (IgG kappa myeloma)
Isatuximab-irfc (Sarclisa)	Anti-CD38 IgG1κ mAb — different epitope than daratumumab; ADCC, CDC, direct apoptosis	Pre-medicate similarly to daratumumab; type & screen BEFORE use; false+ indirect Coombs; different dosing schedule (Cycle 1: QW × 4 doses; cycles 2+: Q2W)
Elotuzumab (Empliciti)	Anti-SLAMF7 mAb → NK cell-mediated ADCC; co-stimulatory T-cell activation	Pre-medicate (dex+antihistamine+H2 blocker+APAP); does NOT interfere with SPEP or immunofixation (important!); lymphopenia; rarely used as first-line
Teclistamab (Tecvayli)	BsAb BCMA × CD3 — redirects T cells to kill BCMA+ myeloma cells	Step-up dosing (hospitalization); CRS 72% (mostly G1–2); ICANS; severe infections; levofloxacin + PJP + VZV prophylaxis; consider tocilizumab pre-dose 1
Elranatamab (Elrexfio)	BsAb BCMA × CD3	Step-up dosing; CRS; infections; ICANS; similar management to teclistamab
Talquetamab (Talvey)	BsAb GPRC5D × CD3 — UNIQUE non-BCMA target	CRS; unique: skin/nail toxicity, dysgeusia, weight loss (GPRC5D expressed on skin/hair/taste); may use as bridge to BCMA CAR-T (v5.2026 footnote)
Linvoseltamab (Lynozyfic)	BsAb BCMA × CD3	NEW in v2.2026; step-up dosing; CRS; infections; cytopenia; 200 mg SC QW then Q4W if ≥VGPR
Cilta-cel (CARVYKTI)	BCMA-directed CAR T-cell therapy — autologous; dual BCMA-binding domains	REMS; leukapheresis → 4–6 wk manufacturing; lymphodepleting chemo (fludarabine/cyclophosphamide) before infusion; CRS; ICANS; delayed neurotoxicity (Parkinsonism described); prolonged cytopenias; 100-day monitoring
Ide-cel (ABECMA)	BCMA-directed CAR T-cell therapy — autologous; single-domain BCMA antibody	REMS; CRS; ICANS; secondary T-cell malignancy (boxed warning); prolonged cytopenias; 100-day monitoring
Selinexor (Xpovio)	XPO1 inhibitor → prevents nuclear export of tumor suppressor proteins → nuclear retention → apoptosis	N/V/anorexia (antiemetic prophylaxis mandatory — ondansetron or olanzapine); weight loss; hyponatremia (monitor Na⁺); thrombocytopenia; fatigue; take with food
Venetoclax (Venclexta)	BCL-2 inhibitor → restores apoptosis in BCL-2-dependent cells	ONLY for t(11;14) patients in MM; TLS risk → ramp-up protocol mandatory; avoid strong CYP3A4 inhibitors; no data in MM outside t(11;14); check for azole antifungal interactions
Belantamab mafodotin (Blenrep)	ADC: anti-BCMA mAb conjugated to MMAF (auristatin microtubule inhibitor)	BLENREP REMS; mandatory slit-lamp eye exam before EVERY dose; lubricating eye drops; grade-based dose modification for keratopathy; thrombocytopenia; nausea; corneal toxicity most limiting
Zoledronic acid (Zometa)	Bisphosphonate — inhibits osteoclast activity (farnesyl pyrophosphate synthase)	Infuse over ≥15 min (renal toxicity with rapid infusion); renal monitoring; dental exam before; ONJ risk; hold if CrCl <30; flu-like symptoms (1st dose); supplement Ca + Vit D
Denosumab (Xgeva)	RANK-L inhibitor → prevents osteoclast formation	SC injection Q4 weeks; PREFERRED in renal impairment; severe hypocalcemia risk (supplement Ca + Vit D always); rebound hypercalcemia/vertebral fractures if discontinued → give bisphosphonate or maintenance Q6 months
Pamidronate (Aredia)	Bisphosphonate — less potent than zoledronic acid	IV over ≥2 hours; focal segmental glomerulosclerosis risk (avoid in nephrotic range proteinuria); dental exam before; supplement Ca + Vit D; osteonecrosis of jaw

18. CLINICAL PEARLS SUMMARY — RAPID REVIEW

Clinical Pearl
SC bortezomib is preferred over IV — significantly less peripheral neuropathy (MMY-3021 trial) with non-inferior efficacy.
Weekly bortezomib dosing is preferred over twice-weekly — similar ORR and VGPR, but fewer grade 3/4 AEs.
Quadruplet regimens (Dara-VRd, Isa-VRd) are preferred for ALL newly diagnosed MM — both HCT-eligible and ineligible.
TYPE AND SCREEN must be done BEFORE starting daratumumab or isatuximab — they cause false-positive indirect Coombs test.
Lenalidomide requires mandatory REMS (RevASSIST) and RENAL DOSE ADJUSTMENT using Cockcroft-Gault CrCl.
For IgG myeloma patients: estimate NORMAL IgG by subtracting M-spike from total IgG. Consider IVIG if corrected IgG <400 mg/dL.
Daratumumab/isatuximab can produce FALSE-POSITIVE M-spike on immunofixation in IgG kappa patients. Use mass spectrometry to differentiate.
Denosumab is PREFERRED bone-targeting agent in renal impairment but requires calcium + vitamin D supplementation and close calcium monitoring.
Zoledronic acid is NOT recommended when CrCl <30 mL/min — switch to denosumab.
If denosumab is discontinued, give bisphosphonate or Q6-month maintenance denosumab to prevent rebound osteoporosis and vertebral fractures.
VTE prophylaxis is MANDATORY with IMiD-based therapy. Use IMPEDE or SAVED score; aspirin for low risk, DOAC/LMWH for high risk.
Carfilzomib ramp-up is REQUIRED: Cycle 1 Day 1 = 20 mg/m² only (regardless of target dose). Monitor BP before EVERY infusion.
Venetoclax has activity in MM ONLY for t(11;14) patients. Do not use in non-t(11;14) outside of a clinical trial.
Belantamab mafodotin (Blenrep) requires MANDATORY eye exam (slit-lamp) before EVERY dose — REMS requirement. No exceptions.
BsAbs (teclistamab, elranatamab, talquetamab, linvoseltamab) require STEP-UP DOSING to reduce CRS risk. Hospitalization for monitoring during step-up.
Talquetamab targets GPRC5D (not BCMA) — unique AEs include skin/nail toxicity and dysgeusia (taste changes). Can be used as bridge to BCMA CAR-T.
Alkylating agents (bendamustine, cyclophosphamide) CAN IMPAIR T-cell collection for CAR-T — plan treatment sequence carefully in potential CAR-T candidates.
Smoldering MM: high-risk (≥2 of: BMPCs >20%, M-protein >2 g/dL, FLCr >20) → clinical trial preferred; daratumumab (cat 1) is now a treatment option.
Duffy-null phenotype in Black/African Americans → lower baseline ANC but physiologically insignificant. Do NOT use rigid reference ranges for dose adjustments.
For dex dose reduction: reduce to 20 mg/week in older/frail patients; discontinue at earliest possible timepoint once response achieved or toxicity present.
Stem cell harvest should be done within first 6 treatment cycles BEFORE prolonged lenalidomide or daratumumab exposure — limits future HCT eligibility.
Two-drug maintenance is recommended for HIGH-RISK MM (e.g., dara + lenalidomide, or bortezomib + lenalidomide).
PJP prophylaxis required for CAR-T and BsAb patients: TMP-SMX (or alternatives) from therapy start, continuing ≥6 months post-infusion OR until CD4 ≥200/mm³.
VZV prophylaxis indefinite for BsAb patients and ≥12 months (preferably indefinite) for CAR-T patients — regardless of vaccination status.
CAR-T ide-cel (Abecma) has boxed warning for SECONDARY T-CELL MALIGNANCIES. Counsel patients and monitor long-term.

19. MANAGEMENT OF RENAL DISEASE IN MM (MYEL-L)

Renal disease defined as serum creatinine >2 mg/dL OR eGFR <60 mL/min/1.73 m².

Workup

• Serum creatinine, electrolytes, uric acid
• Urinalysis with sediment and electrolytes
• 24-hour urine collection for total protein, UPEP, UIFE
• SPEP/SIFE and serum FLCs
• Consider renal ultrasound and renal biopsy
• Consider other diagnoses: amyloid, light chain deposition disease for patients with significant proteinuria

Treatment Approach

• Pulse dexamethasone (rapid effect)
• Regimens containing BORTEZOMIB and/or DARATUMUMAB preferred (rapidly reduce light chain burden)
• Can switch to other regimen once renal function has improved or stabilized
• Goal urine output: 100–150 cc/h (hydration to dilute tubular light chains)
• Monitor fluid status; treat hypercalcemia, hyperuricemia, other metabolic abnormalities
• Discontinue ALL nephrotoxic medications (NSAIDs, aminoglycosides, contrast agents)
• Dialysis for: refractory electrolyte disturbances, uremia, fluid overload

💎 Pearl: Renal dysfunction and advanced age are NOT contraindications to autologous HCT. Systemic therapy should NOT be delayed to perform plasmapheresis or high cutoff dialysis.

⚠ Lenalidomide is renally cleared — MUST adjust dose per CrCl. Pomalidomide does NOT require renal dose adjustment (key differentiator from lenalidomide).

20. CNS MYELOMA — CNSM-1 (NEW IN V1.2026)

Clinical Presentation

• Confusion, headache, visual symptoms, weakness, cranial nerve palsies
• Hyperammonemic encephalopathy is RARE and NOT considered CNS involvement (resolves with systemic therapy)
• Hyperviscosity and hypercalcemia can cause neurologic symptoms but NOT CNS involvement

Diagnosis

• Brain and spine MRI with and without contrast
• Lumbar puncture: flow cytometry, cytopathology, cell count, total protein
• CSF SPEP is NOT appropriate for CNS diagnosis in MM
• Definitive: clonal plasma cells in CSF by immunophenotyping OR tissue diagnosis in affected CNS tissue
• Probable: leptomeningeal enhancement or parenchymal lesions on MRI without definitive clonal plasma cells

Management (MYEL-H)

• Multimodality therapy — radiation + systemic therapy
• Intrathecal chemotherapy: Thiotepa/Hydrocortisone OR Methotrexate/Cytarabine/Hydrocortisone
• Do NOT give concurrent IT methotrexate and radiation — space ≥2 weeks apart (myelopathy risk)
• Novel agents with CNS penetration: pomalidomide, lenalidomide (some BBB penetration observed clinically)
• Venetoclax: preclinical BBB penetration data; consider for t(11;14) if no other options
• CAR-T and BsAbs: prior CNS disease does NOT preclude use; limited data on CNS penetration
• Proteasome inhibitors: LIMITED CNS penetration; no clear signal for activity in CNS disease
• Palliative care integration strongly recommended

21. QUICK REFERENCE ALGORITHM & CHECKLIST

At Diagnosis — Pharmacist Checklist

✓	Action Item
☐	Confirm diagnosis: BMPCs%, M-protein, CRAB/SLiM criteria reviewed
☐	Staging: ISS, R-ISS, R2-ISS calculated; LDH and beta-2 microglobulin obtained
☐	Cytogenetics FISH panel reviewed: del(17p), t(4;14), t(11;14), t(14;16), 1q21, del(1p32), TP53 by NGS
☐	HCT eligibility assessed: age, PS, organ function
☐	Renal function: CrCl calculated (Cockcroft-Gault); lenalidomide dose adjusted if needed
☐	Type and screen ordered BEFORE daratumumab or isatuximab
☐	VTE risk stratified (IMPEDE or SAVED); prophylaxis ordered
☐	VZV prophylaxis ordered (acyclovir or valacyclovir)
☐	Bone-targeting therapy initiated (zoledronic acid or denosumab)
☐	Calcium and vitamin D supplementation ordered
☐	Dental exam recommended before bisphosphonate/denosumab
☐	Hepatitis B, hepatitis C, HIV screening done (before immunotherapy/chemotherapy)
☐	REMS program enrollment confirmed (lenalidomide/pomalidomide/thalidomide/belantamab/CAR-T)
☐	NT-proBNP/BNP reviewed (amyloid workup if elevated)
☐	MRD clonotype baseline obtained or stored for future MRD testing

At Each Clinic Visit — Ongoing Monitoring

✓	Monitoring Parameter
☐	CBC with differential — neutropenia, thrombocytopenia, anemia
☐	Comprehensive metabolic panel — SCr, LFTs, Ca, albumin
☐	SPEP + SIFE and serum FLC assay — disease response assessment
☐	24-h urine total protein/UPEP/UIFE (as clinically indicated)
☐	Blood pressure before each carfilzomib infusion
☐	Assessment for peripheral neuropathy (bortezomib, thalidomide)
☐	Glucose monitoring if on dexamethasone
☐	VTE symptoms; anticoagulation adherence and INR (if warfarin)
☐	ONJ screening (jaw pain, exposed bone) if on bisphosphonate/denosumab
☐	Eye exam (slit-lamp) before each dose of belantamab mafodotin
☐	CRS and ICANS signs for bispecific antibody and CAR-T patients
☐	Infection symptoms; review prophylaxis adherence
☐	Medication reconciliation — drug interactions, OTC supplements

NCCN Guidelines Version 5.2026 — Multiple Myeloma — January 9, 2026  |  For educational use only